Psoriasis

What do patients need to know initially about psoriasis treatment?

It is important to set expectations with the patient based on the treatment selected, not only for patient satisfaction but to forge an enduring bond with the patient so he/she will trust you to guide the treatment plan if the first therapy does not work as well as anticipated. Because psoriasis is a longitudinal disease process, the patient-physician relationship should be, too. Certainly, these principles generally apply among all patient groups and demographics; however, one may take into account a few special circumstances when dealing with psoriasis. In a pediatric patient, I may try to see if topical therapy including calcipotriene can adequately treat the skin disease before pursuing systemic treatment. The rationale is 2-fold: (1) this patient would be committed to an extended period on immunomodulatory therapy if he/she truly requires it, and (2) some of the forms of psoriasis in children, such as guttate psoriasis, may be self-limited, so it is reasonable to see if it will persist before forging ahead with a long-term systemic medication. In patients with a recent history of cancer, I would likely choose an oral medication such as apremilast before a biologic; even though there are no real data to suggest biologics are associated with higher rates of solid-organ malignancy, most practitioners would err on the side of being more conservative. For patients with human immunodeficiency virus, the tendency is to use the agents with more data (eg, tumor necrosis factor α inhibitors) due to safety concerns with an immunomodulatory medication.

What are your go-to treatments?

I tend to be as aggressive as the patient wants to be with therapy. I regularly see patients in whom multiple systemic treatments have failed and a more creative regimen is needed, such as combining a biologic medication with an oral antipsoriatic treatment (eg, apremilast, acitretin). However, I do have patients with moderate to severe psoriasis who have not seen a dermatologist before. I do not find it necessary to have topical treatments fail before starting a biologic; after all, the sequelae of long-term topical steroid use are notable.

With the newer biologics on the market, such as the IL-17 and IL-23 inhibitors, the sky's the limit for psoriasis area and severity index clearance, but the true benefit is that these medications are much more targeted toward the pathogenesis of psoriasis. Unfortunately, we have to be mindful of insurance and formulary restrictions, but when faced with choosing a broad-acting immunomodulatory agent or a more specific/targeted immunomodulatory agent for an inflammatory disease, most dermatologists would choose the more targeted medication. The data support that the newer agents have better psoriasis area and severity index responses and a much greater proportion of clearance, but there is something to be said about biologics such as etanercept, adalimumab, and ustekinumab, which have been on the market for much longer and have shown durable response with a longer track record of safety and efficacy. Recent head-to-head comparisons can help guide treatment. For instance, patients who achieved suboptimal clearance on ustekinumab can safely and reasonably be switched to guselkumab based on the findings of the NAVIGATE study, which looked at this exact situation. More of these studies looking at specific prior treatment failures and improvement upon switching to a newer agent are needed to underscore the efficacy of these drugs and also to help argue for their placement on insurance formularies.

For a new patient with psoriasis, I will screen for psoriatic arthritis, look at involvement (eg, body surface area, individual plaque severity/thickness, locations such as scalp and extremities), and assess patient attitudes toward different treatments. Two patients with the exact same clinical appearance might have completely different strategies, one wanting to be as aggressive as possible to get rid of the psoriasis and the other not believing in systemic treatments and wanting to be as "natural" as possible.

For patients with only cutaneous involvement, the dosing frequency and efficacy of the newer IL-17 and IL-23 classes of medications are hard to beat. If a patient has notable psoriatic arthritis, I still tend to reach for a tumor necrosis factor α inhibitor first. For patients with limited involvement, especially those with scalp and/or palmoplantar psoriasis, I have found that apremilast works quite well. Apremilast, in general, would be a good first-step medication for patients wary of systemic therapy, and with its relatively benign side-effect profile, it has almost completely supplanted methotrexate in my practice. We also have a few newer topical medicines such as a calcipotriene 0.005%-betamethasone dipropionate 0.064% foam and a betamethasone dipropionate spray 0.05% that have proven useful, with more products in the pipeline.

How do you keep patients compliant with treatment?

Setting expectations is most important, and letting patients know what to expect from their first visit really helps to keep them satisfied with the plan and progress. Giving the patient a say in guiding the treatment and perhaps coming up with a rough treatment plan with a defined timeline also helps, such as starting with a topical regimen but moving on to an oral medicine if the topical does not work within 2 to 3 months, and then a biologic if oral therapy does not work well within 3 to 6 months. It is important not to push the patient to pursue a more aggressive therapy unless he/she wants to, otherwise the patient might not be compliant or may stop altogether.

What do you do if they refuse treatment?

If the patient is in your office, clearly he/she does want some help. Try to figure out what is at the root of the treatment refusal. Is the patient refusing topical steroids because he/she is afraid of them? Is the patient unable to stomach having to inject himself/herself? Finding the basis of their reticence may take more time, but we usually can find a mutually agreeable plan of action. Even if the first step is to watch and wait, you want the patient leaving your office knowing that if things do not progress as expected or get worse, they can have faith in you to come back and get more help.

What resources do you recommend to patients for more information?

The National Psoriasis Foundation is a great resource for patients. They have numerous outreach programs and a wealth of patient information. Also, the American Academy of Dermatology is a good resource, not just for patients but for providers; for example, the academy offers appeals letters that can be sent to insurance companies to try to advocate for a specific medication for patients.

Suggested Readings

Help patients appeal denial of psoriasis drugs. American Academy of Dermatology website. https://www.aad.org/members/publications/member-to-member/2017/jan-27-2017/help-patients-appeal-denial-of-psoriasis-drugs. Accessed February 9, 2018.

Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial [published online October 10, 2017]. Br J Dermatol. 2018;178:114-123.

What do patients need to know initially about psoriasis treatment?

It is important to set expectations with the patient based on the treatment selected, not only for patient satisfaction but to forge an enduring bond with the patient so he/she will trust you to guide the treatment plan if the first therapy does not work as well as anticipated. Because psoriasis is a longitudinal disease process, the patient-physician relationship should be, too. Certainly, these principles generally apply among all patient groups and demographics; however, one may take into account a few special circumstances when dealing with psoriasis. In a pediatric patient, I may try to see if topical therapy including calcipotriene can adequately treat the skin disease before pursuing systemic treatment. The rationale is 2-fold: (1) this patient would be committed to an extended period on immunomodulatory therapy if he/she truly requires it, and (2) some of the forms of psoriasis in children, such as guttate psoriasis, may be self-limited, so it is reasonable to see if it will persist before forging ahead with a long-term systemic medication. In patients with a recent history of cancer, I would likely choose an oral medication such as apremilast before a biologic; even though there are no real data to suggest biologics are associated with higher rates of solid-organ malignancy, most practitioners would err on the side of being more conservative. For patients with human immunodeficiency virus, the tendency is to use the agents with more data (eg, tumor necrosis factor α inhibitors) due to safety concerns with an immunomodulatory medication.

What are your go-to treatments?

I tend to be as aggressive as the patient wants to be with therapy. I regularly see patients in whom multiple systemic treatments have failed and a more creative regimen is needed, such as combining a biologic medication with an oral antipsoriatic treatment (eg, apremilast, acitretin). However, I do have patients with moderate to severe psoriasis who have not seen a dermatologist before. I do not find it necessary to have topical treatments fail before starting a biologic; after all, the sequelae of long-term topical steroid use are notable.

With the newer biologics on the market, such as the IL-17 and IL-23 inhibitors, the sky's the limit for psoriasis area and severity index clearance, but the true benefit is that these medications are much more targeted toward the pathogenesis of psoriasis. Unfortunately, we have to be mindful of insurance and formulary restrictions, but when faced with choosing a broad-acting immunomodulatory agent or a more specific/targeted immunomodulatory agent for an inflammatory disease, most dermatologists would choose the more targeted medication. The data support that the newer agents have better psoriasis area and severity index responses and a much greater proportion of clearance, but there is something to be said about biologics such as etanercept, adalimumab, and ustekinumab, which have been on the market for much longer and have shown durable response with a longer track record of safety and efficacy. Recent head-to-head comparisons can help guide treatment. For instance, patients who achieved suboptimal clearance on ustekinumab can safely and reasonably be switched to guselkumab based on the findings of the NAVIGATE study, which looked at this exact situation. More of these studies looking at specific prior treatment failures and improvement upon switching to a newer agent are needed to underscore the efficacy of these drugs and also to help argue for their placement on insurance formularies.

For a new patient with psoriasis, I will screen for psoriatic arthritis, look at involvement (eg, body surface area, individual plaque severity/thickness, locations such as scalp and extremities), and assess patient attitudes toward different treatments. Two patients with the exact same clinical appearance might have completely different strategies, one wanting to be as aggressive as possible to get rid of the psoriasis and the other not believing in systemic treatments and wanting to be as "natural" as possible.

For patients with only cutaneous involvement, the dosing frequency and efficacy of the newer IL-17 and IL-23 classes of medications are hard to beat. If a patient has notable psoriatic arthritis, I still tend to reach for a tumor necrosis factor α inhibitor first. For patients with limited involvement, especially those with scalp and/or palmoplantar psoriasis, I have found that apremilast works quite well. Apremilast, in general, would be a good first-step medication for patients wary of systemic therapy, and with its relatively benign side-effect profile, it has almost completely supplanted methotrexate in my practice. We also have a few newer topical medicines such as a calcipotriene 0.005%-betamethasone dipropionate 0.064% foam and a betamethasone dipropionate spray 0.05% that have proven useful, with more products in the pipeline.

How do you keep patients compliant with treatment?

Setting expectations is most important, and letting patients know what to expect from their first visit really helps to keep them satisfied with the plan and progress. Giving the patient a say in guiding the treatment and perhaps coming up with a rough treatment plan with a defined timeline also helps, such as starting with a topical regimen but moving on to an oral medicine if the topical does not work within 2 to 3 months, and then a biologic if oral therapy does not work well within 3 to 6 months. It is important not to push the patient to pursue a more aggressive therapy unless he/she wants to, otherwise the patient might not be compliant or may stop altogether.

What do you do if they refuse treatment?

If the patient is in your office, clearly he/she does want some help. Try to figure out what is at the root of the treatment refusal. Is the patient refusing topical steroids because he/she is afraid of them? Is the patient unable to stomach having to inject himself/herself? Finding the basis of their reticence may take more time, but we usually can find a mutually agreeable plan of action. Even if the first step is to watch and wait, you want the patient leaving your office knowing that if things do not progress as expected or get worse, they can have faith in you to come back and get more help.

What resources do you recommend to patients for more information?

The National Psoriasis Foundation is a great resource for patients. They have numerous outreach programs and a wealth of patient information. Also, the American Academy of Dermatology is a good resource, not just for patients but for providers; for example, the academy offers appeals letters that can be sent to insurance companies to try to advocate for a specific medication for patients.

Suggested Readings

Help patients appeal denial of psoriasis drugs. American Academy of Dermatology website. https://www.aad.org/members/publications/member-to-member/2017/jan-27-2017/help-patients-appeal-denial-of-psoriasis-drugs. Accessed February 9, 2018.

Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial [published online October 10, 2017]. Br J Dermatol. 2018;178:114-123.

What do patients need to know initially about psoriasis treatment?

It is important to set expectations with the patient based on the treatment selected, not only for patient satisfaction but to forge an enduring bond with the patient so he/she will trust you to guide the treatment plan if the first therapy does not work as well as anticipated. Because psoriasis is a longitudinal disease process, the patient-physician relationship should be, too. Certainly, these principles generally apply among all patient groups and demographics; however, one may take into account a few special circumstances when dealing with psoriasis. In a pediatric patient, I may try to see if topical therapy including calcipotriene can adequately treat the skin disease before pursuing systemic treatment. The rationale is 2-fold: (1) this patient would be committed to an extended period on immunomodulatory therapy if he/she truly requires it, and (2) some of the forms of psoriasis in children, such as guttate psoriasis, may be self-limited, so it is reasonable to see if it will persist before forging ahead with a long-term systemic medication. In patients with a recent history of cancer, I would likely choose an oral medication such as apremilast before a biologic; even though there are no real data to suggest biologics are associated with higher rates of solid-organ malignancy, most practitioners would err on the side of being more conservative. For patients with human immunodeficiency virus, the tendency is to use the agents with more data (eg, tumor necrosis factor α inhibitors) due to safety concerns with an immunomodulatory medication.

What are your go-to treatments?

I tend to be as aggressive as the patient wants to be with therapy. I regularly see patients in whom multiple systemic treatments have failed and a more creative regimen is needed, such as combining a biologic medication with an oral antipsoriatic treatment (eg, apremilast, acitretin). However, I do have patients with moderate to severe psoriasis who have not seen a dermatologist before. I do not find it necessary to have topical treatments fail before starting a biologic; after all, the sequelae of long-term topical steroid use are notable.

With the newer biologics on the market, such as the IL-17 and IL-23 inhibitors, the sky's the limit for psoriasis area and severity index clearance, but the true benefit is that these medications are much more targeted toward the pathogenesis of psoriasis. Unfortunately, we have to be mindful of insurance and formulary restrictions, but when faced with choosing a broad-acting immunomodulatory agent or a more specific/targeted immunomodulatory agent for an inflammatory disease, most dermatologists would choose the more targeted medication. The data support that the newer agents have better psoriasis area and severity index responses and a much greater proportion of clearance, but there is something to be said about biologics such as etanercept, adalimumab, and ustekinumab, which have been on the market for much longer and have shown durable response with a longer track record of safety and efficacy. Recent head-to-head comparisons can help guide treatment. For instance, patients who achieved suboptimal clearance on ustekinumab can safely and reasonably be switched to guselkumab based on the findings of the NAVIGATE study, which looked at this exact situation. More of these studies looking at specific prior treatment failures and improvement upon switching to a newer agent are needed to underscore the efficacy of these drugs and also to help argue for their placement on insurance formularies.

For a new patient with psoriasis, I will screen for psoriatic arthritis, look at involvement (eg, body surface area, individual plaque severity/thickness, locations such as scalp and extremities), and assess patient attitudes toward different treatments. Two patients with the exact same clinical appearance might have completely different strategies, one wanting to be as aggressive as possible to get rid of the psoriasis and the other not believing in systemic treatments and wanting to be as "natural" as possible.

For patients with only cutaneous involvement, the dosing frequency and efficacy of the newer IL-17 and IL-23 classes of medications are hard to beat. If a patient has notable psoriatic arthritis, I still tend to reach for a tumor necrosis factor α inhibitor first. For patients with limited involvement, especially those with scalp and/or palmoplantar psoriasis, I have found that apremilast works quite well. Apremilast, in general, would be a good first-step medication for patients wary of systemic therapy, and with its relatively benign side-effect profile, it has almost completely supplanted methotrexate in my practice. We also have a few newer topical medicines such as a calcipotriene 0.005%-betamethasone dipropionate 0.064% foam and a betamethasone dipropionate spray 0.05% that have proven useful, with more products in the pipeline.

How do you keep patients compliant with treatment?

Setting expectations is most important, and letting patients know what to expect from their first visit really helps to keep them satisfied with the plan and progress. Giving the patient a say in guiding the treatment and perhaps coming up with a rough treatment plan with a defined timeline also helps, such as starting with a topical regimen but moving on to an oral medicine if the topical does not work within 2 to 3 months, and then a biologic if oral therapy does not work well within 3 to 6 months. It is important not to push the patient to pursue a more aggressive therapy unless he/she wants to, otherwise the patient might not be compliant or may stop altogether.

What do you do if they refuse treatment?

If the patient is in your office, clearly he/she does want some help. Try to figure out what is at the root of the treatment refusal. Is the patient refusing topical steroids because he/she is afraid of them? Is the patient unable to stomach having to inject himself/herself? Finding the basis of their reticence may take more time, but we usually can find a mutually agreeable plan of action. Even if the first step is to watch and wait, you want the patient leaving your office knowing that if things do not progress as expected or get worse, they can have faith in you to come back and get more help.

What resources do you recommend to patients for more information?

The National Psoriasis Foundation is a great resource for patients. They have numerous outreach programs and a wealth of patient information. Also, the American Academy of Dermatology is a good resource, not just for patients but for providers; for example, the academy offers appeals letters that can be sent to insurance companies to try to advocate for a specific medication for patients.

Suggested Readings

Help patients appeal denial of psoriasis drugs. American Academy of Dermatology website. https://www.aad.org/members/publications/member-to-member/2017/jan-27-2017/help-patients-appeal-denial-of-psoriasis-drugs. Accessed February 9, 2018.

Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial [published online October 10, 2017]. Br J Dermatol. 2018;178:114-123.

Psoriasis is a chronic autoinflammatory disorder affecting approximately 2% to 4% of the Western population.¹ While there is no absolute cure for psoriasis, novel therapies allow for substantial reduction in symptoms and considerable improvement in quality of life (QoL). In the past few years, multiple treatment guidelines (recommendations based on evidence-based literature reviews) and consensus statements (a set of declarations determined and voted on by a panel of experts in the field) have been developed to guide physicians worldwide in treating psoriasis in the clinical setting (eTable).^2-10

Because psoriasis is a complex disease with multiple comorbidities, applicability of these guidelines may be limited. Although some basic treatment algorithms exist, patient preference, disease severity, and other variables including comorbidities (eg, psoriatic arthritis [PsA], risk of major cardiac events, inflammatory bowel disease [IBD]), history of nonmelanoma skin cancer (NMSC), pregnancy and lactation, and specific contraindications to therapy (eg, renal failure, liver disease, active malignancy) should be considered. In this article, we summarize common themes across existing guidelines and consensus statements for the treatment of psoriasis and highlight areas where there is consistent agreement or lack of sufficient information.

Disease Severity and Treatment Outcomes

There currently are no consensus definitions for mild, moderate, and severe psoriasis, but several consensus statements have attempted to standardize grading systems based on objective values, such as body surface area (BSA) and psoriasis area and severity index (PASI)(a scoring system used to grade the degree of redness, thickness, and scaling of psoriasis plaques), as well as subjective QoL measures.^2,6 Although classification of disease severity varies, mild psoriasis generally is characterized as disease that can be managed with local and topical therapy, and moderate to severe psoriasis typically warrants consideration for escalated treatment with phototherapy or systemic agents.

Most definitions of disease severity in psoriasis reference 5% to 10% BSA involvement as a cutoff that should trigger consideration of systemic treatment; however, these criteria could result in undertreatment of patients with substantial disease. For example, patients who have limited BSA involvement but whose disease has a considerable impact on QoL, as well as those who have debilitating disease in localized areas (eg, palms, soles, scalp, nails) or substantial joint involvement may also be appropriate candidates for systemic treatment.^5,8

Once therapy is initiated, patients should be evaluated for appropriate treatment response at dedicated intervals. While the time to maximum therapeutic benefit depends on the agent of choice, European guidelines recommend that patients be evaluated after an induction phase (typically 16–24 weeks) and define treatment success as either (1) at least 75% improvement in PASI or (2) at least 50% improvement in PASI and a Dermatology Quality of Life Index (DLQI) score of 5 or lower.⁶

Alternatively, the National Psoriasis Foundation (NPF) recommended BSA as the preferred outcome measure in a recent consensus statement and concluded that an outcome of 3% or less BSA involvement or improvement in BSA of 75% or more is considered a desirable treatment response.⁹ Additionally, the Medicare Merit-based Incentive Payment System (MIPS) guidelines for successful systemic treatment response include at least 1 of the following: (1) physician global assessment score of 2 or lower, (2) BSA involvement of less than 3%, (3) PASI score lower than 3, or (4) DLQI score of 5 or lower.¹⁰

Although an array of outcome measures have been utilized in clinical trials and proposed in psoriasis guidelines and consensus statements, BSA is typically a manageable measure of treatment response in a clinical setting; however, DLQI should also be assessed if possible, particularly in patients with debilitating localized disease.⁹

Treatment Options

Because topical treatment regimens can be arduous and typically do not result in sustained clearance, patient expectations should be ascertained prior to initiation of therapy. Topical corticosteroids often can be used as monotherapy in patients with mild psoriasis.³ Topical vitamin D analogues and retinoids also can be effective; however, combined use of these agents with topical steroids should be considered to increase efficacy, and combination formulations can be prescribed to simplify application and improve adherence.

Treatment with UVB or psoralen plus UVA phototherapy is recommended for patients with moderate to severe psoriasis as well as in those who have had minimal response to topical therapy.⁴ Targeted phototherapy with an excimer laser can be used in patients with BSA involvement of less than 10%.

Methotrexate (MTX), cyclosporine, and acitretin are the most commonly prescribed systemic medications for severe psoriasis in the United States.⁵ Despite the risk for hepatotoxicity, MTX appears to have the best combined safety and efficacy profile in terms of serious adverse events compared to other systemic agents.¹¹ Guidelines for MTX monitoring, especially with regard to when to do a liver biopsy, have been substantially liberalized over time, and the recommended interval for biopsy has been extended by years; biopsy was previously recommended after a cumulative MTX dose of 1 to 1.5 g, but guidelines now suggest biopsy after 3.5 to 4 g in low-risk patients.⁵ While abnormally elevated liver function tests during treatment with MTX may necessitate liver biopsy, the use of transient elastography and a panel of serum biomarkers for liver function also can be used to monitor noninvasively for hepatotoxicity before biopsy is considered; these recommendations are likely to be incorporated into newer guidelines in development.¹² Methotrexate has demonstrated safety and increased efficacy when used in combination with biologic agents such as adalimumab, etanercept, infliximab, and secukinumab⁷ and has been studied in combination with many biologics indicated for PsA.¹³

Due to a considerable risk of glomerulosclerosis, cyclosporine is approved for a maximum of 1 year of continuous treatment of psoriasis in the United States and2 years in Europe.^5,7 Cyclosporine is best used as induction therapy in psoriasis patients with severe disease who are seeking faster abatement of symptoms.

Acitretin is another systemic treatment option, although efficacy of this agent is dose dependent. Higher dosing often is limited due to lower tolerability.⁵

Given that many insurance formularies primarily cover traditional systemic therapies and that MTX and phototherapy are generally well tolerated and cost effective, patients may need to be treated with traditional agents before escalating to biologics. Prior to starting treatment with any biologic, patients should typically be screened for tuberculosis (TB), human immunodeficiency virus infection, and immunization for, exposure to, and/or infection with hepatitis B and C virus, and any other active infections. In patients who do not demonstrate hepatitis immunity, the hepatitis B vaccine should be administered prior to starting treatment with a biologic.¹⁴ In psoriasis patients with latent TB, 2 months of treatment should be completed before initiating biologic therapy⁸; once a biologic has been initiated, all patients should be screened annually for TB.

European guidelines for biologic treatment recommend that complete blood count and liver and renal function be evaluated at baseline, at months 1 and 3 of treatment, and then every 3 to 6 months thereafter while on the biologic agent.⁷ These recommendations are more stringent than those indicated in regulatory labeling and, based on the continual accumulation of data regarding the safety of these agents, some investigators have argued that laboratory testing might not be necessary at all.¹⁵

Treatment in Special Populations

Psoriasis patients often present with comorbidities or a complicated medical history, which can make it challenging to decide which therapy is most suitable. Patients with comorbid diseases (eg, PsA, risk of major cardiac event, IBD) or a history of NMSC and those who are pregnant or are lactating require special considerations to ensure treatment safety and efficacy.

Tumor necrosis factor α (TNF-α) and IL-17 inhibitors are used in the treatment of joint disorders and should be considered in patients with PsA. IL-23/IL-12 inhibition appears to have less benefit in patients with PsA, but studies on IL-23 inhibition (p19 antibodies) alone are ongoing.¹⁶ It has been reported that TNF-α inhibition may be beneficial in patients at risk for major cardiac events.^8,17 In patients with IBD, IL-17 inhibitors should be avoided because they may exacerbate the condition; however, TNF-α and IL-23/IL-12 inhibition have shown to be safe in patients with IBD and many agents in these classes are approved by the US Food and Drug Administration for use in this population.^18,19

Although biologics may increase the risk of developing NMSC²⁰ and should generally be avoided in patients with any active malignancy, specific guidelines for screening and initiation of treatment in patients with a history of cancer are not clearly outlined. Prior to initiating systemic therapy in any patient, a careful medical history should be obtained. These agents often are not prescribed in patients with a history of cancer until remission has been established for at least 5 years, with the exception of patients with a history of treated NMSC.⁸ Annual skin monitoring for NMSC should be undertaken for psoriasis patients on most immunomodulating systemic therapies.

Recommendations for biologic treatment in psoriasis patients who are pregnant or lactating also are limited. European guidelines have noted pregnancy as an absolute contraindication to treatment with biologics,⁷but the regulatory guidance has recently changed for some agents, so this recommendation also may evolve.²¹ British⁸ and US⁵ guidelines do not consider pregnancy a contraindication for treatment with biologics.

Information on the safety of TNF-α antagonists during pregnancy comes primarily from use in patients with IBD and rheumatologic disease. To date, reports on the incidence of congenital malformations have been generally reassuring. Because IgG antibodies are actively transferred across the placenta in the late-second or the third trimesters, neonates born to mothers on biologic treatments may have high levels of some biologic drugs at birth. As a result, live vaccination should be avoided in neonates whose mothers were treated with IgG-based biologics.

Changing Treatment Agents

Patients may need to stop and change treatment agents due to ineffectiveness, personal preference, or worsening disease. When transitioning from any systemic or biologic agent to another (other than MTX), the British Association of Dermatologists recommends a washout period of at least 1 month before initiating a new therapy.⁸ Most guidelines do not define parameters for therapy escalation when patients fail multiple systemic agents, so physicians should use clinical judgment along with consideration of patient preference and comorbidity profile to ascertain which agent is most appropriate.

Conclusion

Keeping psoriasis treatment guidelines updated can be difficult, especially as new therapeutic options for psoriasis and treatment regimens rapidly evolve. Regulatory recommendations also vary worldwide, but most guidelines are reasonably consistent without being overly prescriptive, appropriately allowing for flexibility for application in clinical practice. Nonetheless, physicians should keep in mind new or changing guidelines while tailoring psoriasis treatment recommendations to best suit their individual patients.

Psoriasis is a chronic autoinflammatory disorder affecting approximately 2% to 4% of the Western population.¹ While there is no absolute cure for psoriasis, novel therapies allow for substantial reduction in symptoms and considerable improvement in quality of life (QoL). In the past few years, multiple treatment guidelines (recommendations based on evidence-based literature reviews) and consensus statements (a set of declarations determined and voted on by a panel of experts in the field) have been developed to guide physicians worldwide in treating psoriasis in the clinical setting (eTable).^2-10

Because psoriasis is a complex disease with multiple comorbidities, applicability of these guidelines may be limited. Although some basic treatment algorithms exist, patient preference, disease severity, and other variables including comorbidities (eg, psoriatic arthritis [PsA], risk of major cardiac events, inflammatory bowel disease [IBD]), history of nonmelanoma skin cancer (NMSC), pregnancy and lactation, and specific contraindications to therapy (eg, renal failure, liver disease, active malignancy) should be considered. In this article, we summarize common themes across existing guidelines and consensus statements for the treatment of psoriasis and highlight areas where there is consistent agreement or lack of sufficient information.

Disease Severity and Treatment Outcomes

There currently are no consensus definitions for mild, moderate, and severe psoriasis, but several consensus statements have attempted to standardize grading systems based on objective values, such as body surface area (BSA) and psoriasis area and severity index (PASI)(a scoring system used to grade the degree of redness, thickness, and scaling of psoriasis plaques), as well as subjective QoL measures.^2,6 Although classification of disease severity varies, mild psoriasis generally is characterized as disease that can be managed with local and topical therapy, and moderate to severe psoriasis typically warrants consideration for escalated treatment with phototherapy or systemic agents.

Most definitions of disease severity in psoriasis reference 5% to 10% BSA involvement as a cutoff that should trigger consideration of systemic treatment; however, these criteria could result in undertreatment of patients with substantial disease. For example, patients who have limited BSA involvement but whose disease has a considerable impact on QoL, as well as those who have debilitating disease in localized areas (eg, palms, soles, scalp, nails) or substantial joint involvement may also be appropriate candidates for systemic treatment.^5,8

Once therapy is initiated, patients should be evaluated for appropriate treatment response at dedicated intervals. While the time to maximum therapeutic benefit depends on the agent of choice, European guidelines recommend that patients be evaluated after an induction phase (typically 16–24 weeks) and define treatment success as either (1) at least 75% improvement in PASI or (2) at least 50% improvement in PASI and a Dermatology Quality of Life Index (DLQI) score of 5 or lower.⁶

Alternatively, the National Psoriasis Foundation (NPF) recommended BSA as the preferred outcome measure in a recent consensus statement and concluded that an outcome of 3% or less BSA involvement or improvement in BSA of 75% or more is considered a desirable treatment response.⁹ Additionally, the Medicare Merit-based Incentive Payment System (MIPS) guidelines for successful systemic treatment response include at least 1 of the following: (1) physician global assessment score of 2 or lower, (2) BSA involvement of less than 3%, (3) PASI score lower than 3, or (4) DLQI score of 5 or lower.¹⁰

Although an array of outcome measures have been utilized in clinical trials and proposed in psoriasis guidelines and consensus statements, BSA is typically a manageable measure of treatment response in a clinical setting; however, DLQI should also be assessed if possible, particularly in patients with debilitating localized disease.⁹

Treatment Options

Because topical treatment regimens can be arduous and typically do not result in sustained clearance, patient expectations should be ascertained prior to initiation of therapy. Topical corticosteroids often can be used as monotherapy in patients with mild psoriasis.³ Topical vitamin D analogues and retinoids also can be effective; however, combined use of these agents with topical steroids should be considered to increase efficacy, and combination formulations can be prescribed to simplify application and improve adherence.

Treatment with UVB or psoralen plus UVA phototherapy is recommended for patients with moderate to severe psoriasis as well as in those who have had minimal response to topical therapy.⁴ Targeted phototherapy with an excimer laser can be used in patients with BSA involvement of less than 10%.

Methotrexate (MTX), cyclosporine, and acitretin are the most commonly prescribed systemic medications for severe psoriasis in the United States.⁵ Despite the risk for hepatotoxicity, MTX appears to have the best combined safety and efficacy profile in terms of serious adverse events compared to other systemic agents.¹¹ Guidelines for MTX monitoring, especially with regard to when to do a liver biopsy, have been substantially liberalized over time, and the recommended interval for biopsy has been extended by years; biopsy was previously recommended after a cumulative MTX dose of 1 to 1.5 g, but guidelines now suggest biopsy after 3.5 to 4 g in low-risk patients.⁵ While abnormally elevated liver function tests during treatment with MTX may necessitate liver biopsy, the use of transient elastography and a panel of serum biomarkers for liver function also can be used to monitor noninvasively for hepatotoxicity before biopsy is considered; these recommendations are likely to be incorporated into newer guidelines in development.¹² Methotrexate has demonstrated safety and increased efficacy when used in combination with biologic agents such as adalimumab, etanercept, infliximab, and secukinumab⁷ and has been studied in combination with many biologics indicated for PsA.¹³

Due to a considerable risk of glomerulosclerosis, cyclosporine is approved for a maximum of 1 year of continuous treatment of psoriasis in the United States and2 years in Europe.^5,7 Cyclosporine is best used as induction therapy in psoriasis patients with severe disease who are seeking faster abatement of symptoms.

Acitretin is another systemic treatment option, although efficacy of this agent is dose dependent. Higher dosing often is limited due to lower tolerability.⁵

Given that many insurance formularies primarily cover traditional systemic therapies and that MTX and phototherapy are generally well tolerated and cost effective, patients may need to be treated with traditional agents before escalating to biologics. Prior to starting treatment with any biologic, patients should typically be screened for tuberculosis (TB), human immunodeficiency virus infection, and immunization for, exposure to, and/or infection with hepatitis B and C virus, and any other active infections. In patients who do not demonstrate hepatitis immunity, the hepatitis B vaccine should be administered prior to starting treatment with a biologic.¹⁴ In psoriasis patients with latent TB, 2 months of treatment should be completed before initiating biologic therapy⁸; once a biologic has been initiated, all patients should be screened annually for TB.

European guidelines for biologic treatment recommend that complete blood count and liver and renal function be evaluated at baseline, at months 1 and 3 of treatment, and then every 3 to 6 months thereafter while on the biologic agent.⁷ These recommendations are more stringent than those indicated in regulatory labeling and, based on the continual accumulation of data regarding the safety of these agents, some investigators have argued that laboratory testing might not be necessary at all.¹⁵

Treatment in Special Populations

Psoriasis patients often present with comorbidities or a complicated medical history, which can make it challenging to decide which therapy is most suitable. Patients with comorbid diseases (eg, PsA, risk of major cardiac event, IBD) or a history of NMSC and those who are pregnant or are lactating require special considerations to ensure treatment safety and efficacy.

Tumor necrosis factor α (TNF-α) and IL-17 inhibitors are used in the treatment of joint disorders and should be considered in patients with PsA. IL-23/IL-12 inhibition appears to have less benefit in patients with PsA, but studies on IL-23 inhibition (p19 antibodies) alone are ongoing.¹⁶ It has been reported that TNF-α inhibition may be beneficial in patients at risk for major cardiac events.^8,17 In patients with IBD, IL-17 inhibitors should be avoided because they may exacerbate the condition; however, TNF-α and IL-23/IL-12 inhibition have shown to be safe in patients with IBD and many agents in these classes are approved by the US Food and Drug Administration for use in this population.^18,19

Although biologics may increase the risk of developing NMSC²⁰ and should generally be avoided in patients with any active malignancy, specific guidelines for screening and initiation of treatment in patients with a history of cancer are not clearly outlined. Prior to initiating systemic therapy in any patient, a careful medical history should be obtained. These agents often are not prescribed in patients with a history of cancer until remission has been established for at least 5 years, with the exception of patients with a history of treated NMSC.⁸ Annual skin monitoring for NMSC should be undertaken for psoriasis patients on most immunomodulating systemic therapies.

Recommendations for biologic treatment in psoriasis patients who are pregnant or lactating also are limited. European guidelines have noted pregnancy as an absolute contraindication to treatment with biologics,⁷but the regulatory guidance has recently changed for some agents, so this recommendation also may evolve.²¹ British⁸ and US⁵ guidelines do not consider pregnancy a contraindication for treatment with biologics.

Information on the safety of TNF-α antagonists during pregnancy comes primarily from use in patients with IBD and rheumatologic disease. To date, reports on the incidence of congenital malformations have been generally reassuring. Because IgG antibodies are actively transferred across the placenta in the late-second or the third trimesters, neonates born to mothers on biologic treatments may have high levels of some biologic drugs at birth. As a result, live vaccination should be avoided in neonates whose mothers were treated with IgG-based biologics.

Changing Treatment Agents

Patients may need to stop and change treatment agents due to ineffectiveness, personal preference, or worsening disease. When transitioning from any systemic or biologic agent to another (other than MTX), the British Association of Dermatologists recommends a washout period of at least 1 month before initiating a new therapy.⁸ Most guidelines do not define parameters for therapy escalation when patients fail multiple systemic agents, so physicians should use clinical judgment along with consideration of patient preference and comorbidity profile to ascertain which agent is most appropriate.

Conclusion

Keeping psoriasis treatment guidelines updated can be difficult, especially as new therapeutic options for psoriasis and treatment regimens rapidly evolve. Regulatory recommendations also vary worldwide, but most guidelines are reasonably consistent without being overly prescriptive, appropriately allowing for flexibility for application in clinical practice. Nonetheless, physicians should keep in mind new or changing guidelines while tailoring psoriasis treatment recommendations to best suit their individual patients.

Psoriasis is a chronic autoinflammatory disorder affecting approximately 2% to 4% of the Western population.¹ While there is no absolute cure for psoriasis, novel therapies allow for substantial reduction in symptoms and considerable improvement in quality of life (QoL). In the past few years, multiple treatment guidelines (recommendations based on evidence-based literature reviews) and consensus statements (a set of declarations determined and voted on by a panel of experts in the field) have been developed to guide physicians worldwide in treating psoriasis in the clinical setting (eTable).^2-10

Because psoriasis is a complex disease with multiple comorbidities, applicability of these guidelines may be limited. Although some basic treatment algorithms exist, patient preference, disease severity, and other variables including comorbidities (eg, psoriatic arthritis [PsA], risk of major cardiac events, inflammatory bowel disease [IBD]), history of nonmelanoma skin cancer (NMSC), pregnancy and lactation, and specific contraindications to therapy (eg, renal failure, liver disease, active malignancy) should be considered. In this article, we summarize common themes across existing guidelines and consensus statements for the treatment of psoriasis and highlight areas where there is consistent agreement or lack of sufficient information.

Disease Severity and Treatment Outcomes

There currently are no consensus definitions for mild, moderate, and severe psoriasis, but several consensus statements have attempted to standardize grading systems based on objective values, such as body surface area (BSA) and psoriasis area and severity index (PASI)(a scoring system used to grade the degree of redness, thickness, and scaling of psoriasis plaques), as well as subjective QoL measures.^2,6 Although classification of disease severity varies, mild psoriasis generally is characterized as disease that can be managed with local and topical therapy, and moderate to severe psoriasis typically warrants consideration for escalated treatment with phototherapy or systemic agents.

Most definitions of disease severity in psoriasis reference 5% to 10% BSA involvement as a cutoff that should trigger consideration of systemic treatment; however, these criteria could result in undertreatment of patients with substantial disease. For example, patients who have limited BSA involvement but whose disease has a considerable impact on QoL, as well as those who have debilitating disease in localized areas (eg, palms, soles, scalp, nails) or substantial joint involvement may also be appropriate candidates for systemic treatment.^5,8

Once therapy is initiated, patients should be evaluated for appropriate treatment response at dedicated intervals. While the time to maximum therapeutic benefit depends on the agent of choice, European guidelines recommend that patients be evaluated after an induction phase (typically 16–24 weeks) and define treatment success as either (1) at least 75% improvement in PASI or (2) at least 50% improvement in PASI and a Dermatology Quality of Life Index (DLQI) score of 5 or lower.⁶

Alternatively, the National Psoriasis Foundation (NPF) recommended BSA as the preferred outcome measure in a recent consensus statement and concluded that an outcome of 3% or less BSA involvement or improvement in BSA of 75% or more is considered a desirable treatment response.⁹ Additionally, the Medicare Merit-based Incentive Payment System (MIPS) guidelines for successful systemic treatment response include at least 1 of the following: (1) physician global assessment score of 2 or lower, (2) BSA involvement of less than 3%, (3) PASI score lower than 3, or (4) DLQI score of 5 or lower.¹⁰

Although an array of outcome measures have been utilized in clinical trials and proposed in psoriasis guidelines and consensus statements, BSA is typically a manageable measure of treatment response in a clinical setting; however, DLQI should also be assessed if possible, particularly in patients with debilitating localized disease.⁹

Treatment Options

Because topical treatment regimens can be arduous and typically do not result in sustained clearance, patient expectations should be ascertained prior to initiation of therapy. Topical corticosteroids often can be used as monotherapy in patients with mild psoriasis.³ Topical vitamin D analogues and retinoids also can be effective; however, combined use of these agents with topical steroids should be considered to increase efficacy, and combination formulations can be prescribed to simplify application and improve adherence.

Treatment with UVB or psoralen plus UVA phototherapy is recommended for patients with moderate to severe psoriasis as well as in those who have had minimal response to topical therapy.⁴ Targeted phototherapy with an excimer laser can be used in patients with BSA involvement of less than 10%.

Methotrexate (MTX), cyclosporine, and acitretin are the most commonly prescribed systemic medications for severe psoriasis in the United States.⁵ Despite the risk for hepatotoxicity, MTX appears to have the best combined safety and efficacy profile in terms of serious adverse events compared to other systemic agents.¹¹ Guidelines for MTX monitoring, especially with regard to when to do a liver biopsy, have been substantially liberalized over time, and the recommended interval for biopsy has been extended by years; biopsy was previously recommended after a cumulative MTX dose of 1 to 1.5 g, but guidelines now suggest biopsy after 3.5 to 4 g in low-risk patients.⁵ While abnormally elevated liver function tests during treatment with MTX may necessitate liver biopsy, the use of transient elastography and a panel of serum biomarkers for liver function also can be used to monitor noninvasively for hepatotoxicity before biopsy is considered; these recommendations are likely to be incorporated into newer guidelines in development.¹² Methotrexate has demonstrated safety and increased efficacy when used in combination with biologic agents such as adalimumab, etanercept, infliximab, and secukinumab⁷ and has been studied in combination with many biologics indicated for PsA.¹³

Due to a considerable risk of glomerulosclerosis, cyclosporine is approved for a maximum of 1 year of continuous treatment of psoriasis in the United States and2 years in Europe.^5,7 Cyclosporine is best used as induction therapy in psoriasis patients with severe disease who are seeking faster abatement of symptoms.

Acitretin is another systemic treatment option, although efficacy of this agent is dose dependent. Higher dosing often is limited due to lower tolerability.⁵

Given that many insurance formularies primarily cover traditional systemic therapies and that MTX and phototherapy are generally well tolerated and cost effective, patients may need to be treated with traditional agents before escalating to biologics. Prior to starting treatment with any biologic, patients should typically be screened for tuberculosis (TB), human immunodeficiency virus infection, and immunization for, exposure to, and/or infection with hepatitis B and C virus, and any other active infections. In patients who do not demonstrate hepatitis immunity, the hepatitis B vaccine should be administered prior to starting treatment with a biologic.¹⁴ In psoriasis patients with latent TB, 2 months of treatment should be completed before initiating biologic therapy⁸; once a biologic has been initiated, all patients should be screened annually for TB.

European guidelines for biologic treatment recommend that complete blood count and liver and renal function be evaluated at baseline, at months 1 and 3 of treatment, and then every 3 to 6 months thereafter while on the biologic agent.⁷ These recommendations are more stringent than those indicated in regulatory labeling and, based on the continual accumulation of data regarding the safety of these agents, some investigators have argued that laboratory testing might not be necessary at all.¹⁵

Treatment in Special Populations

Psoriasis patients often present with comorbidities or a complicated medical history, which can make it challenging to decide which therapy is most suitable. Patients with comorbid diseases (eg, PsA, risk of major cardiac event, IBD) or a history of NMSC and those who are pregnant or are lactating require special considerations to ensure treatment safety and efficacy.

Tumor necrosis factor α (TNF-α) and IL-17 inhibitors are used in the treatment of joint disorders and should be considered in patients with PsA. IL-23/IL-12 inhibition appears to have less benefit in patients with PsA, but studies on IL-23 inhibition (p19 antibodies) alone are ongoing.¹⁶ It has been reported that TNF-α inhibition may be beneficial in patients at risk for major cardiac events.^8,17 In patients with IBD, IL-17 inhibitors should be avoided because they may exacerbate the condition; however, TNF-α and IL-23/IL-12 inhibition have shown to be safe in patients with IBD and many agents in these classes are approved by the US Food and Drug Administration for use in this population.^18,19

Although biologics may increase the risk of developing NMSC²⁰ and should generally be avoided in patients with any active malignancy, specific guidelines for screening and initiation of treatment in patients with a history of cancer are not clearly outlined. Prior to initiating systemic therapy in any patient, a careful medical history should be obtained. These agents often are not prescribed in patients with a history of cancer until remission has been established for at least 5 years, with the exception of patients with a history of treated NMSC.⁸ Annual skin monitoring for NMSC should be undertaken for psoriasis patients on most immunomodulating systemic therapies.

Recommendations for biologic treatment in psoriasis patients who are pregnant or lactating also are limited. European guidelines have noted pregnancy as an absolute contraindication to treatment with biologics,⁷but the regulatory guidance has recently changed for some agents, so this recommendation also may evolve.²¹ British⁸ and US⁵ guidelines do not consider pregnancy a contraindication for treatment with biologics.

Information on the safety of TNF-α antagonists during pregnancy comes primarily from use in patients with IBD and rheumatologic disease. To date, reports on the incidence of congenital malformations have been generally reassuring. Because IgG antibodies are actively transferred across the placenta in the late-second or the third trimesters, neonates born to mothers on biologic treatments may have high levels of some biologic drugs at birth. As a result, live vaccination should be avoided in neonates whose mothers were treated with IgG-based biologics.

Changing Treatment Agents

Patients may need to stop and change treatment agents due to ineffectiveness, personal preference, or worsening disease. When transitioning from any systemic or biologic agent to another (other than MTX), the British Association of Dermatologists recommends a washout period of at least 1 month before initiating a new therapy.⁸ Most guidelines do not define parameters for therapy escalation when patients fail multiple systemic agents, so physicians should use clinical judgment along with consideration of patient preference and comorbidity profile to ascertain which agent is most appropriate.

Conclusion

Keeping psoriasis treatment guidelines updated can be difficult, especially as new therapeutic options for psoriasis and treatment regimens rapidly evolve. Regulatory recommendations also vary worldwide, but most guidelines are reasonably consistent without being overly prescriptive, appropriately allowing for flexibility for application in clinical practice. Nonetheless, physicians should keep in mind new or changing guidelines while tailoring psoriasis treatment recommendations to best suit their individual patients.

Psoriasis is a chronic, autoimmune-mediated disease estimated to affect 2.8% of the US population.¹ The pathogenesis of psoriasis is thought to involve a complex process triggered by a combination of genetic and environmental factors that induce tumor necrosis factor (TNF) α secretion by keratinocytes, which in turn activates dendritic cells. Activated dendritic cells produce IL-23, leading to helper T cell (T_H17) differentiation.^2,3 T_H17 cells secrete IL-17A, which has been shown to promote psoriatic skin changes.⁴ Therefore, TNF-α, IL-23, and IL-17A have been recognized as key targets for psoriasis therapy.

The newest biologic agents targeting IL-17–mediated pathways include ixekizumab, brodalumab, and bimekizumab. Secukinumab, the first US Food and Drug Administration (FDA)–approved IL-17 inhibitor, has been available since 2015 and therefore is not included in this review. IL-23 inhibitors that are FDA approved or being evaluated in clinical trials include guselkumab, tildrakizumab, and risankizumab. In addition, certolizumab pegol, a TNF-α inhibitor, is being studied for use in psoriasis.

METHODS

We reviewed the published results of phase 3 clinical trials for ixekizumab, brodalumab, bimekizumab, guselkumab, tildrakizumab, risankizumab, and certolizumab pegol. We performed an English-language literature search (January 1, 2012 to October 15, 2017) of articles indexed for PubMed/MEDLINE using the following combinations of keywords: IL-23 and psoriasis; IL-17 and psoriasis; tumor necrosis factor and psoriasis; [drug name] and psoriasis. If data from phase 3 clinical trials were not yet available, data from phase 2 clinical trials were incorporated in our analysis. We also reviewed citations within articles to identify relevant sources.

RESULTS

Phase 3 clinical trial design, efficacy, and adverse events (AEs) for ixekizumab and brodalumab are reported in eTable 1^5-10 and for guselkumab and tildrakizumab in eTable 2.^11-14 Phase 2 clinical trial design, efficacy, and AEs are presented for risankizumab in eTable 3^15-18 and for certolizumab pegol in eTable 4.^17,19 No published clinical trial data were found for bimekizumab.

IL-17 Inhibitors

Ixekizumab
This recombinant, high-affinity IgG4κ antibody selectively binds and neutralizes IL-17A.^5,6 Three phase 3 clinical trials—UNCOVER-1, UNCOVER-2, and UNCOVER-3—evaluated ixekizumab for moderate to severe plaque psoriasis.⁷

The 3 UNCOVER trials were randomized, double-blind, phase 3 trials of 1296, 1224, and 1346 patients, respectively, assigned to a placebo group; a group treated with ixekizumab 80 mg every 2 weeks; and a group treated with ixekizumab 80 mg every 4 weeks. Both ixekizumab groups received a loading dose of 160 mg at week 0.^5,6 UNCOVER-2 and UNCOVER-3 also included a comparator group of patients on etanercept 50 mg.⁵ Co-primary end points included the percentage of patients reaching a psoriasis area and severity index (PASI) of 75 and with a static physician global assessment (PGA) score of clear (0) or almost clear (1) at week 12.^5,6

Ixekizumab achieved greater efficacy than placebo: 89.1%, 89.7%, and 87.3% of patients achieved PASI 75 in the every 2-week dosing group, and 82.6%, 77.5% and 84.2% achieved PASI 75 in the every 4-week dosing group in UNCOVER-1, UNCOVER-2, and UNCOVER-3, respectively (P<.001 for both treatment arms compared to placebo in all trials). The percentage of patients achieving a static PGA score of 0 or 1 also was higher in the ixekizumab groups in the 2-week and 4-week dosing groups in all UNCOVER trials—81.8% and 76.4% in UNCOVER-1, 83.2% and 72.9% in UNCOVER-2, and 80.5% and 75.4% in UNCOVER-3—compared to 3.2%, 2.4%, and 6.7% in the placebo groups of the 3 trials (P<.001 for both ixekizumab groups compared to placebo in all trials).^5,6 Ixekizumab also was found to be more effective than etanercept for both co-primary end points in both UNCOVER-2 and UNCOVER-3 (eTable 1).⁵

Safety data for all UNCOVER trials were pooled and reported.⁶ At week 12 the rate of at least 1 AE was 58.4% in patients on ixekizumab every 2 weeks and 58.8% in patients on ixekizumab every 4 weeks compared to 54.0% in the etanercept group in UNCOVER-2 and UNCOVER-3 and 46.8% in the placebo group. At week 12, 72 nonfatal serious AEs were reported: 12 in the placebo group, 14 in the etanercept group, 20 in the ixekizumab every 2 weeks group, and 26 in the ixekizumab every 4 weeks group.⁶

The most common AE across all groups was nasopharyngitis. Overall, infections were more frequent in patients treated with ixekizumab than in patients treated with placebo or etanercept. Specifically, oral candidiasis occurred more frequently in the ixekizumab groups, with a higher rate in the 2-week dosing group than in the 4-week dosing group.⁶ Two myocardial infarctions (MIs) occurred: 1 in the etanercept group and 1 in the placebo group.⁵

Brodalumab
This human monoclonal antibody binds to IL-17ra.^8,9 Three double-blind, placebo-controlled, phase 3 trials—AMAGINE-1, AMAGINE-2, and AMAGINE-3—evaluated its use for plaque psoriasis.¹⁰

In AMAGINE-1 (N=661), patients were randomized to receive brodalumab 140 mg or 210 mg (every 2 weeks for 12 weeks), or placebo.⁸ In AMAGINE-2 (N=1831) and AMAGINE-3 (N=1881), patients were randomized to receive brodalumab 140 mg or 210 mg (every 2 weeks for 12 weeks), ustekinumab 45 mg or 90 mg by weight (at weeks 0 and 4, then every 12 weeks thereafter), or placebo. In all trials, patients on brodalumab received a dose at week 0 and week 1. Co-primary end points were PASI 75 and a static PGA score of 0 or 1 at 12 weeks compared to placebo and to ustekinumab (in AMAGINE-2 and AMAGINE-3 only).⁸

At week 12, 83.3%, 86.3%, and 85.1% of patients on brodalumab 210 mg, and 60.3%, 66.6%, and 69.2% of patients on brodalumab 140 mg, achieved PASI 75 in AMAGINE-1, AMAGINE-2, and AMAGINE-3, respectively, compared to 2.7%, 8.1%, and 6.0% in the placebo groups (P<.001 between both brodalumab groups and placebo in all trials).⁸ Both brodalumab groups were noninferior but not significantly superior to ustekinumab, which achieved a PASI 75 of 70.0% in AMAGINE-2 and 69.3% in AMAGINE-3. The PASI 90 rate was higher, however, in both brodalumab groups compared to ustekinumab but significance was not reported (eTable 1).⁹ For both brodalumab groups, significantly more patients achieved a static PGA value of 0 or 1 compared to placebo (P<.001 across all trials). However, only the brodalumab 210-mg group achieved a significantly higher rate of static PGA 0 or 1 compared to ustekinumab in AMAGINE-2 and AMAGINE-3 (P<.001).⁹

After 12 weeks, the percentage of patients reporting at least 1 AE was 59.0%, 57.8%, and 56.8% in the brodalumab 210-mg group in AMAGINE-1, AMAGINE-2, and AMAGINE-3, respectively; 58.0%, 60.1%, and 52.6% in the brodalumab 140-mg group; and 51.0%, 53.4%, and 48.6% in the placebo group. Patients taking ustekinumab had an AE rate of 59.0% in AMAGINE-2 and 53.7% in AMAGINE-3. The most common AE was nasopharyngitis, followed by upper respiratory infection (URI) and headache across all trials.^8,9 Serious AEs were rare: 10 in AMAGINE-1, 31 in AMAGINE-2, and 24 in AMAGINE-3 across all groups. One death occurred from stroke in the brodalumab 210-mg group in AMAGINE-2.⁹

IL-23 Inhibitors

Guselkumab
This drug is a human IgG1κ antibody that binds to the p19 subunit of IL-23, thereby inhibiting IL-23 signaling.^11,12 Guselkumab was approved by the FDA in July 2017 for moderate to severe plaque psoriasis.¹³

VOYAGE 1 and VOYAGE 2 were phase 3, double-blind, placebo- and active comparator–controlled trials of 837 and 992 patients, respectively, randomized to receive adalimumab (80 mg at week 0 and 40 mg at week 1, then at 40 mg every 2 weeks thereafter), guselkumab 100 mg at weeks 0, 4, and 12, or placebo.¹¹ Co-primary end points for both trials were the percentage of patients reaching PASI 90 and an investigator global assessment (IGA) score of cleared (0) or minimal (1) at week 16.¹¹

By week 16 of both trials, PASI 90 values were statistically superior for guselkumab (VOYAGE 1, 73.3%; VOYAGE 2, 70.0%) compared to adalimumab (VOYAGE 1, 49.7%; VOYAGE 2, 46.8%) and placebo (VOYAGE 1, 2.9%; VOYAGE 2, 2.4%)(P<.001). Moreover, patients on guselkumab achieved a higher rate of IGA values of 0 and 1 at week 12 (85.1% in VOYAGE 1 and 84.1% in VOYAGE 2) than patients on adalimumab (65.9% in VOYAGE 1 and 67.7% in VOYAGE 2) and placebo (6.9% in VOYAGE 1 and 8.5% in VOYAGE 2)(P<.001).^11,12

The frequency of AEs was comparable across all groups in both trials.^11,12 During the 16-week treatment period, 51.7% and 47.6% of the guselkumab groups in VOYAGE 1 and VOYAGE 2, respectively; 51.1% and 48.4% of the adalimumab groups; and 49.4% and 44.8% of the placebo groups reported at least 1 AE. The most common AEs in all groups were nasopharyngitis, headache, and URI.^11,12

Serious AEs also occurred at similar rates: 2.4% and 1.6% in the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively; 2.4% and 1.8% in the adalimumab group; and 1.7% and 1.2% in the placebo group.^11,12 One case of malignancy occurred in the VOYAGE 1 trial: basal cell carcinoma in the guselkumab group.¹¹ Three major cardiovascular events occurred across both trials: 1 MI in the guselkumab group in each trial and 1 MI in the adalimumab group in VOYAGE 1.^11,12

Tildrakizumab
A high-affinity, humanized IgG1κ antibody, tildrakizumab targets the p19 subunit of IL-23. As of February 2018, 2 double-blind, randomized phase 3 trials have studied tildrakizumab with published results: reSURFACE 1 and reSURFACE 2.¹⁴

reSURFACE 1 (N=772) and reSURFACE 2 (N=1090) randomized patients to receive tildrakizumab 100 or 200 mg (at weeks 0 and 4), etanercept 50 mg (twice weekly) for 12 weeks (reSURFACE 2 only), or placebo. Co-primary end points were the percentage of patients achieving PASI 75 and the percentage of patients achieving a PGA score of 0 or 1 at week 12.¹⁴

In reSURFACE 1, significantly more patients receiving tildrakizumab attained PASI 75 at week 12 compared to placebo: 200 mg, 62.0%; 100 mg, 64.0%; and placebo, 6.0% (P<.001 for tildrakizumab groups compared to placebo). Moreover, significantly proportionally more patients received a PGA score of 0 or 1 compared to placebo: 100 mg, 59%; 200 mg, 58.0%; placebo, 7.0% (P<.001 for both tildrakizumab groups compared to placebo).¹⁴

In reSURFACE 2, significantly more patients receiving tildrakizumab achieved PASI 75 compared to etanercept and placebo at week 12: 200 mg, 66.0%; 100mg, 61.0%; etanercept, 48.0%; placebo, 6.0% (P<.001 for both tildrakizumab groups compared to placebo; P<.05 for both tildrakizumab groups compared to etanercept). Additionally, significantly more patients in the tildrakizumab groups experienced a PGA score of 0 or 1 at week 12 compared to placebo: 200 mg, 59%; 100 mg, 55.0%; placebo, 5% (P<.001 for both tildrakizumab groups compared to placebo).¹⁴

Adverse events were reported at a similar rate across all groups. For reSURFACE 1 and reSURFACE 2, at least 1 AE by week 12 was reported by 42.2% and 45.2% of patients in the 200-mg group; 47.2% and 45.9% in the 100-mg group; and 48.1% and 55.1% in the placebo groups.¹⁴The most common AEs were nasopharyngitis, URI (reSURFACE 1), and erythema at the injection site (reSURFACE 2). One case of serious infection was reported in each of the tildrakizumab groups: 1 case of drug-related hypersensitivity reaction in the 200-mg group, and 1 major cardiovascular event in the 100-mg group of reSURFACE 1. There was 1 serious AE in reSURFACE 2 that led to death in which the cause was undetermined.¹⁴

Risankizumab
This humanized IgG1 antibody binds the p19 unit of IL-23.^15,16 The drug is undergoing 3 phase 3 trials—ultIMMa-1, ultIMMa-2, and IMMvent—for which only preliminary data have been published and are reported here.^16,17 There is 1 phase 2 randomized, dose-ranging trial with published data.¹⁵

ultIMMa-1 and ultIMMa-2 comprised 506 and 491 patients, respectively, randomized to receive risankizumab (150 mg at weeks 0, 4, and 16), ustekinumab (45 mg or 90 mg, by weight, at weeks 0, 4, and 16), or placebo. Co-primary end points were PASI 90 and a PGA score of 0 or 1 at week 16.¹⁷

In ultIMMa-1 and ultIMMa-2, 75.0% and 75.0% of patients on risankizumab 150 mg achieved PASI 90 compared to 42.0% and 48.0% on ustekinumab and 5.0% and 2.0% on placebo at 16 weeks (P<.001 between both placebo and ustekinumab in both trials).¹⁷ In both trials, patients receiving risankizumab achieved higher rates of a static PGA score of 0 or 1 (88.0% and 84.0%) compared to ustekinumab (63.0% and 62.0%) and placebo (8.0% and 5.0%) at 16 weeks (P<.001 for both trials).¹⁸

At week 16, 2.0% of patients on risankizumab reported a serious AE in both trials, compared to 8.0% and 3.0% of patients on ustekinumab and 3.0% and 1.0% on placebo. No new safety concerns were noted.¹⁷

In the phase 3 IMMvent trial, 605 patients were randomized to receive risankizumab (150 mg at weeks 0, 4, and 16) or adalimumab (80 mg at week 0, 40 mg at week 1, then 40 mg every 2 weeks). Co-primary end points were PASI 90 and a static PGA score of 0 or 1 at week 16.¹⁷

In IMMvent, risankizumab was significantly more effective than adalimumab for PASI 75 (risankizumab, 72.0%; adalimumab, 47.0%) and a static PGA score of 0 or 1 (risankizumab 84.0%; adalimumab, 60.0%) (P<.001 risankizumab compared to adalimumab for both end points).¹⁷

At week 16, serious AEs were reported in 3.0% of patients on risankizumab and 3.0% of patients on adalimumab. One patient receiving risankizumab died of an acute MI during the treatment phase.¹⁷

TNF Inhibitor

Certolizumab Pegol
Certolizumab pegol is a human PEGylated anti-TNF agent. In vitro studies have shown that certolizumab binds to soluble and membrane-bound TNF.¹⁹ Unlike other TNF inhibitors, certolizumab pegol is a Fab‘ portion of anti-TNF conjugated to a molecule of polyethylene glycol.¹⁹ The drug is approved in the United States for treating psoriatic arthritis, Crohn disease, and rheumatoid arthritis; its potential for treating psoriasis has been confirmed. Results of 1 phase 2 trial have been published¹⁹; data from 3 phase 3 trials are forthcoming.

This randomized, placebo-controlled, double-blind phase 2 study comprised 176 patients who received certolizumab 200 mg, certolizumab 400 mg, or placebo. The dosing schedule was 400 mg at week 0, followed by either 200 or 400 mg every other week until week 10. Co-primary end points were PASI 75 and a PGA score of 0 or 1 at week 12.¹⁹

Certolizumab was significantly more effective than placebo at week 12: 74.6% of the 200-mg group and 82.8% of the 400-mg group achieved PASI 75 compared to 6.8% of the placebo group (P<.001). Certolizumab also performed better for the PGA score: 52.5% and 72.4% of patients attained a score of 0 or 1 in the 200-mg and 400-mg groups compared to 1.7% in the placebo group.¹⁹

Adverse events were reported equally across all groups: 72% of patients in the 200-mg group, 70% in the 400-mg group, and 71% in the placebo group reported at least 1 AE, most commonly nasopharyngitis, headache, and pruritis.¹⁹

COMMENT

With the development of new insights into the pathogenesis of psoriasis, therapies that are targeted toward key cytokines may contribute to improved management of the disease. The results of these clinical trials demonstrate numerous promising options for psoriatic patients.

IL-17 Inhibitors Ixekizumab and Brodalumab

When comparing these 2 biologics, it is important to consider that these studies were not performed head to head, thereby inhibiting direct comparisons. Moreover, dosage ranges of the investigative drugs were not identical, which also makes comparisons challenging. However, when looking at the highest dosages of ixekizumab and brodalumab, results indicate that ixekizumab may be slightly more effective than brodalumab based on the percentage of patients who achieved a PASI 75 and a static PGA score of 0 or 1 (eTable 1).

Phase 3 trials have shown ixekizumab to maintain efficacy over 60 weeks of treatment.⁶ Ixekizumab also has been shown to alleviate other symptoms of psoriasis, such as itching, pain, and nail involvement.^20,21 Furthermore, ixekizumab appears to be equally effective in patients with or without prior exposure to biologics²²; therefore, ixekizumab may benefit patients who have not experienced success with other biologics.

Across the UNCOVER trials, 11 cases of inflammatory bowel disease were reported in patients receiving ixekizumab (ulcerative colitis in 7; Crohn disease in 4)⁶; it appears that at least 3 of these cases were new diagnoses. In light of a study suggesting that IL-17A might have a protective function in the intestine,²³ these findings may have important clinical implications and require follow-up studies.

Brodalumab also has been shown to maintain efficacy and acceptable safety for as long as 120 weeks.²⁴ In the extension period of the AMAGINE-1 trial, patients who experienced a return of disease during a withdrawal period recaptured static PGA success with re-treatment for 12 weeks (re-treatment was successful in 97% of those given a dosage of 210 mg and in 84% of those given 140 mg).⁸

Furthermore, phase 2 trials also have shown that brodalumab is effective in patients with a history of biologic use.²⁵ Across all AMAGINE trials, only 1 case of Crohn disease was reported in a patient taking brodalumab.⁹ There are concerns about depression, despite data from AMAGINE-1 stating patients on brodalumab actually had greater improvements in Hospital Anxiety and Depression Scale scores after 12 weeks of treatment (P<.001) for both brodalumab 140 mg and 210 mg compared to placebo.⁸ Regardless, brodalumab has a black-box warning for suicidal ideation and behavior, and availability is restricted through a Risk Evaluation and Mitigation Strategy (REMS) program.²⁶

Bimekizumab

Although no phase 2 or phase 3 clinical trial data have been published for bimekizumab (phase 2 trials are underway), it has been shown in a phase 1 trial to be effective for psoriasis. Bimekizumab also is unique; it is the first dual inhibitor of IL-17A and IL-17F.¹⁸

IL-23 Inhibitors Guselkumab, Tildrakizumab, and Risankizumab

Making comparisons among the IL-23 inhibitors also is difficult; studies were not head-to-head comparison trials, and the VOYAGE and reSURFACE studies used different time points for primary end points. Furthermore, only phase 2 trial data are available for risankizumab. Despite these limitations, results of these trials suggest that guselkumab and risankizumab may be slightly more efficacious than tildrakizumab. However, future studies, including head-to-head studies, would ultimately provide further information on how these agents compare.

Guselkumab was shown to remain efficacious at 48 weeks, though patients on maintenance dosing had better results than those who were re-treated.¹² Moreover, guselkumab was found to be effective in hard-to-treat areas, such as the scalp,¹¹ and in patients who did not respond to adalimumab. Guselkumab may therefore benefit patients who have experienced limited clinical improvement on other biologics.¹²

Tildrakizumab was shown to improve PASI 75 and PGA scores through week 28 of treatment. Moreover, a higher percentage of patients taking tildrakizumab scored 0 or 1 on the dermatology life quality index, suggesting that the drug improves quality of life.¹⁴ No specific safety concerns arose in either reSURFACE trial; however, long-term studies are needed for further evaluation.

Risankizumab appears to be a promising new therapy based on phase 2 trial results. Improvements also were seen in dermatology life quality index scores, scalp and fingernail symptoms, and palmoplantar psoriasis.¹⁵ Of note, neutralizing antidrug antibodies were found in 3 patients during this study,¹⁵ which may present potential problems for long-term efficacy. However, preliminary data from 3 phase 3 trials—ultIMMa-1, ultIMMa-2, and IMMvent—are promising.¹⁷

CONCLUSION

Advances in the understanding of psoriasis have led to new targeted therapies. Ongoing clinical trials have shown encouraging results for treating physical and psychological symptoms of psoriasis. The findings of these trials support the idea that therapies targeting IL-23, specifically its p19 subunit, are effective against psoriasis while sparing IL-12. Long-term data from open-label extension studies would help guide clinical recommendations regarding the safety profiles of these agents and determine their long-term utility.

Psoriasis is a chronic, autoimmune-mediated disease estimated to affect 2.8% of the US population.¹ The pathogenesis of psoriasis is thought to involve a complex process triggered by a combination of genetic and environmental factors that induce tumor necrosis factor (TNF) α secretion by keratinocytes, which in turn activates dendritic cells. Activated dendritic cells produce IL-23, leading to helper T cell (T_H17) differentiation.^2,3 T_H17 cells secrete IL-17A, which has been shown to promote psoriatic skin changes.⁴ Therefore, TNF-α, IL-23, and IL-17A have been recognized as key targets for psoriasis therapy.

The newest biologic agents targeting IL-17–mediated pathways include ixekizumab, brodalumab, and bimekizumab. Secukinumab, the first US Food and Drug Administration (FDA)–approved IL-17 inhibitor, has been available since 2015 and therefore is not included in this review. IL-23 inhibitors that are FDA approved or being evaluated in clinical trials include guselkumab, tildrakizumab, and risankizumab. In addition, certolizumab pegol, a TNF-α inhibitor, is being studied for use in psoriasis.

METHODS

We reviewed the published results of phase 3 clinical trials for ixekizumab, brodalumab, bimekizumab, guselkumab, tildrakizumab, risankizumab, and certolizumab pegol. We performed an English-language literature search (January 1, 2012 to October 15, 2017) of articles indexed for PubMed/MEDLINE using the following combinations of keywords: IL-23 and psoriasis; IL-17 and psoriasis; tumor necrosis factor and psoriasis; [drug name] and psoriasis. If data from phase 3 clinical trials were not yet available, data from phase 2 clinical trials were incorporated in our analysis. We also reviewed citations within articles to identify relevant sources.

RESULTS

Phase 3 clinical trial design, efficacy, and adverse events (AEs) for ixekizumab and brodalumab are reported in eTable 1^5-10 and for guselkumab and tildrakizumab in eTable 2.^11-14 Phase 2 clinical trial design, efficacy, and AEs are presented for risankizumab in eTable 3^15-18 and for certolizumab pegol in eTable 4.^17,19 No published clinical trial data were found for bimekizumab.

IL-17 Inhibitors

Ixekizumab
This recombinant, high-affinity IgG4κ antibody selectively binds and neutralizes IL-17A.^5,6 Three phase 3 clinical trials—UNCOVER-1, UNCOVER-2, and UNCOVER-3—evaluated ixekizumab for moderate to severe plaque psoriasis.⁷

The 3 UNCOVER trials were randomized, double-blind, phase 3 trials of 1296, 1224, and 1346 patients, respectively, assigned to a placebo group; a group treated with ixekizumab 80 mg every 2 weeks; and a group treated with ixekizumab 80 mg every 4 weeks. Both ixekizumab groups received a loading dose of 160 mg at week 0.^5,6 UNCOVER-2 and UNCOVER-3 also included a comparator group of patients on etanercept 50 mg.⁵ Co-primary end points included the percentage of patients reaching a psoriasis area and severity index (PASI) of 75 and with a static physician global assessment (PGA) score of clear (0) or almost clear (1) at week 12.^5,6

Ixekizumab achieved greater efficacy than placebo: 89.1%, 89.7%, and 87.3% of patients achieved PASI 75 in the every 2-week dosing group, and 82.6%, 77.5% and 84.2% achieved PASI 75 in the every 4-week dosing group in UNCOVER-1, UNCOVER-2, and UNCOVER-3, respectively (P<.001 for both treatment arms compared to placebo in all trials). The percentage of patients achieving a static PGA score of 0 or 1 also was higher in the ixekizumab groups in the 2-week and 4-week dosing groups in all UNCOVER trials—81.8% and 76.4% in UNCOVER-1, 83.2% and 72.9% in UNCOVER-2, and 80.5% and 75.4% in UNCOVER-3—compared to 3.2%, 2.4%, and 6.7% in the placebo groups of the 3 trials (P<.001 for both ixekizumab groups compared to placebo in all trials).^5,6 Ixekizumab also was found to be more effective than etanercept for both co-primary end points in both UNCOVER-2 and UNCOVER-3 (eTable 1).⁵

Safety data for all UNCOVER trials were pooled and reported.⁶ At week 12 the rate of at least 1 AE was 58.4% in patients on ixekizumab every 2 weeks and 58.8% in patients on ixekizumab every 4 weeks compared to 54.0% in the etanercept group in UNCOVER-2 and UNCOVER-3 and 46.8% in the placebo group. At week 12, 72 nonfatal serious AEs were reported: 12 in the placebo group, 14 in the etanercept group, 20 in the ixekizumab every 2 weeks group, and 26 in the ixekizumab every 4 weeks group.⁶

The most common AE across all groups was nasopharyngitis. Overall, infections were more frequent in patients treated with ixekizumab than in patients treated with placebo or etanercept. Specifically, oral candidiasis occurred more frequently in the ixekizumab groups, with a higher rate in the 2-week dosing group than in the 4-week dosing group.⁶ Two myocardial infarctions (MIs) occurred: 1 in the etanercept group and 1 in the placebo group.⁵

Brodalumab
This human monoclonal antibody binds to IL-17ra.^8,9 Three double-blind, placebo-controlled, phase 3 trials—AMAGINE-1, AMAGINE-2, and AMAGINE-3—evaluated its use for plaque psoriasis.¹⁰

In AMAGINE-1 (N=661), patients were randomized to receive brodalumab 140 mg or 210 mg (every 2 weeks for 12 weeks), or placebo.⁸ In AMAGINE-2 (N=1831) and AMAGINE-3 (N=1881), patients were randomized to receive brodalumab 140 mg or 210 mg (every 2 weeks for 12 weeks), ustekinumab 45 mg or 90 mg by weight (at weeks 0 and 4, then every 12 weeks thereafter), or placebo. In all trials, patients on brodalumab received a dose at week 0 and week 1. Co-primary end points were PASI 75 and a static PGA score of 0 or 1 at 12 weeks compared to placebo and to ustekinumab (in AMAGINE-2 and AMAGINE-3 only).⁸

At week 12, 83.3%, 86.3%, and 85.1% of patients on brodalumab 210 mg, and 60.3%, 66.6%, and 69.2% of patients on brodalumab 140 mg, achieved PASI 75 in AMAGINE-1, AMAGINE-2, and AMAGINE-3, respectively, compared to 2.7%, 8.1%, and 6.0% in the placebo groups (P<.001 between both brodalumab groups and placebo in all trials).⁸ Both brodalumab groups were noninferior but not significantly superior to ustekinumab, which achieved a PASI 75 of 70.0% in AMAGINE-2 and 69.3% in AMAGINE-3. The PASI 90 rate was higher, however, in both brodalumab groups compared to ustekinumab but significance was not reported (eTable 1).⁹ For both brodalumab groups, significantly more patients achieved a static PGA value of 0 or 1 compared to placebo (P<.001 across all trials). However, only the brodalumab 210-mg group achieved a significantly higher rate of static PGA 0 or 1 compared to ustekinumab in AMAGINE-2 and AMAGINE-3 (P<.001).⁹

After 12 weeks, the percentage of patients reporting at least 1 AE was 59.0%, 57.8%, and 56.8% in the brodalumab 210-mg group in AMAGINE-1, AMAGINE-2, and AMAGINE-3, respectively; 58.0%, 60.1%, and 52.6% in the brodalumab 140-mg group; and 51.0%, 53.4%, and 48.6% in the placebo group. Patients taking ustekinumab had an AE rate of 59.0% in AMAGINE-2 and 53.7% in AMAGINE-3. The most common AE was nasopharyngitis, followed by upper respiratory infection (URI) and headache across all trials.^8,9 Serious AEs were rare: 10 in AMAGINE-1, 31 in AMAGINE-2, and 24 in AMAGINE-3 across all groups. One death occurred from stroke in the brodalumab 210-mg group in AMAGINE-2.⁹

IL-23 Inhibitors

Guselkumab
This drug is a human IgG1κ antibody that binds to the p19 subunit of IL-23, thereby inhibiting IL-23 signaling.^11,12 Guselkumab was approved by the FDA in July 2017 for moderate to severe plaque psoriasis.¹³

VOYAGE 1 and VOYAGE 2 were phase 3, double-blind, placebo- and active comparator–controlled trials of 837 and 992 patients, respectively, randomized to receive adalimumab (80 mg at week 0 and 40 mg at week 1, then at 40 mg every 2 weeks thereafter), guselkumab 100 mg at weeks 0, 4, and 12, or placebo.¹¹ Co-primary end points for both trials were the percentage of patients reaching PASI 90 and an investigator global assessment (IGA) score of cleared (0) or minimal (1) at week 16.¹¹

By week 16 of both trials, PASI 90 values were statistically superior for guselkumab (VOYAGE 1, 73.3%; VOYAGE 2, 70.0%) compared to adalimumab (VOYAGE 1, 49.7%; VOYAGE 2, 46.8%) and placebo (VOYAGE 1, 2.9%; VOYAGE 2, 2.4%)(P<.001). Moreover, patients on guselkumab achieved a higher rate of IGA values of 0 and 1 at week 12 (85.1% in VOYAGE 1 and 84.1% in VOYAGE 2) than patients on adalimumab (65.9% in VOYAGE 1 and 67.7% in VOYAGE 2) and placebo (6.9% in VOYAGE 1 and 8.5% in VOYAGE 2)(P<.001).^11,12

The frequency of AEs was comparable across all groups in both trials.^11,12 During the 16-week treatment period, 51.7% and 47.6% of the guselkumab groups in VOYAGE 1 and VOYAGE 2, respectively; 51.1% and 48.4% of the adalimumab groups; and 49.4% and 44.8% of the placebo groups reported at least 1 AE. The most common AEs in all groups were nasopharyngitis, headache, and URI.^11,12

Serious AEs also occurred at similar rates: 2.4% and 1.6% in the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively; 2.4% and 1.8% in the adalimumab group; and 1.7% and 1.2% in the placebo group.^11,12 One case of malignancy occurred in the VOYAGE 1 trial: basal cell carcinoma in the guselkumab group.¹¹ Three major cardiovascular events occurred across both trials: 1 MI in the guselkumab group in each trial and 1 MI in the adalimumab group in VOYAGE 1.^11,12

Tildrakizumab
A high-affinity, humanized IgG1κ antibody, tildrakizumab targets the p19 subunit of IL-23. As of February 2018, 2 double-blind, randomized phase 3 trials have studied tildrakizumab with published results: reSURFACE 1 and reSURFACE 2.¹⁴

reSURFACE 1 (N=772) and reSURFACE 2 (N=1090) randomized patients to receive tildrakizumab 100 or 200 mg (at weeks 0 and 4), etanercept 50 mg (twice weekly) for 12 weeks (reSURFACE 2 only), or placebo. Co-primary end points were the percentage of patients achieving PASI 75 and the percentage of patients achieving a PGA score of 0 or 1 at week 12.¹⁴

In reSURFACE 1, significantly more patients receiving tildrakizumab attained PASI 75 at week 12 compared to placebo: 200 mg, 62.0%; 100 mg, 64.0%; and placebo, 6.0% (P<.001 for tildrakizumab groups compared to placebo). Moreover, significantly proportionally more patients received a PGA score of 0 or 1 compared to placebo: 100 mg, 59%; 200 mg, 58.0%; placebo, 7.0% (P<.001 for both tildrakizumab groups compared to placebo).¹⁴

In reSURFACE 2, significantly more patients receiving tildrakizumab achieved PASI 75 compared to etanercept and placebo at week 12: 200 mg, 66.0%; 100mg, 61.0%; etanercept, 48.0%; placebo, 6.0% (P<.001 for both tildrakizumab groups compared to placebo; P<.05 for both tildrakizumab groups compared to etanercept). Additionally, significantly more patients in the tildrakizumab groups experienced a PGA score of 0 or 1 at week 12 compared to placebo: 200 mg, 59%; 100 mg, 55.0%; placebo, 5% (P<.001 for both tildrakizumab groups compared to placebo).¹⁴

Adverse events were reported at a similar rate across all groups. For reSURFACE 1 and reSURFACE 2, at least 1 AE by week 12 was reported by 42.2% and 45.2% of patients in the 200-mg group; 47.2% and 45.9% in the 100-mg group; and 48.1% and 55.1% in the placebo groups.¹⁴The most common AEs were nasopharyngitis, URI (reSURFACE 1), and erythema at the injection site (reSURFACE 2). One case of serious infection was reported in each of the tildrakizumab groups: 1 case of drug-related hypersensitivity reaction in the 200-mg group, and 1 major cardiovascular event in the 100-mg group of reSURFACE 1. There was 1 serious AE in reSURFACE 2 that led to death in which the cause was undetermined.¹⁴

Risankizumab
This humanized IgG1 antibody binds the p19 unit of IL-23.^15,16 The drug is undergoing 3 phase 3 trials—ultIMMa-1, ultIMMa-2, and IMMvent—for which only preliminary data have been published and are reported here.^16,17 There is 1 phase 2 randomized, dose-ranging trial with published data.¹⁵

ultIMMa-1 and ultIMMa-2 comprised 506 and 491 patients, respectively, randomized to receive risankizumab (150 mg at weeks 0, 4, and 16), ustekinumab (45 mg or 90 mg, by weight, at weeks 0, 4, and 16), or placebo. Co-primary end points were PASI 90 and a PGA score of 0 or 1 at week 16.¹⁷

In ultIMMa-1 and ultIMMa-2, 75.0% and 75.0% of patients on risankizumab 150 mg achieved PASI 90 compared to 42.0% and 48.0% on ustekinumab and 5.0% and 2.0% on placebo at 16 weeks (P<.001 between both placebo and ustekinumab in both trials).¹⁷ In both trials, patients receiving risankizumab achieved higher rates of a static PGA score of 0 or 1 (88.0% and 84.0%) compared to ustekinumab (63.0% and 62.0%) and placebo (8.0% and 5.0%) at 16 weeks (P<.001 for both trials).¹⁸

At week 16, 2.0% of patients on risankizumab reported a serious AE in both trials, compared to 8.0% and 3.0% of patients on ustekinumab and 3.0% and 1.0% on placebo. No new safety concerns were noted.¹⁷

In the phase 3 IMMvent trial, 605 patients were randomized to receive risankizumab (150 mg at weeks 0, 4, and 16) or adalimumab (80 mg at week 0, 40 mg at week 1, then 40 mg every 2 weeks). Co-primary end points were PASI 90 and a static PGA score of 0 or 1 at week 16.¹⁷

In IMMvent, risankizumab was significantly more effective than adalimumab for PASI 75 (risankizumab, 72.0%; adalimumab, 47.0%) and a static PGA score of 0 or 1 (risankizumab 84.0%; adalimumab, 60.0%) (P<.001 risankizumab compared to adalimumab for both end points).¹⁷

At week 16, serious AEs were reported in 3.0% of patients on risankizumab and 3.0% of patients on adalimumab. One patient receiving risankizumab died of an acute MI during the treatment phase.¹⁷

TNF Inhibitor

Certolizumab Pegol
Certolizumab pegol is a human PEGylated anti-TNF agent. In vitro studies have shown that certolizumab binds to soluble and membrane-bound TNF.¹⁹ Unlike other TNF inhibitors, certolizumab pegol is a Fab‘ portion of anti-TNF conjugated to a molecule of polyethylene glycol.¹⁹ The drug is approved in the United States for treating psoriatic arthritis, Crohn disease, and rheumatoid arthritis; its potential for treating psoriasis has been confirmed. Results of 1 phase 2 trial have been published¹⁹; data from 3 phase 3 trials are forthcoming.

This randomized, placebo-controlled, double-blind phase 2 study comprised 176 patients who received certolizumab 200 mg, certolizumab 400 mg, or placebo. The dosing schedule was 400 mg at week 0, followed by either 200 or 400 mg every other week until week 10. Co-primary end points were PASI 75 and a PGA score of 0 or 1 at week 12.¹⁹

Certolizumab was significantly more effective than placebo at week 12: 74.6% of the 200-mg group and 82.8% of the 400-mg group achieved PASI 75 compared to 6.8% of the placebo group (P<.001). Certolizumab also performed better for the PGA score: 52.5% and 72.4% of patients attained a score of 0 or 1 in the 200-mg and 400-mg groups compared to 1.7% in the placebo group.¹⁹

Adverse events were reported equally across all groups: 72% of patients in the 200-mg group, 70% in the 400-mg group, and 71% in the placebo group reported at least 1 AE, most commonly nasopharyngitis, headache, and pruritis.¹⁹

COMMENT

With the development of new insights into the pathogenesis of psoriasis, therapies that are targeted toward key cytokines may contribute to improved management of the disease. The results of these clinical trials demonstrate numerous promising options for psoriatic patients.

IL-17 Inhibitors Ixekizumab and Brodalumab

When comparing these 2 biologics, it is important to consider that these studies were not performed head to head, thereby inhibiting direct comparisons. Moreover, dosage ranges of the investigative drugs were not identical, which also makes comparisons challenging. However, when looking at the highest dosages of ixekizumab and brodalumab, results indicate that ixekizumab may be slightly more effective than brodalumab based on the percentage of patients who achieved a PASI 75 and a static PGA score of 0 or 1 (eTable 1).

Phase 3 trials have shown ixekizumab to maintain efficacy over 60 weeks of treatment.⁶ Ixekizumab also has been shown to alleviate other symptoms of psoriasis, such as itching, pain, and nail involvement.^20,21 Furthermore, ixekizumab appears to be equally effective in patients with or without prior exposure to biologics²²; therefore, ixekizumab may benefit patients who have not experienced success with other biologics.

Across the UNCOVER trials, 11 cases of inflammatory bowel disease were reported in patients receiving ixekizumab (ulcerative colitis in 7; Crohn disease in 4)⁶; it appears that at least 3 of these cases were new diagnoses. In light of a study suggesting that IL-17A might have a protective function in the intestine,²³ these findings may have important clinical implications and require follow-up studies.

Brodalumab also has been shown to maintain efficacy and acceptable safety for as long as 120 weeks.²⁴ In the extension period of the AMAGINE-1 trial, patients who experienced a return of disease during a withdrawal period recaptured static PGA success with re-treatment for 12 weeks (re-treatment was successful in 97% of those given a dosage of 210 mg and in 84% of those given 140 mg).⁸

Furthermore, phase 2 trials also have shown that brodalumab is effective in patients with a history of biologic use.²⁵ Across all AMAGINE trials, only 1 case of Crohn disease was reported in a patient taking brodalumab.⁹ There are concerns about depression, despite data from AMAGINE-1 stating patients on brodalumab actually had greater improvements in Hospital Anxiety and Depression Scale scores after 12 weeks of treatment (P<.001) for both brodalumab 140 mg and 210 mg compared to placebo.⁸ Regardless, brodalumab has a black-box warning for suicidal ideation and behavior, and availability is restricted through a Risk Evaluation and Mitigation Strategy (REMS) program.²⁶

Bimekizumab

Although no phase 2 or phase 3 clinical trial data have been published for bimekizumab (phase 2 trials are underway), it has been shown in a phase 1 trial to be effective for psoriasis. Bimekizumab also is unique; it is the first dual inhibitor of IL-17A and IL-17F.¹⁸

IL-23 Inhibitors Guselkumab, Tildrakizumab, and Risankizumab

Making comparisons among the IL-23 inhibitors also is difficult; studies were not head-to-head comparison trials, and the VOYAGE and reSURFACE studies used different time points for primary end points. Furthermore, only phase 2 trial data are available for risankizumab. Despite these limitations, results of these trials suggest that guselkumab and risankizumab may be slightly more efficacious than tildrakizumab. However, future studies, including head-to-head studies, would ultimately provide further information on how these agents compare.

Guselkumab was shown to remain efficacious at 48 weeks, though patients on maintenance dosing had better results than those who were re-treated.¹² Moreover, guselkumab was found to be effective in hard-to-treat areas, such as the scalp,¹¹ and in patients who did not respond to adalimumab. Guselkumab may therefore benefit patients who have experienced limited clinical improvement on other biologics.¹²

Tildrakizumab was shown to improve PASI 75 and PGA scores through week 28 of treatment. Moreover, a higher percentage of patients taking tildrakizumab scored 0 or 1 on the dermatology life quality index, suggesting that the drug improves quality of life.¹⁴ No specific safety concerns arose in either reSURFACE trial; however, long-term studies are needed for further evaluation.

Risankizumab appears to be a promising new therapy based on phase 2 trial results. Improvements also were seen in dermatology life quality index scores, scalp and fingernail symptoms, and palmoplantar psoriasis.¹⁵ Of note, neutralizing antidrug antibodies were found in 3 patients during this study,¹⁵ which may present potential problems for long-term efficacy. However, preliminary data from 3 phase 3 trials—ultIMMa-1, ultIMMa-2, and IMMvent—are promising.¹⁷

CONCLUSION

Advances in the understanding of psoriasis have led to new targeted therapies. Ongoing clinical trials have shown encouraging results for treating physical and psychological symptoms of psoriasis. The findings of these trials support the idea that therapies targeting IL-23, specifically its p19 subunit, are effective against psoriasis while sparing IL-12. Long-term data from open-label extension studies would help guide clinical recommendations regarding the safety profiles of these agents and determine their long-term utility.

Psoriasis is a chronic, autoimmune-mediated disease estimated to affect 2.8% of the US population.¹ The pathogenesis of psoriasis is thought to involve a complex process triggered by a combination of genetic and environmental factors that induce tumor necrosis factor (TNF) α secretion by keratinocytes, which in turn activates dendritic cells. Activated dendritic cells produce IL-23, leading to helper T cell (T_H17) differentiation.^2,3 T_H17 cells secrete IL-17A, which has been shown to promote psoriatic skin changes.⁴ Therefore, TNF-α, IL-23, and IL-17A have been recognized as key targets for psoriasis therapy.

The newest biologic agents targeting IL-17–mediated pathways include ixekizumab, brodalumab, and bimekizumab. Secukinumab, the first US Food and Drug Administration (FDA)–approved IL-17 inhibitor, has been available since 2015 and therefore is not included in this review. IL-23 inhibitors that are FDA approved or being evaluated in clinical trials include guselkumab, tildrakizumab, and risankizumab. In addition, certolizumab pegol, a TNF-α inhibitor, is being studied for use in psoriasis.

METHODS

We reviewed the published results of phase 3 clinical trials for ixekizumab, brodalumab, bimekizumab, guselkumab, tildrakizumab, risankizumab, and certolizumab pegol. We performed an English-language literature search (January 1, 2012 to October 15, 2017) of articles indexed for PubMed/MEDLINE using the following combinations of keywords: IL-23 and psoriasis; IL-17 and psoriasis; tumor necrosis factor and psoriasis; [drug name] and psoriasis. If data from phase 3 clinical trials were not yet available, data from phase 2 clinical trials were incorporated in our analysis. We also reviewed citations within articles to identify relevant sources.

RESULTS

Phase 3 clinical trial design, efficacy, and adverse events (AEs) for ixekizumab and brodalumab are reported in eTable 1^5-10 and for guselkumab and tildrakizumab in eTable 2.^11-14 Phase 2 clinical trial design, efficacy, and AEs are presented for risankizumab in eTable 3^15-18 and for certolizumab pegol in eTable 4.^17,19 No published clinical trial data were found for bimekizumab.

IL-17 Inhibitors

Ixekizumab
This recombinant, high-affinity IgG4κ antibody selectively binds and neutralizes IL-17A.^5,6 Three phase 3 clinical trials—UNCOVER-1, UNCOVER-2, and UNCOVER-3—evaluated ixekizumab for moderate to severe plaque psoriasis.⁷

The 3 UNCOVER trials were randomized, double-blind, phase 3 trials of 1296, 1224, and 1346 patients, respectively, assigned to a placebo group; a group treated with ixekizumab 80 mg every 2 weeks; and a group treated with ixekizumab 80 mg every 4 weeks. Both ixekizumab groups received a loading dose of 160 mg at week 0.^5,6 UNCOVER-2 and UNCOVER-3 also included a comparator group of patients on etanercept 50 mg.⁵ Co-primary end points included the percentage of patients reaching a psoriasis area and severity index (PASI) of 75 and with a static physician global assessment (PGA) score of clear (0) or almost clear (1) at week 12.^5,6

Ixekizumab achieved greater efficacy than placebo: 89.1%, 89.7%, and 87.3% of patients achieved PASI 75 in the every 2-week dosing group, and 82.6%, 77.5% and 84.2% achieved PASI 75 in the every 4-week dosing group in UNCOVER-1, UNCOVER-2, and UNCOVER-3, respectively (P<.001 for both treatment arms compared to placebo in all trials). The percentage of patients achieving a static PGA score of 0 or 1 also was higher in the ixekizumab groups in the 2-week and 4-week dosing groups in all UNCOVER trials—81.8% and 76.4% in UNCOVER-1, 83.2% and 72.9% in UNCOVER-2, and 80.5% and 75.4% in UNCOVER-3—compared to 3.2%, 2.4%, and 6.7% in the placebo groups of the 3 trials (P<.001 for both ixekizumab groups compared to placebo in all trials).^5,6 Ixekizumab also was found to be more effective than etanercept for both co-primary end points in both UNCOVER-2 and UNCOVER-3 (eTable 1).⁵

Safety data for all UNCOVER trials were pooled and reported.⁶ At week 12 the rate of at least 1 AE was 58.4% in patients on ixekizumab every 2 weeks and 58.8% in patients on ixekizumab every 4 weeks compared to 54.0% in the etanercept group in UNCOVER-2 and UNCOVER-3 and 46.8% in the placebo group. At week 12, 72 nonfatal serious AEs were reported: 12 in the placebo group, 14 in the etanercept group, 20 in the ixekizumab every 2 weeks group, and 26 in the ixekizumab every 4 weeks group.⁶

The most common AE across all groups was nasopharyngitis. Overall, infections were more frequent in patients treated with ixekizumab than in patients treated with placebo or etanercept. Specifically, oral candidiasis occurred more frequently in the ixekizumab groups, with a higher rate in the 2-week dosing group than in the 4-week dosing group.⁶ Two myocardial infarctions (MIs) occurred: 1 in the etanercept group and 1 in the placebo group.⁵

Brodalumab
This human monoclonal antibody binds to IL-17ra.^8,9 Three double-blind, placebo-controlled, phase 3 trials—AMAGINE-1, AMAGINE-2, and AMAGINE-3—evaluated its use for plaque psoriasis.¹⁰

In AMAGINE-1 (N=661), patients were randomized to receive brodalumab 140 mg or 210 mg (every 2 weeks for 12 weeks), or placebo.⁸ In AMAGINE-2 (N=1831) and AMAGINE-3 (N=1881), patients were randomized to receive brodalumab 140 mg or 210 mg (every 2 weeks for 12 weeks), ustekinumab 45 mg or 90 mg by weight (at weeks 0 and 4, then every 12 weeks thereafter), or placebo. In all trials, patients on brodalumab received a dose at week 0 and week 1. Co-primary end points were PASI 75 and a static PGA score of 0 or 1 at 12 weeks compared to placebo and to ustekinumab (in AMAGINE-2 and AMAGINE-3 only).⁸

At week 12, 83.3%, 86.3%, and 85.1% of patients on brodalumab 210 mg, and 60.3%, 66.6%, and 69.2% of patients on brodalumab 140 mg, achieved PASI 75 in AMAGINE-1, AMAGINE-2, and AMAGINE-3, respectively, compared to 2.7%, 8.1%, and 6.0% in the placebo groups (P<.001 between both brodalumab groups and placebo in all trials).⁸ Both brodalumab groups were noninferior but not significantly superior to ustekinumab, which achieved a PASI 75 of 70.0% in AMAGINE-2 and 69.3% in AMAGINE-3. The PASI 90 rate was higher, however, in both brodalumab groups compared to ustekinumab but significance was not reported (eTable 1).⁹ For both brodalumab groups, significantly more patients achieved a static PGA value of 0 or 1 compared to placebo (P<.001 across all trials). However, only the brodalumab 210-mg group achieved a significantly higher rate of static PGA 0 or 1 compared to ustekinumab in AMAGINE-2 and AMAGINE-3 (P<.001).⁹

After 12 weeks, the percentage of patients reporting at least 1 AE was 59.0%, 57.8%, and 56.8% in the brodalumab 210-mg group in AMAGINE-1, AMAGINE-2, and AMAGINE-3, respectively; 58.0%, 60.1%, and 52.6% in the brodalumab 140-mg group; and 51.0%, 53.4%, and 48.6% in the placebo group. Patients taking ustekinumab had an AE rate of 59.0% in AMAGINE-2 and 53.7% in AMAGINE-3. The most common AE was nasopharyngitis, followed by upper respiratory infection (URI) and headache across all trials.^8,9 Serious AEs were rare: 10 in AMAGINE-1, 31 in AMAGINE-2, and 24 in AMAGINE-3 across all groups. One death occurred from stroke in the brodalumab 210-mg group in AMAGINE-2.⁹

IL-23 Inhibitors

Guselkumab
This drug is a human IgG1κ antibody that binds to the p19 subunit of IL-23, thereby inhibiting IL-23 signaling.^11,12 Guselkumab was approved by the FDA in July 2017 for moderate to severe plaque psoriasis.¹³

VOYAGE 1 and VOYAGE 2 were phase 3, double-blind, placebo- and active comparator–controlled trials of 837 and 992 patients, respectively, randomized to receive adalimumab (80 mg at week 0 and 40 mg at week 1, then at 40 mg every 2 weeks thereafter), guselkumab 100 mg at weeks 0, 4, and 12, or placebo.¹¹ Co-primary end points for both trials were the percentage of patients reaching PASI 90 and an investigator global assessment (IGA) score of cleared (0) or minimal (1) at week 16.¹¹

By week 16 of both trials, PASI 90 values were statistically superior for guselkumab (VOYAGE 1, 73.3%; VOYAGE 2, 70.0%) compared to adalimumab (VOYAGE 1, 49.7%; VOYAGE 2, 46.8%) and placebo (VOYAGE 1, 2.9%; VOYAGE 2, 2.4%)(P<.001). Moreover, patients on guselkumab achieved a higher rate of IGA values of 0 and 1 at week 12 (85.1% in VOYAGE 1 and 84.1% in VOYAGE 2) than patients on adalimumab (65.9% in VOYAGE 1 and 67.7% in VOYAGE 2) and placebo (6.9% in VOYAGE 1 and 8.5% in VOYAGE 2)(P<.001).^11,12

The frequency of AEs was comparable across all groups in both trials.^11,12 During the 16-week treatment period, 51.7% and 47.6% of the guselkumab groups in VOYAGE 1 and VOYAGE 2, respectively; 51.1% and 48.4% of the adalimumab groups; and 49.4% and 44.8% of the placebo groups reported at least 1 AE. The most common AEs in all groups were nasopharyngitis, headache, and URI.^11,12

Serious AEs also occurred at similar rates: 2.4% and 1.6% in the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively; 2.4% and 1.8% in the adalimumab group; and 1.7% and 1.2% in the placebo group.^11,12 One case of malignancy occurred in the VOYAGE 1 trial: basal cell carcinoma in the guselkumab group.¹¹ Three major cardiovascular events occurred across both trials: 1 MI in the guselkumab group in each trial and 1 MI in the adalimumab group in VOYAGE 1.^11,12

Tildrakizumab
A high-affinity, humanized IgG1κ antibody, tildrakizumab targets the p19 subunit of IL-23. As of February 2018, 2 double-blind, randomized phase 3 trials have studied tildrakizumab with published results: reSURFACE 1 and reSURFACE 2.¹⁴

reSURFACE 1 (N=772) and reSURFACE 2 (N=1090) randomized patients to receive tildrakizumab 100 or 200 mg (at weeks 0 and 4), etanercept 50 mg (twice weekly) for 12 weeks (reSURFACE 2 only), or placebo. Co-primary end points were the percentage of patients achieving PASI 75 and the percentage of patients achieving a PGA score of 0 or 1 at week 12.¹⁴

In reSURFACE 1, significantly more patients receiving tildrakizumab attained PASI 75 at week 12 compared to placebo: 200 mg, 62.0%; 100 mg, 64.0%; and placebo, 6.0% (P<.001 for tildrakizumab groups compared to placebo). Moreover, significantly proportionally more patients received a PGA score of 0 or 1 compared to placebo: 100 mg, 59%; 200 mg, 58.0%; placebo, 7.0% (P<.001 for both tildrakizumab groups compared to placebo).¹⁴

In reSURFACE 2, significantly more patients receiving tildrakizumab achieved PASI 75 compared to etanercept and placebo at week 12: 200 mg, 66.0%; 100mg, 61.0%; etanercept, 48.0%; placebo, 6.0% (P<.001 for both tildrakizumab groups compared to placebo; P<.05 for both tildrakizumab groups compared to etanercept). Additionally, significantly more patients in the tildrakizumab groups experienced a PGA score of 0 or 1 at week 12 compared to placebo: 200 mg, 59%; 100 mg, 55.0%; placebo, 5% (P<.001 for both tildrakizumab groups compared to placebo).¹⁴

Adverse events were reported at a similar rate across all groups. For reSURFACE 1 and reSURFACE 2, at least 1 AE by week 12 was reported by 42.2% and 45.2% of patients in the 200-mg group; 47.2% and 45.9% in the 100-mg group; and 48.1% and 55.1% in the placebo groups.¹⁴The most common AEs were nasopharyngitis, URI (reSURFACE 1), and erythema at the injection site (reSURFACE 2). One case of serious infection was reported in each of the tildrakizumab groups: 1 case of drug-related hypersensitivity reaction in the 200-mg group, and 1 major cardiovascular event in the 100-mg group of reSURFACE 1. There was 1 serious AE in reSURFACE 2 that led to death in which the cause was undetermined.¹⁴

Risankizumab
This humanized IgG1 antibody binds the p19 unit of IL-23.^15,16 The drug is undergoing 3 phase 3 trials—ultIMMa-1, ultIMMa-2, and IMMvent—for which only preliminary data have been published and are reported here.^16,17 There is 1 phase 2 randomized, dose-ranging trial with published data.¹⁵

ultIMMa-1 and ultIMMa-2 comprised 506 and 491 patients, respectively, randomized to receive risankizumab (150 mg at weeks 0, 4, and 16), ustekinumab (45 mg or 90 mg, by weight, at weeks 0, 4, and 16), or placebo. Co-primary end points were PASI 90 and a PGA score of 0 or 1 at week 16.¹⁷

In ultIMMa-1 and ultIMMa-2, 75.0% and 75.0% of patients on risankizumab 150 mg achieved PASI 90 compared to 42.0% and 48.0% on ustekinumab and 5.0% and 2.0% on placebo at 16 weeks (P<.001 between both placebo and ustekinumab in both trials).¹⁷ In both trials, patients receiving risankizumab achieved higher rates of a static PGA score of 0 or 1 (88.0% and 84.0%) compared to ustekinumab (63.0% and 62.0%) and placebo (8.0% and 5.0%) at 16 weeks (P<.001 for both trials).¹⁸

At week 16, 2.0% of patients on risankizumab reported a serious AE in both trials, compared to 8.0% and 3.0% of patients on ustekinumab and 3.0% and 1.0% on placebo. No new safety concerns were noted.¹⁷

In the phase 3 IMMvent trial, 605 patients were randomized to receive risankizumab (150 mg at weeks 0, 4, and 16) or adalimumab (80 mg at week 0, 40 mg at week 1, then 40 mg every 2 weeks). Co-primary end points were PASI 90 and a static PGA score of 0 or 1 at week 16.¹⁷

In IMMvent, risankizumab was significantly more effective than adalimumab for PASI 75 (risankizumab, 72.0%; adalimumab, 47.0%) and a static PGA score of 0 or 1 (risankizumab 84.0%; adalimumab, 60.0%) (P<.001 risankizumab compared to adalimumab for both end points).¹⁷

At week 16, serious AEs were reported in 3.0% of patients on risankizumab and 3.0% of patients on adalimumab. One patient receiving risankizumab died of an acute MI during the treatment phase.¹⁷

TNF Inhibitor

Certolizumab Pegol
Certolizumab pegol is a human PEGylated anti-TNF agent. In vitro studies have shown that certolizumab binds to soluble and membrane-bound TNF.¹⁹ Unlike other TNF inhibitors, certolizumab pegol is a Fab‘ portion of anti-TNF conjugated to a molecule of polyethylene glycol.¹⁹ The drug is approved in the United States for treating psoriatic arthritis, Crohn disease, and rheumatoid arthritis; its potential for treating psoriasis has been confirmed. Results of 1 phase 2 trial have been published¹⁹; data from 3 phase 3 trials are forthcoming.

This randomized, placebo-controlled, double-blind phase 2 study comprised 176 patients who received certolizumab 200 mg, certolizumab 400 mg, or placebo. The dosing schedule was 400 mg at week 0, followed by either 200 or 400 mg every other week until week 10. Co-primary end points were PASI 75 and a PGA score of 0 or 1 at week 12.¹⁹

Certolizumab was significantly more effective than placebo at week 12: 74.6% of the 200-mg group and 82.8% of the 400-mg group achieved PASI 75 compared to 6.8% of the placebo group (P<.001). Certolizumab also performed better for the PGA score: 52.5% and 72.4% of patients attained a score of 0 or 1 in the 200-mg and 400-mg groups compared to 1.7% in the placebo group.¹⁹

Adverse events were reported equally across all groups: 72% of patients in the 200-mg group, 70% in the 400-mg group, and 71% in the placebo group reported at least 1 AE, most commonly nasopharyngitis, headache, and pruritis.¹⁹

COMMENT

With the development of new insights into the pathogenesis of psoriasis, therapies that are targeted toward key cytokines may contribute to improved management of the disease. The results of these clinical trials demonstrate numerous promising options for psoriatic patients.

IL-17 Inhibitors Ixekizumab and Brodalumab

When comparing these 2 biologics, it is important to consider that these studies were not performed head to head, thereby inhibiting direct comparisons. Moreover, dosage ranges of the investigative drugs were not identical, which also makes comparisons challenging. However, when looking at the highest dosages of ixekizumab and brodalumab, results indicate that ixekizumab may be slightly more effective than brodalumab based on the percentage of patients who achieved a PASI 75 and a static PGA score of 0 or 1 (eTable 1).

Phase 3 trials have shown ixekizumab to maintain efficacy over 60 weeks of treatment.⁶ Ixekizumab also has been shown to alleviate other symptoms of psoriasis, such as itching, pain, and nail involvement.^20,21 Furthermore, ixekizumab appears to be equally effective in patients with or without prior exposure to biologics²²; therefore, ixekizumab may benefit patients who have not experienced success with other biologics.

Across the UNCOVER trials, 11 cases of inflammatory bowel disease were reported in patients receiving ixekizumab (ulcerative colitis in 7; Crohn disease in 4)⁶; it appears that at least 3 of these cases were new diagnoses. In light of a study suggesting that IL-17A might have a protective function in the intestine,²³ these findings may have important clinical implications and require follow-up studies.

Brodalumab also has been shown to maintain efficacy and acceptable safety for as long as 120 weeks.²⁴ In the extension period of the AMAGINE-1 trial, patients who experienced a return of disease during a withdrawal period recaptured static PGA success with re-treatment for 12 weeks (re-treatment was successful in 97% of those given a dosage of 210 mg and in 84% of those given 140 mg).⁸

Furthermore, phase 2 trials also have shown that brodalumab is effective in patients with a history of biologic use.²⁵ Across all AMAGINE trials, only 1 case of Crohn disease was reported in a patient taking brodalumab.⁹ There are concerns about depression, despite data from AMAGINE-1 stating patients on brodalumab actually had greater improvements in Hospital Anxiety and Depression Scale scores after 12 weeks of treatment (P<.001) for both brodalumab 140 mg and 210 mg compared to placebo.⁸ Regardless, brodalumab has a black-box warning for suicidal ideation and behavior, and availability is restricted through a Risk Evaluation and Mitigation Strategy (REMS) program.²⁶

Bimekizumab

Although no phase 2 or phase 3 clinical trial data have been published for bimekizumab (phase 2 trials are underway), it has been shown in a phase 1 trial to be effective for psoriasis. Bimekizumab also is unique; it is the first dual inhibitor of IL-17A and IL-17F.¹⁸

IL-23 Inhibitors Guselkumab, Tildrakizumab, and Risankizumab

Making comparisons among the IL-23 inhibitors also is difficult; studies were not head-to-head comparison trials, and the VOYAGE and reSURFACE studies used different time points for primary end points. Furthermore, only phase 2 trial data are available for risankizumab. Despite these limitations, results of these trials suggest that guselkumab and risankizumab may be slightly more efficacious than tildrakizumab. However, future studies, including head-to-head studies, would ultimately provide further information on how these agents compare.

Guselkumab was shown to remain efficacious at 48 weeks, though patients on maintenance dosing had better results than those who were re-treated.¹² Moreover, guselkumab was found to be effective in hard-to-treat areas, such as the scalp,¹¹ and in patients who did not respond to adalimumab. Guselkumab may therefore benefit patients who have experienced limited clinical improvement on other biologics.¹²

Tildrakizumab was shown to improve PASI 75 and PGA scores through week 28 of treatment. Moreover, a higher percentage of patients taking tildrakizumab scored 0 or 1 on the dermatology life quality index, suggesting that the drug improves quality of life.¹⁴ No specific safety concerns arose in either reSURFACE trial; however, long-term studies are needed for further evaluation.

Risankizumab appears to be a promising new therapy based on phase 2 trial results. Improvements also were seen in dermatology life quality index scores, scalp and fingernail symptoms, and palmoplantar psoriasis.¹⁵ Of note, neutralizing antidrug antibodies were found in 3 patients during this study,¹⁵ which may present potential problems for long-term efficacy. However, preliminary data from 3 phase 3 trials—ultIMMa-1, ultIMMa-2, and IMMvent—are promising.¹⁷

CONCLUSION

Advances in the understanding of psoriasis have led to new targeted therapies. Ongoing clinical trials have shown encouraging results for treating physical and psychological symptoms of psoriasis. The findings of these trials support the idea that therapies targeting IL-23, specifically its p19 subunit, are effective against psoriasis while sparing IL-12. Long-term data from open-label extension studies would help guide clinical recommendations regarding the safety profiles of these agents and determine their long-term utility.

We are now in the midst of a second revolution in the care of patients with psoriasis. Since biologic therapies for psoriasis were first introduced in 2003 with the approval of alefacept, the psoriasis treatment paradigm has shifted and continues to evolve. Interestingly, the first 2 biologic agents approved for psoriasis, alefacept and efalizumab, are no longer on the market in the United States.

We certainly have made progress since the early days of psoriasis treatment. Over the years, we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this knowledge, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes, and metabolic syndrome. It is therefore the role of the dermatologist to serve as the gatekeeper for these individuals and help to screen for comorbidities of psoriasis, as well as provide appropriate counseling and referral.

Additionally, psoriasis therapies have been approved for new segments of the population. In 2016, the US Food and Drug Administration approved a supplemental biologics license application for use of etanercept in children aged 4 years and older with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Last year, the US Food and Drug Administration also approved an expanded indication for ustekinumab for the treatment of adolescents (aged 12 years and older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Another treatment development included the approval of apremilast as a new oral therapeutic option for psoriasis patients. This agent, which is approved for both psoriasis and psoriatic arthritis, has become an attractive therapy for many patients who are new to systemic treatment. Many patients prefer an oral medication and like the fact that no routine laboratory monitoring is required. Often patients leave their dermatologist’s office with 2- to 4-weeks’ worth of samples and can begin their course immediately.

A treat-to-target approach also has been established for psoriasis. In 2016, the Medical Board of the National Psoriasis Foundation¹ created specific treatment goals in order to make achieving clear or almost clear skin the new standard of care. A consensus-building study conducted among 25 psoriasis experts revealed that the most preferred instrument for evaluating disease severity was body surface area (BSA). The time at which most participants preferred to evaluate patient response after starting a new psoriasis therapy was 3 months, and an acceptable response at this timepoint was considered to be either BSA involvement of 3% or less or improvement in BSA involvement of 75% or more compared to baseline. The target response at 3 months after starting treatment was BSA involvement of 1% or less. During the maintenance period, evaluation every 6 months was most preferred, and the target response at every 6-month follow-up evaluation was BSA involvement of 1% or less.¹ These standards enable and encourage both clinicians and patients to maximize their treatment success.

Over the past several years, a variety of new biologic agents also have come to the market, including 3 IL-17 inhibitors (ixekizumab, brodalumab, and secukinumab) and one IL-23 inhibitor (guselkumab). All of these agents have added new options to the armamentarium for psoriasis treatment and are highly effective. Overall, the clinical improvement and safety profiles for these agents are promising, and these new drugs may be equal to or more efficacious than the currently available therapeutic options for psoriasis treatment; however, long-term studies are still needed to further establish the safety and efficacy profiles for these biologic agents. Even more novel therapies are in development, as will be discussed by Lee et al² in this issue.

It is the purpose of this special issue to review new standards of care for psoriasis in 2018. We hope that you find this issue enjoyable and informative.

We are now in the midst of a second revolution in the care of patients with psoriasis. Since biologic therapies for psoriasis were first introduced in 2003 with the approval of alefacept, the psoriasis treatment paradigm has shifted and continues to evolve. Interestingly, the first 2 biologic agents approved for psoriasis, alefacept and efalizumab, are no longer on the market in the United States.

We certainly have made progress since the early days of psoriasis treatment. Over the years, we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this knowledge, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes, and metabolic syndrome. It is therefore the role of the dermatologist to serve as the gatekeeper for these individuals and help to screen for comorbidities of psoriasis, as well as provide appropriate counseling and referral.

Additionally, psoriasis therapies have been approved for new segments of the population. In 2016, the US Food and Drug Administration approved a supplemental biologics license application for use of etanercept in children aged 4 years and older with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Last year, the US Food and Drug Administration also approved an expanded indication for ustekinumab for the treatment of adolescents (aged 12 years and older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Another treatment development included the approval of apremilast as a new oral therapeutic option for psoriasis patients. This agent, which is approved for both psoriasis and psoriatic arthritis, has become an attractive therapy for many patients who are new to systemic treatment. Many patients prefer an oral medication and like the fact that no routine laboratory monitoring is required. Often patients leave their dermatologist’s office with 2- to 4-weeks’ worth of samples and can begin their course immediately.

A treat-to-target approach also has been established for psoriasis. In 2016, the Medical Board of the National Psoriasis Foundation¹ created specific treatment goals in order to make achieving clear or almost clear skin the new standard of care. A consensus-building study conducted among 25 psoriasis experts revealed that the most preferred instrument for evaluating disease severity was body surface area (BSA). The time at which most participants preferred to evaluate patient response after starting a new psoriasis therapy was 3 months, and an acceptable response at this timepoint was considered to be either BSA involvement of 3% or less or improvement in BSA involvement of 75% or more compared to baseline. The target response at 3 months after starting treatment was BSA involvement of 1% or less. During the maintenance period, evaluation every 6 months was most preferred, and the target response at every 6-month follow-up evaluation was BSA involvement of 1% or less.¹ These standards enable and encourage both clinicians and patients to maximize their treatment success.

Over the past several years, a variety of new biologic agents also have come to the market, including 3 IL-17 inhibitors (ixekizumab, brodalumab, and secukinumab) and one IL-23 inhibitor (guselkumab). All of these agents have added new options to the armamentarium for psoriasis treatment and are highly effective. Overall, the clinical improvement and safety profiles for these agents are promising, and these new drugs may be equal to or more efficacious than the currently available therapeutic options for psoriasis treatment; however, long-term studies are still needed to further establish the safety and efficacy profiles for these biologic agents. Even more novel therapies are in development, as will be discussed by Lee et al² in this issue.

It is the purpose of this special issue to review new standards of care for psoriasis in 2018. We hope that you find this issue enjoyable and informative.

We are now in the midst of a second revolution in the care of patients with psoriasis. Since biologic therapies for psoriasis were first introduced in 2003 with the approval of alefacept, the psoriasis treatment paradigm has shifted and continues to evolve. Interestingly, the first 2 biologic agents approved for psoriasis, alefacept and efalizumab, are no longer on the market in the United States.

We certainly have made progress since the early days of psoriasis treatment. Over the years, we have come to understand the nature of psoriasis as a systemic inflammatory condition rather than as simply a skin disease. With this knowledge, we have continued to identify systemic comorbidities associated with psoriasis, including cardiovascular risk, diabetes, and metabolic syndrome. It is therefore the role of the dermatologist to serve as the gatekeeper for these individuals and help to screen for comorbidities of psoriasis, as well as provide appropriate counseling and referral.

Additionally, psoriasis therapies have been approved for new segments of the population. In 2016, the US Food and Drug Administration approved a supplemental biologics license application for use of etanercept in children aged 4 years and older with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Last year, the US Food and Drug Administration also approved an expanded indication for ustekinumab for the treatment of adolescents (aged 12 years and older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Another treatment development included the approval of apremilast as a new oral therapeutic option for psoriasis patients. This agent, which is approved for both psoriasis and psoriatic arthritis, has become an attractive therapy for many patients who are new to systemic treatment. Many patients prefer an oral medication and like the fact that no routine laboratory monitoring is required. Often patients leave their dermatologist’s office with 2- to 4-weeks’ worth of samples and can begin their course immediately.

A treat-to-target approach also has been established for psoriasis. In 2016, the Medical Board of the National Psoriasis Foundation¹ created specific treatment goals in order to make achieving clear or almost clear skin the new standard of care. A consensus-building study conducted among 25 psoriasis experts revealed that the most preferred instrument for evaluating disease severity was body surface area (BSA). The time at which most participants preferred to evaluate patient response after starting a new psoriasis therapy was 3 months, and an acceptable response at this timepoint was considered to be either BSA involvement of 3% or less or improvement in BSA involvement of 75% or more compared to baseline. The target response at 3 months after starting treatment was BSA involvement of 1% or less. During the maintenance period, evaluation every 6 months was most preferred, and the target response at every 6-month follow-up evaluation was BSA involvement of 1% or less.¹ These standards enable and encourage both clinicians and patients to maximize their treatment success.

Over the past several years, a variety of new biologic agents also have come to the market, including 3 IL-17 inhibitors (ixekizumab, brodalumab, and secukinumab) and one IL-23 inhibitor (guselkumab). All of these agents have added new options to the armamentarium for psoriasis treatment and are highly effective. Overall, the clinical improvement and safety profiles for these agents are promising, and these new drugs may be equal to or more efficacious than the currently available therapeutic options for psoriasis treatment; however, long-term studies are still needed to further establish the safety and efficacy profiles for these biologic agents. Even more novel therapies are in development, as will be discussed by Lee et al² in this issue.

It is the purpose of this special issue to review new standards of care for psoriasis in 2018. We hope that you find this issue enjoyable and informative.

Dysregulated immune responses including elevations in the inflammatory cytokines tumor necrosis factor (TNF),^1-4 IL- 1 β ,³ and IL-12/23^5-7 have been identified in hidradenitis suppurativa (HS). Targeted biologic agents may offer an opportunity to intervene in specific aberrant inflammatory pathways to effectively treat HS while minimizing a dverse effects (AEs). There is growing evidence, however, that treatment of HS with a single biologic agent is not effective in all patients.^6,8-17 The TNF antagonist adalimumab has been shown to achieve clinical response in approximately 50% of patients (N = 633). ¹⁸In smaller and uncontrolled studies, clinical response was achieved in 70% (7/10) of patients treated with the IL-1 antagonist anakinra¹⁶ and 47 % (8/17) of patients treated with the IL-12/23 antagonist ustekinumab¹⁹ ; however, larger rigorous studies are needed. There is an urgent need for more effective therapeutic strategies for this condition.²⁰

The administration of concurrent biologics may offer the potential for improved disease control through synergistic targeting of multiple inflammatory pathways, particularly for severe and recalcitrant HS. This approach may be effective given insights from mechanistic studies suggesting the involvement of multiple inflammatory pathways in the disease pathogenesis.^3,21 Concurrent anticytokine biologics have been used safely and effectively in other inflammatory diseases; for example, combination therapy with TNF and IL-12/23 antagonists have resulted in near-complete to complete resolution of severe psoriatic skin and joint disease without AEs.^22-24

An increased risk for infection without increased efficacy associated with the use of concurrent anticytokine biologics for treatment of rheumatoid arthritis (RA) has raised concerns about the safety of this therapeutic approach. In a study of concurrent etanercept and anakinra therapy for RA (N=244), the combined therapy was not more efficacious than etanercept alone (American College of Rheumatology 50% response at week 24: etanercept 25 mg twice weekly, 41%; etanercept 25 mg twice weekly plus anakinra 100 mg once daily, 31%; etanercept 25 mg once weekly plus anakinra 100 mg once daily, 39% [P=.914]).²⁵ Combination therapy also was associated with a higher overall incidence of serious AEs, serious infections requiring antibiotics or hospitalizations, and serious infections leading to study withdrawal. Reported infections included pneumonia, cellulitis, herpes zoster, pneumonitis, and pyelonephritis, but no opportunistic infections or tuberculosis were reported. A single case of lymphoma was reported in the full-dose etanercept plus anakinra group; however, the association with therapy is unclear, as RA itself is associated with an increased risk of malignancy.²⁵

Although these results are notable, caution must be exercised in extrapolating safety and efficacy data for treatment with concurrent biologics from the RA literature for management of HS for several reasons. First, RA is an autoimmune disease that is associated with an increased risk for genitourinary and bronchopulmonary infections and septic arthritis, even in the absence of treatment with steroids and immunomodulatory drugs.^26,27 Increased risk for development of lymphoma, lung cancer, and nonmelanoma skin cancer also has been associated with RA.^28,29 The exact etiology of this increased risk is unknown, but it is thought to relate to immunologic disturbances and chronic systemic inflammation associated with RA.²⁹ Furthermore, RA disease characteristics and comorbidities that may contribute to an increased risk for infection and malignancy include advanced age as well as a history of leukopenia, chronic lung disease, diabetes mellitus, alcoholism, and/or smoking.³⁰ Infection and malignancy risk in RA also may be compounded by immunomodulatory therapies.^31,32

Conversely, although microbes are believed to play an important role in HS initiation and progression, HS is neither considered an infectious disease nor associated with an increased risk for infection.³³ Increased malignancy risk generally is not reported with HS, and systematic therapeutic trials of biologic therapies for HS have been notable for an absence of infectious or malignant AEs compared to placebo.^{12,14,16,18,19} From a mechanistic standpoint, data suggest that HS may be fundamentally distinct from RA and other autoimmune diseases; therefore, it may not be appropriate to extrapolate safety data from the latter to guide therapeutic strategies for the former.

The concept that different inflammatory diseases harbor distinct risks for comorbidities and AEs associated with medications is further supported by data from patients with PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne), a monogenic autoinflammatory disease characterized by inflammasome activation and subsequent increased signaling via IL-1.³⁴Patients with PAPA syndrome often require a combination therapeutic regimen including simultaneous antibiotics, systemic retinoids and steroids, disease-modifying antirheumatic drugs, and more than 1 concurrent anticytokine biologic to manage their condition. Despite management with multiple immunosuppressants and immunomodulators, patients with PAPA syndrome rarely develop localized or systemic infections, supporting our hypothesis that different systemic immune-mediated disorders may render a distinct susceptibility to infectious complications. Clinically, patients with PAPA syndrome can have cutaneous disease manifestations consistent with HS, suggesting the possibility of shared underlying inflammatory mechanisms due at least partially to inflammasome activation. This clinical observation may help explain why concurrent anticytokine biologic therapies in conjunction with combinations of steroids and other immunomodulators may be safe and effective in HS patients.

We have safely and effectively treated 2 patients with severe HS with extended courses of concurrent TNF and IL-1 antagonists. Both patients had previously failed treatment with multiple therapeutic interventions, including topical and systemic antibiotics, disease-modifying antirheumatic drugs, hormonal therapy, biologic monotherapy with several targeted agents, and wide local excision. In the setting of concurrent certolizumab plus anakinra in the first patient and adalimumab plus anakinra in the second, both patients reported reduced drainage, pain, and number of disease flares. Both patients also were maintained on extended treatment courses (11 months and 2 years, respectively) without evidence of infection or malignancy.

Concurrent biologics may be safe and effective in managing recalcitrant HS; however, large prospective studies are needed to confirm these anecdotal findings. As our understanding of HS pathogenesis expands, novel and more effective therapeutic options will be developed. Until then, concurrent biologics may be a potential option for patients with severe recalcitrant HS.

Dysregulated immune responses including elevations in the inflammatory cytokines tumor necrosis factor (TNF),^1-4 IL- 1 β ,³ and IL-12/23^5-7 have been identified in hidradenitis suppurativa (HS). Targeted biologic agents may offer an opportunity to intervene in specific aberrant inflammatory pathways to effectively treat HS while minimizing a dverse effects (AEs). There is growing evidence, however, that treatment of HS with a single biologic agent is not effective in all patients.^6,8-17 The TNF antagonist adalimumab has been shown to achieve clinical response in approximately 50% of patients (N = 633). ¹⁸In smaller and uncontrolled studies, clinical response was achieved in 70% (7/10) of patients treated with the IL-1 antagonist anakinra¹⁶ and 47 % (8/17) of patients treated with the IL-12/23 antagonist ustekinumab¹⁹ ; however, larger rigorous studies are needed. There is an urgent need for more effective therapeutic strategies for this condition.²⁰

The administration of concurrent biologics may offer the potential for improved disease control through synergistic targeting of multiple inflammatory pathways, particularly for severe and recalcitrant HS. This approach may be effective given insights from mechanistic studies suggesting the involvement of multiple inflammatory pathways in the disease pathogenesis.^3,21 Concurrent anticytokine biologics have been used safely and effectively in other inflammatory diseases; for example, combination therapy with TNF and IL-12/23 antagonists have resulted in near-complete to complete resolution of severe psoriatic skin and joint disease without AEs.^22-24

An increased risk for infection without increased efficacy associated with the use of concurrent anticytokine biologics for treatment of rheumatoid arthritis (RA) has raised concerns about the safety of this therapeutic approach. In a study of concurrent etanercept and anakinra therapy for RA (N=244), the combined therapy was not more efficacious than etanercept alone (American College of Rheumatology 50% response at week 24: etanercept 25 mg twice weekly, 41%; etanercept 25 mg twice weekly plus anakinra 100 mg once daily, 31%; etanercept 25 mg once weekly plus anakinra 100 mg once daily, 39% [P=.914]).²⁵ Combination therapy also was associated with a higher overall incidence of serious AEs, serious infections requiring antibiotics or hospitalizations, and serious infections leading to study withdrawal. Reported infections included pneumonia, cellulitis, herpes zoster, pneumonitis, and pyelonephritis, but no opportunistic infections or tuberculosis were reported. A single case of lymphoma was reported in the full-dose etanercept plus anakinra group; however, the association with therapy is unclear, as RA itself is associated with an increased risk of malignancy.²⁵

Although these results are notable, caution must be exercised in extrapolating safety and efficacy data for treatment with concurrent biologics from the RA literature for management of HS for several reasons. First, RA is an autoimmune disease that is associated with an increased risk for genitourinary and bronchopulmonary infections and septic arthritis, even in the absence of treatment with steroids and immunomodulatory drugs.^26,27 Increased risk for development of lymphoma, lung cancer, and nonmelanoma skin cancer also has been associated with RA.^28,29 The exact etiology of this increased risk is unknown, but it is thought to relate to immunologic disturbances and chronic systemic inflammation associated with RA.²⁹ Furthermore, RA disease characteristics and comorbidities that may contribute to an increased risk for infection and malignancy include advanced age as well as a history of leukopenia, chronic lung disease, diabetes mellitus, alcoholism, and/or smoking.³⁰ Infection and malignancy risk in RA also may be compounded by immunomodulatory therapies.^31,32

Conversely, although microbes are believed to play an important role in HS initiation and progression, HS is neither considered an infectious disease nor associated with an increased risk for infection.³³ Increased malignancy risk generally is not reported with HS, and systematic therapeutic trials of biologic therapies for HS have been notable for an absence of infectious or malignant AEs compared to placebo.^{12,14,16,18,19} From a mechanistic standpoint, data suggest that HS may be fundamentally distinct from RA and other autoimmune diseases; therefore, it may not be appropriate to extrapolate safety data from the latter to guide therapeutic strategies for the former.

The concept that different inflammatory diseases harbor distinct risks for comorbidities and AEs associated with medications is further supported by data from patients with PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne), a monogenic autoinflammatory disease characterized by inflammasome activation and subsequent increased signaling via IL-1.³⁴Patients with PAPA syndrome often require a combination therapeutic regimen including simultaneous antibiotics, systemic retinoids and steroids, disease-modifying antirheumatic drugs, and more than 1 concurrent anticytokine biologic to manage their condition. Despite management with multiple immunosuppressants and immunomodulators, patients with PAPA syndrome rarely develop localized or systemic infections, supporting our hypothesis that different systemic immune-mediated disorders may render a distinct susceptibility to infectious complications. Clinically, patients with PAPA syndrome can have cutaneous disease manifestations consistent with HS, suggesting the possibility of shared underlying inflammatory mechanisms due at least partially to inflammasome activation. This clinical observation may help explain why concurrent anticytokine biologic therapies in conjunction with combinations of steroids and other immunomodulators may be safe and effective in HS patients.

We have safely and effectively treated 2 patients with severe HS with extended courses of concurrent TNF and IL-1 antagonists. Both patients had previously failed treatment with multiple therapeutic interventions, including topical and systemic antibiotics, disease-modifying antirheumatic drugs, hormonal therapy, biologic monotherapy with several targeted agents, and wide local excision. In the setting of concurrent certolizumab plus anakinra in the first patient and adalimumab plus anakinra in the second, both patients reported reduced drainage, pain, and number of disease flares. Both patients also were maintained on extended treatment courses (11 months and 2 years, respectively) without evidence of infection or malignancy.

Concurrent biologics may be safe and effective in managing recalcitrant HS; however, large prospective studies are needed to confirm these anecdotal findings. As our understanding of HS pathogenesis expands, novel and more effective therapeutic options will be developed. Until then, concurrent biologics may be a potential option for patients with severe recalcitrant HS.

Dysregulated immune responses including elevations in the inflammatory cytokines tumor necrosis factor (TNF),^1-4 IL- 1 β ,³ and IL-12/23^5-7 have been identified in hidradenitis suppurativa (HS). Targeted biologic agents may offer an opportunity to intervene in specific aberrant inflammatory pathways to effectively treat HS while minimizing a dverse effects (AEs). There is growing evidence, however, that treatment of HS with a single biologic agent is not effective in all patients.^6,8-17 The TNF antagonist adalimumab has been shown to achieve clinical response in approximately 50% of patients (N = 633). ¹⁸In smaller and uncontrolled studies, clinical response was achieved in 70% (7/10) of patients treated with the IL-1 antagonist anakinra¹⁶ and 47 % (8/17) of patients treated with the IL-12/23 antagonist ustekinumab¹⁹ ; however, larger rigorous studies are needed. There is an urgent need for more effective therapeutic strategies for this condition.²⁰

The administration of concurrent biologics may offer the potential for improved disease control through synergistic targeting of multiple inflammatory pathways, particularly for severe and recalcitrant HS. This approach may be effective given insights from mechanistic studies suggesting the involvement of multiple inflammatory pathways in the disease pathogenesis.^3,21 Concurrent anticytokine biologics have been used safely and effectively in other inflammatory diseases; for example, combination therapy with TNF and IL-12/23 antagonists have resulted in near-complete to complete resolution of severe psoriatic skin and joint disease without AEs.^22-24

An increased risk for infection without increased efficacy associated with the use of concurrent anticytokine biologics for treatment of rheumatoid arthritis (RA) has raised concerns about the safety of this therapeutic approach. In a study of concurrent etanercept and anakinra therapy for RA (N=244), the combined therapy was not more efficacious than etanercept alone (American College of Rheumatology 50% response at week 24: etanercept 25 mg twice weekly, 41%; etanercept 25 mg twice weekly plus anakinra 100 mg once daily, 31%; etanercept 25 mg once weekly plus anakinra 100 mg once daily, 39% [P=.914]).²⁵ Combination therapy also was associated with a higher overall incidence of serious AEs, serious infections requiring antibiotics or hospitalizations, and serious infections leading to study withdrawal. Reported infections included pneumonia, cellulitis, herpes zoster, pneumonitis, and pyelonephritis, but no opportunistic infections or tuberculosis were reported. A single case of lymphoma was reported in the full-dose etanercept plus anakinra group; however, the association with therapy is unclear, as RA itself is associated with an increased risk of malignancy.²⁵

Although these results are notable, caution must be exercised in extrapolating safety and efficacy data for treatment with concurrent biologics from the RA literature for management of HS for several reasons. First, RA is an autoimmune disease that is associated with an increased risk for genitourinary and bronchopulmonary infections and septic arthritis, even in the absence of treatment with steroids and immunomodulatory drugs.^26,27 Increased risk for development of lymphoma, lung cancer, and nonmelanoma skin cancer also has been associated with RA.^28,29 The exact etiology of this increased risk is unknown, but it is thought to relate to immunologic disturbances and chronic systemic inflammation associated with RA.²⁹ Furthermore, RA disease characteristics and comorbidities that may contribute to an increased risk for infection and malignancy include advanced age as well as a history of leukopenia, chronic lung disease, diabetes mellitus, alcoholism, and/or smoking.³⁰ Infection and malignancy risk in RA also may be compounded by immunomodulatory therapies.^31,32

Conversely, although microbes are believed to play an important role in HS initiation and progression, HS is neither considered an infectious disease nor associated with an increased risk for infection.³³ Increased malignancy risk generally is not reported with HS, and systematic therapeutic trials of biologic therapies for HS have been notable for an absence of infectious or malignant AEs compared to placebo.^{12,14,16,18,19} From a mechanistic standpoint, data suggest that HS may be fundamentally distinct from RA and other autoimmune diseases; therefore, it may not be appropriate to extrapolate safety data from the latter to guide therapeutic strategies for the former.

The concept that different inflammatory diseases harbor distinct risks for comorbidities and AEs associated with medications is further supported by data from patients with PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum, and acne), a monogenic autoinflammatory disease characterized by inflammasome activation and subsequent increased signaling via IL-1.³⁴Patients with PAPA syndrome often require a combination therapeutic regimen including simultaneous antibiotics, systemic retinoids and steroids, disease-modifying antirheumatic drugs, and more than 1 concurrent anticytokine biologic to manage their condition. Despite management with multiple immunosuppressants and immunomodulators, patients with PAPA syndrome rarely develop localized or systemic infections, supporting our hypothesis that different systemic immune-mediated disorders may render a distinct susceptibility to infectious complications. Clinically, patients with PAPA syndrome can have cutaneous disease manifestations consistent with HS, suggesting the possibility of shared underlying inflammatory mechanisms due at least partially to inflammasome activation. This clinical observation may help explain why concurrent anticytokine biologic therapies in conjunction with combinations of steroids and other immunomodulators may be safe and effective in HS patients.

We have safely and effectively treated 2 patients with severe HS with extended courses of concurrent TNF and IL-1 antagonists. Both patients had previously failed treatment with multiple therapeutic interventions, including topical and systemic antibiotics, disease-modifying antirheumatic drugs, hormonal therapy, biologic monotherapy with several targeted agents, and wide local excision. In the setting of concurrent certolizumab plus anakinra in the first patient and adalimumab plus anakinra in the second, both patients reported reduced drainage, pain, and number of disease flares. Both patients also were maintained on extended treatment courses (11 months and 2 years, respectively) without evidence of infection or malignancy.

Concurrent biologics may be safe and effective in managing recalcitrant HS; however, large prospective studies are needed to confirm these anecdotal findings. As our understanding of HS pathogenesis expands, novel and more effective therapeutic options will be developed. Until then, concurrent biologics may be a potential option for patients with severe recalcitrant HS.

Psoriasis is a chronic inflammatory disease that affects approximately 2% to 3% of the US population.¹ Patients with psoriasis are more likely to have cardiovascular risk factors (eg, obesity, metabolic syndrome) than individuals without psoriasis.² In fact, recent evidence has suggested that a diagnosis of psoriasis is an independent risk factor for cardiometabolic diseases including diabetes, major adverse cardiovascular events, and obesity.³ Given the well-recognized health benefits of physical activity and the associated reduction in coronary heart disease risk,⁴ patients with psoriasis specifically may benefit from regular participation in physical activity. Thus, an enhanced understanding of the relationship between psoriasis and vigorous physical activity would help determine the role of initiating and recommending interventions that implement physical activity for patients with psoriasis. A review was conducted to determine the relationship between psoriasis and vigorous physical activity.

Methods

An English-language literature search of PubMed articles indexed for MEDLINE (January 1, 1946–October 15, 2017) as well as articles in the Embase database (January 1, 1947–October 15, 2017) and Cochrane Library (January 1, 1992–October 15, 2017) using the terms psoriasis and physical activity was performed. The search strategy was established based on a prior review of vigorous physical activity in eczema.⁵ The article titles and/or abstracts were reviewed, and the studies were excluded if they did not evaluate physical activity in patients with psoriasis. Studies without a control group also were excluded. Articles on patients with psoriatic arthritis and studies that involved modification of dietary intake also were excluded.

Two reviewers (M.A. and E.B.L.) independently extracted data from the studies and compiled the results. The following factors were included in the data extracted: study year, location, and design; method of diagnosis of psoriasis; total number of patients included in the study; and age, gender, and level of physical activity of the study patients. Level of physical activity was the exposure, and diagnosis of psoriasis was the dependent variable. Physical activity was defined differently across the studies that were evaluated. To determine study quality, we implemented the Newcastle–Ottawa Scale (NOS), a 9-star scoring system that includes items such as selection criteria, comparability, and study outcome.⁶ Studies with an NOS score of 7 or higher were included in the meta-analysis.

Results

The literature search generated 353 nonduplicate articles. A thorough review of the articles yielded 4 studies that were incorporated in the final analysis.^7-10 We aimed to perform a meta-analysis; however, only 1 of the studies included in the final analysis had an NOS score of 7 or higher along with adequate data to be incorporated into our study.¹⁰ As a result, the meta-analysis was converted to a regular review.

The cross-sectional study we reviewed, which had an NOS score of 7, included males and females in the United States aged 20 to 59 years.¹⁰ Data were collected using the population-based National Health and Nutrition Examination Survey from 2003 to 2006. The survey measured the likelihood of participation in leisure-time moderate to vigorous physical activity (MVPA) and metabolic equivalent task (MET) minutes of MVPA in the past 30 days. Of 6549 participants, 385 were excluded from the analysis due to missing values for 1 or more of the study variables. Of the remaining 6164 participants, 84 (1.4%) reported having a diagnosis of psoriasis with few or no psoriasis patches at the time of the survey, and 71 (1.2%) reported having a diagnosis of psoriasis with few to extensive patches at the time of the survey.¹⁰

Participants with psoriasis were less likely to participate in MVPA in the previous 30 days compared to participants without psoriasis, but the association was not statistically significant.¹⁰ The study demonstrated that, on average, participants with psoriasis spent 31% (95% confidence interval [CI], −0.57 to −0.05) fewer MET minutes on leisure-time MVPA versus participants without psoriasis; however, this association was not statistically significant. It is important to note that the diagnosis of psoriasis was self-reported, and measures of disease duration or areas of involvement were not incorporated.

Comment

Our review revealed that vigorous physical activity may be reduced in patients with psoriasis compared to those without psoriasis. Initially, we aimed to perform a systematic review of the literature; however, only 1 study met the criteria for the systematic review, highlighting the need for more robust studies evaluating this subject.

Do et al¹⁰ demonstrated that psoriasis patients were less likely to participate in MVPA, but the findings were not statistically significant. Of those who participated in MVPA, MET minutes were fewer among patients with few to extensive skin lesions compared to those without psoriasis. The investigators suggested that psoriasis patients with more severe disease tend to exercise less and ultimately would benefit from regular vigorous physical activity.

Frankel et al⁷ performed a prospective cohort study in US women to evaluate the role of physical activity in preventing psoriasis. The investigators reported that the most physically active quintile had a lower multivariate relative risk of psoriasis (0.72; 95% CI, 0.59–0.89; P<.001 for trend) compared to the least active quintile.⁷ Additionally, vigorous physical activity, which was defined as 6 or more MET minutes, was associated with a significantly lower risk of incident psoriasis (0.66; 95% CI, 0.54–0.81; P<.001 for trend), which maintained significance after adjusting for body mass index (BMI). The investigators suggested that, by decreasing chronic inflammation and lowering levels of proinflammatory cytokines, vigorous physical activity may reduce the risk of psoriasis development in women.⁷ It is plausible that vigorous physical activity modifies the state of chronic inflammation, which could subsequently reduce the risk of developing psoriasis; however, further long-term, randomized, prospective studies are needed to verify the relationship between physical activity and development of psoriasis.

Torres et al⁸ performed a cross-sectional questionnaire study to assess physical activity in patients with severe psoriasis (defined as >10% body surface area involvement and/or disease requiring systemic therapy or phototherapy) versus healthy controls. Physical activity level was measured using the International Physical Activity Questionnaire. The odds ratio of low-level physical activity compared to non–low-level physical activity among psoriasis patients versus controls was 3.42 (95% CI, 1.47–7.91; P=.002). Additionally, the average total MET minutes of psoriasis patients were significantly reduced compared to those of the healthy controls (P=.001). Thus, the investigators suggested that vigorous physical activity is less likely in psoriasis patients, which may contribute to the increased risk of cardiovascular disease in this population.⁸ Vigorous physical activity would benefit patients with psoriasis to help lower the chronic state of inflammation and cardiometabolic comorbidities.

Demirel et al⁹ performed a study to compare aerobic exercise capacity and daily physical activity level in psoriasis patients (n=30) compared to controls (n=30). Daily physical activity, measured with an accelerometer, was significantly higher in male patients with psoriasis compared to controls (P=.021). No significant difference was reported in maximal aerobic capacity in both male and female psoriasis patients versus controls. The investigators suggested that the level of daily physical activity is not limited in psoriasis patients, yet the small sample size may limit the generalizability of the study.

The ability to dissipate heat during exercise seems to be diminished in patients with psoriasis. Specifically, it has been suggested that psoriasis lesions interfere with normal perspiration.¹¹ Moreover, joint involvement in patients with psoriatic arthritis may lead to physical functional disabilities that can interfere with the ability of these patients to participate in regular physical activity.^12-14 For this reason, our review excluded articles that evaluated patients with psoriatic arthritis. Despite this exclusion, it is important to consider that comorbid psoriatic arthritis in clinical practice may impede patients with psoriasis from participating in physical activity. Additionally, various social aspects also may limit physical activity in psoriasis patients; for instance, psoriasis patients often avoid activities that involve increased exposure of the skin (eg, communal showers, wearing sports attire).¹⁵

Furthermore, obese psoriasis patients are less likely to exercise compared to obese individuals without psoriasis.¹⁶ In patients with higher BMI, the risk of psoriasis is increased.¹⁷ A systematic review suggested that weight loss may improve psoriasis severity.¹⁸ Bariatric surgery also may improve psoriasis.¹⁹ Moreover, obesity may interfere with response to biologic therapies for psoriasis. Specifically, higher BMI is linked with lower response to fixed-dose biologic therapies compared to weight-based biologic options (eg, infliximab).^20,21

Conclusion

Given the increased risk of myocardial infarction in patients with psoriasis, it is important to recognize the barriers to physical activity that psoriasis patients face.²² Due to the considerable health benefits associated with regular physical activity, physicians should encourage patients with psoriasis to participate in physical activity as tolerated. Of note, the studies included in this review varied in their definitions of psoriasis disease severity and measures of physical activity level. Long-term, randomized, prospective studies are needed to clarify the relationship between psoriasis and physical activity. Evidence from these studies would help guide clinical recommendations regarding the role of physical activity for patients with psoriasis.

Psoriasis is a chronic inflammatory disease that affects approximately 2% to 3% of the US population.¹ Patients with psoriasis are more likely to have cardiovascular risk factors (eg, obesity, metabolic syndrome) than individuals without psoriasis.² In fact, recent evidence has suggested that a diagnosis of psoriasis is an independent risk factor for cardiometabolic diseases including diabetes, major adverse cardiovascular events, and obesity.³ Given the well-recognized health benefits of physical activity and the associated reduction in coronary heart disease risk,⁴ patients with psoriasis specifically may benefit from regular participation in physical activity. Thus, an enhanced understanding of the relationship between psoriasis and vigorous physical activity would help determine the role of initiating and recommending interventions that implement physical activity for patients with psoriasis. A review was conducted to determine the relationship between psoriasis and vigorous physical activity.

Methods

An English-language literature search of PubMed articles indexed for MEDLINE (January 1, 1946–October 15, 2017) as well as articles in the Embase database (January 1, 1947–October 15, 2017) and Cochrane Library (January 1, 1992–October 15, 2017) using the terms psoriasis and physical activity was performed. The search strategy was established based on a prior review of vigorous physical activity in eczema.⁵ The article titles and/or abstracts were reviewed, and the studies were excluded if they did not evaluate physical activity in patients with psoriasis. Studies without a control group also were excluded. Articles on patients with psoriatic arthritis and studies that involved modification of dietary intake also were excluded.

Two reviewers (M.A. and E.B.L.) independently extracted data from the studies and compiled the results. The following factors were included in the data extracted: study year, location, and design; method of diagnosis of psoriasis; total number of patients included in the study; and age, gender, and level of physical activity of the study patients. Level of physical activity was the exposure, and diagnosis of psoriasis was the dependent variable. Physical activity was defined differently across the studies that were evaluated. To determine study quality, we implemented the Newcastle–Ottawa Scale (NOS), a 9-star scoring system that includes items such as selection criteria, comparability, and study outcome.⁶ Studies with an NOS score of 7 or higher were included in the meta-analysis.

Results

The literature search generated 353 nonduplicate articles. A thorough review of the articles yielded 4 studies that were incorporated in the final analysis.^7-10 We aimed to perform a meta-analysis; however, only 1 of the studies included in the final analysis had an NOS score of 7 or higher along with adequate data to be incorporated into our study.¹⁰ As a result, the meta-analysis was converted to a regular review.

The cross-sectional study we reviewed, which had an NOS score of 7, included males and females in the United States aged 20 to 59 years.¹⁰ Data were collected using the population-based National Health and Nutrition Examination Survey from 2003 to 2006. The survey measured the likelihood of participation in leisure-time moderate to vigorous physical activity (MVPA) and metabolic equivalent task (MET) minutes of MVPA in the past 30 days. Of 6549 participants, 385 were excluded from the analysis due to missing values for 1 or more of the study variables. Of the remaining 6164 participants, 84 (1.4%) reported having a diagnosis of psoriasis with few or no psoriasis patches at the time of the survey, and 71 (1.2%) reported having a diagnosis of psoriasis with few to extensive patches at the time of the survey.¹⁰

Participants with psoriasis were less likely to participate in MVPA in the previous 30 days compared to participants without psoriasis, but the association was not statistically significant.¹⁰ The study demonstrated that, on average, participants with psoriasis spent 31% (95% confidence interval [CI], −0.57 to −0.05) fewer MET minutes on leisure-time MVPA versus participants without psoriasis; however, this association was not statistically significant. It is important to note that the diagnosis of psoriasis was self-reported, and measures of disease duration or areas of involvement were not incorporated.

Comment

Our review revealed that vigorous physical activity may be reduced in patients with psoriasis compared to those without psoriasis. Initially, we aimed to perform a systematic review of the literature; however, only 1 study met the criteria for the systematic review, highlighting the need for more robust studies evaluating this subject.

Do et al¹⁰ demonstrated that psoriasis patients were less likely to participate in MVPA, but the findings were not statistically significant. Of those who participated in MVPA, MET minutes were fewer among patients with few to extensive skin lesions compared to those without psoriasis. The investigators suggested that psoriasis patients with more severe disease tend to exercise less and ultimately would benefit from regular vigorous physical activity.

Frankel et al⁷ performed a prospective cohort study in US women to evaluate the role of physical activity in preventing psoriasis. The investigators reported that the most physically active quintile had a lower multivariate relative risk of psoriasis (0.72; 95% CI, 0.59–0.89; P<.001 for trend) compared to the least active quintile.⁷ Additionally, vigorous physical activity, which was defined as 6 or more MET minutes, was associated with a significantly lower risk of incident psoriasis (0.66; 95% CI, 0.54–0.81; P<.001 for trend), which maintained significance after adjusting for body mass index (BMI). The investigators suggested that, by decreasing chronic inflammation and lowering levels of proinflammatory cytokines, vigorous physical activity may reduce the risk of psoriasis development in women.⁷ It is plausible that vigorous physical activity modifies the state of chronic inflammation, which could subsequently reduce the risk of developing psoriasis; however, further long-term, randomized, prospective studies are needed to verify the relationship between physical activity and development of psoriasis.

Torres et al⁸ performed a cross-sectional questionnaire study to assess physical activity in patients with severe psoriasis (defined as >10% body surface area involvement and/or disease requiring systemic therapy or phototherapy) versus healthy controls. Physical activity level was measured using the International Physical Activity Questionnaire. The odds ratio of low-level physical activity compared to non–low-level physical activity among psoriasis patients versus controls was 3.42 (95% CI, 1.47–7.91; P=.002). Additionally, the average total MET minutes of psoriasis patients were significantly reduced compared to those of the healthy controls (P=.001). Thus, the investigators suggested that vigorous physical activity is less likely in psoriasis patients, which may contribute to the increased risk of cardiovascular disease in this population.⁸ Vigorous physical activity would benefit patients with psoriasis to help lower the chronic state of inflammation and cardiometabolic comorbidities.

Demirel et al⁹ performed a study to compare aerobic exercise capacity and daily physical activity level in psoriasis patients (n=30) compared to controls (n=30). Daily physical activity, measured with an accelerometer, was significantly higher in male patients with psoriasis compared to controls (P=.021). No significant difference was reported in maximal aerobic capacity in both male and female psoriasis patients versus controls. The investigators suggested that the level of daily physical activity is not limited in psoriasis patients, yet the small sample size may limit the generalizability of the study.

The ability to dissipate heat during exercise seems to be diminished in patients with psoriasis. Specifically, it has been suggested that psoriasis lesions interfere with normal perspiration.¹¹ Moreover, joint involvement in patients with psoriatic arthritis may lead to physical functional disabilities that can interfere with the ability of these patients to participate in regular physical activity.^12-14 For this reason, our review excluded articles that evaluated patients with psoriatic arthritis. Despite this exclusion, it is important to consider that comorbid psoriatic arthritis in clinical practice may impede patients with psoriasis from participating in physical activity. Additionally, various social aspects also may limit physical activity in psoriasis patients; for instance, psoriasis patients often avoid activities that involve increased exposure of the skin (eg, communal showers, wearing sports attire).¹⁵

Furthermore, obese psoriasis patients are less likely to exercise compared to obese individuals without psoriasis.¹⁶ In patients with higher BMI, the risk of psoriasis is increased.¹⁷ A systematic review suggested that weight loss may improve psoriasis severity.¹⁸ Bariatric surgery also may improve psoriasis.¹⁹ Moreover, obesity may interfere with response to biologic therapies for psoriasis. Specifically, higher BMI is linked with lower response to fixed-dose biologic therapies compared to weight-based biologic options (eg, infliximab).^20,21

Conclusion

Given the increased risk of myocardial infarction in patients with psoriasis, it is important to recognize the barriers to physical activity that psoriasis patients face.²² Due to the considerable health benefits associated with regular physical activity, physicians should encourage patients with psoriasis to participate in physical activity as tolerated. Of note, the studies included in this review varied in their definitions of psoriasis disease severity and measures of physical activity level. Long-term, randomized, prospective studies are needed to clarify the relationship between psoriasis and physical activity. Evidence from these studies would help guide clinical recommendations regarding the role of physical activity for patients with psoriasis.

Psoriasis is a chronic inflammatory disease that affects approximately 2% to 3% of the US population.¹ Patients with psoriasis are more likely to have cardiovascular risk factors (eg, obesity, metabolic syndrome) than individuals without psoriasis.² In fact, recent evidence has suggested that a diagnosis of psoriasis is an independent risk factor for cardiometabolic diseases including diabetes, major adverse cardiovascular events, and obesity.³ Given the well-recognized health benefits of physical activity and the associated reduction in coronary heart disease risk,⁴ patients with psoriasis specifically may benefit from regular participation in physical activity. Thus, an enhanced understanding of the relationship between psoriasis and vigorous physical activity would help determine the role of initiating and recommending interventions that implement physical activity for patients with psoriasis. A review was conducted to determine the relationship between psoriasis and vigorous physical activity.

Methods

An English-language literature search of PubMed articles indexed for MEDLINE (January 1, 1946–October 15, 2017) as well as articles in the Embase database (January 1, 1947–October 15, 2017) and Cochrane Library (January 1, 1992–October 15, 2017) using the terms psoriasis and physical activity was performed. The search strategy was established based on a prior review of vigorous physical activity in eczema.⁵ The article titles and/or abstracts were reviewed, and the studies were excluded if they did not evaluate physical activity in patients with psoriasis. Studies without a control group also were excluded. Articles on patients with psoriatic arthritis and studies that involved modification of dietary intake also were excluded.

Two reviewers (M.A. and E.B.L.) independently extracted data from the studies and compiled the results. The following factors were included in the data extracted: study year, location, and design; method of diagnosis of psoriasis; total number of patients included in the study; and age, gender, and level of physical activity of the study patients. Level of physical activity was the exposure, and diagnosis of psoriasis was the dependent variable. Physical activity was defined differently across the studies that were evaluated. To determine study quality, we implemented the Newcastle–Ottawa Scale (NOS), a 9-star scoring system that includes items such as selection criteria, comparability, and study outcome.⁶ Studies with an NOS score of 7 or higher were included in the meta-analysis.

Results

The literature search generated 353 nonduplicate articles. A thorough review of the articles yielded 4 studies that were incorporated in the final analysis.^7-10 We aimed to perform a meta-analysis; however, only 1 of the studies included in the final analysis had an NOS score of 7 or higher along with adequate data to be incorporated into our study.¹⁰ As a result, the meta-analysis was converted to a regular review.

The cross-sectional study we reviewed, which had an NOS score of 7, included males and females in the United States aged 20 to 59 years.¹⁰ Data were collected using the population-based National Health and Nutrition Examination Survey from 2003 to 2006. The survey measured the likelihood of participation in leisure-time moderate to vigorous physical activity (MVPA) and metabolic equivalent task (MET) minutes of MVPA in the past 30 days. Of 6549 participants, 385 were excluded from the analysis due to missing values for 1 or more of the study variables. Of the remaining 6164 participants, 84 (1.4%) reported having a diagnosis of psoriasis with few or no psoriasis patches at the time of the survey, and 71 (1.2%) reported having a diagnosis of psoriasis with few to extensive patches at the time of the survey.¹⁰

Participants with psoriasis were less likely to participate in MVPA in the previous 30 days compared to participants without psoriasis, but the association was not statistically significant.¹⁰ The study demonstrated that, on average, participants with psoriasis spent 31% (95% confidence interval [CI], −0.57 to −0.05) fewer MET minutes on leisure-time MVPA versus participants without psoriasis; however, this association was not statistically significant. It is important to note that the diagnosis of psoriasis was self-reported, and measures of disease duration or areas of involvement were not incorporated.

Comment

Our review revealed that vigorous physical activity may be reduced in patients with psoriasis compared to those without psoriasis. Initially, we aimed to perform a systematic review of the literature; however, only 1 study met the criteria for the systematic review, highlighting the need for more robust studies evaluating this subject.

Do et al¹⁰ demonstrated that psoriasis patients were less likely to participate in MVPA, but the findings were not statistically significant. Of those who participated in MVPA, MET minutes were fewer among patients with few to extensive skin lesions compared to those without psoriasis. The investigators suggested that psoriasis patients with more severe disease tend to exercise less and ultimately would benefit from regular vigorous physical activity.

Frankel et al⁷ performed a prospective cohort study in US women to evaluate the role of physical activity in preventing psoriasis. The investigators reported that the most physically active quintile had a lower multivariate relative risk of psoriasis (0.72; 95% CI, 0.59–0.89; P<.001 for trend) compared to the least active quintile.⁷ Additionally, vigorous physical activity, which was defined as 6 or more MET minutes, was associated with a significantly lower risk of incident psoriasis (0.66; 95% CI, 0.54–0.81; P<.001 for trend), which maintained significance after adjusting for body mass index (BMI). The investigators suggested that, by decreasing chronic inflammation and lowering levels of proinflammatory cytokines, vigorous physical activity may reduce the risk of psoriasis development in women.⁷ It is plausible that vigorous physical activity modifies the state of chronic inflammation, which could subsequently reduce the risk of developing psoriasis; however, further long-term, randomized, prospective studies are needed to verify the relationship between physical activity and development of psoriasis.

Torres et al⁸ performed a cross-sectional questionnaire study to assess physical activity in patients with severe psoriasis (defined as >10% body surface area involvement and/or disease requiring systemic therapy or phototherapy) versus healthy controls. Physical activity level was measured using the International Physical Activity Questionnaire. The odds ratio of low-level physical activity compared to non–low-level physical activity among psoriasis patients versus controls was 3.42 (95% CI, 1.47–7.91; P=.002). Additionally, the average total MET minutes of psoriasis patients were significantly reduced compared to those of the healthy controls (P=.001). Thus, the investigators suggested that vigorous physical activity is less likely in psoriasis patients, which may contribute to the increased risk of cardiovascular disease in this population.⁸ Vigorous physical activity would benefit patients with psoriasis to help lower the chronic state of inflammation and cardiometabolic comorbidities.

Demirel et al⁹ performed a study to compare aerobic exercise capacity and daily physical activity level in psoriasis patients (n=30) compared to controls (n=30). Daily physical activity, measured with an accelerometer, was significantly higher in male patients with psoriasis compared to controls (P=.021). No significant difference was reported in maximal aerobic capacity in both male and female psoriasis patients versus controls. The investigators suggested that the level of daily physical activity is not limited in psoriasis patients, yet the small sample size may limit the generalizability of the study.

The ability to dissipate heat during exercise seems to be diminished in patients with psoriasis. Specifically, it has been suggested that psoriasis lesions interfere with normal perspiration.¹¹ Moreover, joint involvement in patients with psoriatic arthritis may lead to physical functional disabilities that can interfere with the ability of these patients to participate in regular physical activity.^12-14 For this reason, our review excluded articles that evaluated patients with psoriatic arthritis. Despite this exclusion, it is important to consider that comorbid psoriatic arthritis in clinical practice may impede patients with psoriasis from participating in physical activity. Additionally, various social aspects also may limit physical activity in psoriasis patients; for instance, psoriasis patients often avoid activities that involve increased exposure of the skin (eg, communal showers, wearing sports attire).¹⁵

Furthermore, obese psoriasis patients are less likely to exercise compared to obese individuals without psoriasis.¹⁶ In patients with higher BMI, the risk of psoriasis is increased.¹⁷ A systematic review suggested that weight loss may improve psoriasis severity.¹⁸ Bariatric surgery also may improve psoriasis.¹⁹ Moreover, obesity may interfere with response to biologic therapies for psoriasis. Specifically, higher BMI is linked with lower response to fixed-dose biologic therapies compared to weight-based biologic options (eg, infliximab).^20,21

Conclusion

Given the increased risk of myocardial infarction in patients with psoriasis, it is important to recognize the barriers to physical activity that psoriasis patients face.²² Due to the considerable health benefits associated with regular physical activity, physicians should encourage patients with psoriasis to participate in physical activity as tolerated. Of note, the studies included in this review varied in their definitions of psoriasis disease severity and measures of physical activity level. Long-term, randomized, prospective studies are needed to clarify the relationship between psoriasis and physical activity. Evidence from these studies would help guide clinical recommendations regarding the role of physical activity for patients with psoriasis.

KAUAI, HAWAII – A topical halobetasol/tazarotene fixed-combination lotion for moderate to severe psoriasis hit all of its efficacy and safety endpoints in two phase 3 randomized, double-blind, multicenter clinical trials, Linda Stein Gold, MD, reported at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

The fixed combination of halobetasol 0.01%/tazarotene 0.045% lotion takes advantage of an observation made 20 years ago: When tazarotene is combined with a potent topical corticosteroid, therapeutic efficacy is amplified synergistically while the problematic local side effects of each agent are diminished, explained Dr. Stein Gold, director of dermatology research at the Henry Ford Health System, Detroit.

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com

KAUAI, HAWAII – A topical halobetasol/tazarotene fixed-combination lotion for moderate to severe psoriasis hit all of its efficacy and safety endpoints in two phase 3 randomized, double-blind, multicenter clinical trials, Linda Stein Gold, MD, reported at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

The fixed combination of halobetasol 0.01%/tazarotene 0.045% lotion takes advantage of an observation made 20 years ago: When tazarotene is combined with a potent topical corticosteroid, therapeutic efficacy is amplified synergistically while the problematic local side effects of each agent are diminished, explained Dr. Stein Gold, director of dermatology research at the Henry Ford Health System, Detroit.

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com

KAUAI, HAWAII – A topical halobetasol/tazarotene fixed-combination lotion for moderate to severe psoriasis hit all of its efficacy and safety endpoints in two phase 3 randomized, double-blind, multicenter clinical trials, Linda Stein Gold, MD, reported at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

The fixed combination of halobetasol 0.01%/tazarotene 0.045% lotion takes advantage of an observation made 20 years ago: When tazarotene is combined with a potent topical corticosteroid, therapeutic efficacy is amplified synergistically while the problematic local side effects of each agent are diminished, explained Dr. Stein Gold, director of dermatology research at the Henry Ford Health System, Detroit.

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com

SAN DIEGO – Online consultations between dermatologists, patients with psoriasis, and the patients’ primary care physicians were as effective as in-person consultations in successfully treating the disease in a multicenter, randomized study of 296 patients.

“Innovative telehealth delivery models that emphasize collaboration, quality, and efficiency can be transformative to improving patient-centered outcomes in chronic disease,” April W. Armstrong, MD, said at the annual meeting of the American Academy of Dermatology. The online model she tested fostered “increased patient engagement” and provided “comprehensive specialist support,” said Dr. Armstrong, director of the psoriasis program at the University of Southern California, Los Angeles.

To objectively assess whether online consultations are as effective as in-person examinations, Dr. Armstrong and her associates at three U.S. centers randomized adult psoriasis patients from across the disease spectrum to receive 1 year of dermatology care either in person or online. Patients enrolled in the online arm received training in taking digital images of their skin lesions and uploading the data for remote access by their dermatologist and primary care physician. The frequency of in-person and online consultations was left to the discretion of each patient and his or her physician.

Among the 148 patients randomized to each arm, 17 in the online group and 13 in the in-person group withdrew from the study or were lost to follow-up. The researchers analyzed the results on an intention-to-treat basis.

They assessed three parameters of treatment efficacy that they measured at baseline and then every 3 months out to 1 year: Psoriasis Area and Severity Index, body surface area score, and patient global self-assessment. A comparison of changes between the two treatment arms after 1 year for the first two measures met the study’s prespecified definition of equivalence, Dr. Armstrong reported. The third measure, a patient’s global self-assessment, showed lower patient-assessed disease severity after 1 year among the patients managed online, compared with those managed in person.

The incidence of adverse events and serious adverse events was similar in the two treatment arms.

Dr. Armstrong had no relevant financial disclosures.

mzoler@frontlinemedcom.com

Source: Armstrong A et al. AAD 2018, abstract 6730..

SAN DIEGO – Online consultations between dermatologists, patients with psoriasis, and the patients’ primary care physicians were as effective as in-person consultations in successfully treating the disease in a multicenter, randomized study of 296 patients.

“Innovative telehealth delivery models that emphasize collaboration, quality, and efficiency can be transformative to improving patient-centered outcomes in chronic disease,” April W. Armstrong, MD, said at the annual meeting of the American Academy of Dermatology. The online model she tested fostered “increased patient engagement” and provided “comprehensive specialist support,” said Dr. Armstrong, director of the psoriasis program at the University of Southern California, Los Angeles.

To objectively assess whether online consultations are as effective as in-person examinations, Dr. Armstrong and her associates at three U.S. centers randomized adult psoriasis patients from across the disease spectrum to receive 1 year of dermatology care either in person or online. Patients enrolled in the online arm received training in taking digital images of their skin lesions and uploading the data for remote access by their dermatologist and primary care physician. The frequency of in-person and online consultations was left to the discretion of each patient and his or her physician.

Among the 148 patients randomized to each arm, 17 in the online group and 13 in the in-person group withdrew from the study or were lost to follow-up. The researchers analyzed the results on an intention-to-treat basis.

They assessed three parameters of treatment efficacy that they measured at baseline and then every 3 months out to 1 year: Psoriasis Area and Severity Index, body surface area score, and patient global self-assessment. A comparison of changes between the two treatment arms after 1 year for the first two measures met the study’s prespecified definition of equivalence, Dr. Armstrong reported. The third measure, a patient’s global self-assessment, showed lower patient-assessed disease severity after 1 year among the patients managed online, compared with those managed in person.

The incidence of adverse events and serious adverse events was similar in the two treatment arms.

Dr. Armstrong had no relevant financial disclosures.

mzoler@frontlinemedcom.com

Source: Armstrong A et al. AAD 2018, abstract 6730..

SAN DIEGO – Online consultations between dermatologists, patients with psoriasis, and the patients’ primary care physicians were as effective as in-person consultations in successfully treating the disease in a multicenter, randomized study of 296 patients.

“Innovative telehealth delivery models that emphasize collaboration, quality, and efficiency can be transformative to improving patient-centered outcomes in chronic disease,” April W. Armstrong, MD, said at the annual meeting of the American Academy of Dermatology. The online model she tested fostered “increased patient engagement” and provided “comprehensive specialist support,” said Dr. Armstrong, director of the psoriasis program at the University of Southern California, Los Angeles.

To objectively assess whether online consultations are as effective as in-person examinations, Dr. Armstrong and her associates at three U.S. centers randomized adult psoriasis patients from across the disease spectrum to receive 1 year of dermatology care either in person or online. Patients enrolled in the online arm received training in taking digital images of their skin lesions and uploading the data for remote access by their dermatologist and primary care physician. The frequency of in-person and online consultations was left to the discretion of each patient and his or her physician.

Among the 148 patients randomized to each arm, 17 in the online group and 13 in the in-person group withdrew from the study or were lost to follow-up. The researchers analyzed the results on an intention-to-treat basis.

They assessed three parameters of treatment efficacy that they measured at baseline and then every 3 months out to 1 year: Psoriasis Area and Severity Index, body surface area score, and patient global self-assessment. A comparison of changes between the two treatment arms after 1 year for the first two measures met the study’s prespecified definition of equivalence, Dr. Armstrong reported. The third measure, a patient’s global self-assessment, showed lower patient-assessed disease severity after 1 year among the patients managed online, compared with those managed in person.

The incidence of adverse events and serious adverse events was similar in the two treatment arms.

Dr. Armstrong had no relevant financial disclosures.

mzoler@frontlinemedcom.com

Source: Armstrong A et al. AAD 2018, abstract 6730..

SAN DIEGO – A new endeavor that aims to promote the concept of the combined clinic approach to caring for psoriatic patients is now underway.

PPACMAN (Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network) is made up of dermatologists and rheumatologists who play a key role in the management of psoriatic disease and are interested in combined clinics, with the mission “to nucleate psoriatic disease combined clinics and centers to advance a multilevel approach to psoriatic patients, increase disease awareness, and accelerate management,” according to Joseph Merola, MD, codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.

There are now about 12 centers in North America with formal rheumatology-dermatology clinics for patients with psoriasis and psoriatic arthritis, including the one at Brigham and Women’s, where Dr. Merola and his colleagues have seen the “myriad benefits that come with having a combined clinic,” he said in a video interview at the annual meeting of the American Academy of Dermatology. The idea behind starting PPACMAN was to help form new clinics at academic centers but, also, “to start to catalyze local-regional partnerships in the community so we could get dermatologists and rheumatologists in the community to start interacting, communicating, [and] sharing patients,” he explained.

“The group is really very much focused on this mission of getting combined ... treatment models out there,” added Dr. Merola, president and chair of the board of PPACMAN, which is a 501c3 nonprofit organization.

In the interview, he discusses other benefits of the combined clinic model and other elements of the PPACMAN mission, including education and the potential for shared EMR templates.

SAN DIEGO – A new endeavor that aims to promote the concept of the combined clinic approach to caring for psoriatic patients is now underway.

PPACMAN (Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network) is made up of dermatologists and rheumatologists who play a key role in the management of psoriatic disease and are interested in combined clinics, with the mission “to nucleate psoriatic disease combined clinics and centers to advance a multilevel approach to psoriatic patients, increase disease awareness, and accelerate management,” according to Joseph Merola, MD, codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.

There are now about 12 centers in North America with formal rheumatology-dermatology clinics for patients with psoriasis and psoriatic arthritis, including the one at Brigham and Women’s, where Dr. Merola and his colleagues have seen the “myriad benefits that come with having a combined clinic,” he said in a video interview at the annual meeting of the American Academy of Dermatology. The idea behind starting PPACMAN was to help form new clinics at academic centers but, also, “to start to catalyze local-regional partnerships in the community so we could get dermatologists and rheumatologists in the community to start interacting, communicating, [and] sharing patients,” he explained.

“The group is really very much focused on this mission of getting combined ... treatment models out there,” added Dr. Merola, president and chair of the board of PPACMAN, which is a 501c3 nonprofit organization.

In the interview, he discusses other benefits of the combined clinic model and other elements of the PPACMAN mission, including education and the potential for shared EMR templates.

SAN DIEGO – A new endeavor that aims to promote the concept of the combined clinic approach to caring for psoriatic patients is now underway.

PPACMAN (Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network) is made up of dermatologists and rheumatologists who play a key role in the management of psoriatic disease and are interested in combined clinics, with the mission “to nucleate psoriatic disease combined clinics and centers to advance a multilevel approach to psoriatic patients, increase disease awareness, and accelerate management,” according to Joseph Merola, MD, codirector of the center for skin and related musculoskeletal diseases at Brigham and Women’s Hospital, Boston.

There are now about 12 centers in North America with formal rheumatology-dermatology clinics for patients with psoriasis and psoriatic arthritis, including the one at Brigham and Women’s, where Dr. Merola and his colleagues have seen the “myriad benefits that come with having a combined clinic,” he said in a video interview at the annual meeting of the American Academy of Dermatology. The idea behind starting PPACMAN was to help form new clinics at academic centers but, also, “to start to catalyze local-regional partnerships in the community so we could get dermatologists and rheumatologists in the community to start interacting, communicating, [and] sharing patients,” he explained.

“The group is really very much focused on this mission of getting combined ... treatment models out there,” added Dr. Merola, president and chair of the board of PPACMAN, which is a 501c3 nonprofit organization.

In the interview, he discusses other benefits of the combined clinic model and other elements of the PPACMAN mission, including education and the potential for shared EMR templates.

SAN DIEGO – Could some of the monoclonal antibodies posting striking results in psoriasis trials be doing more than quelling symptoms?

At least some researchers think so, as evidenced by a brief discussion during AAD 2018 of the durable responses some guselkumab-treated patients achieved in the VOYAGE 2 trial.

“Isn’t this amazing?” asked Kristian Reich, MD, after listening to several late-breaking, solidly positive trials of monoclonal antibodies for plaque psoriasis. “I think it’s fantastic that we now have drugs that clear 50% or more of a patient’s psoriasis. We should not be taking this for granted.”

Although PASI 90 responses were much better maintained in the guselkumab group that stayed on therapy, they did not fade quickly. The median time to loss of PASI 90 response was 15 weeks (23 weeks after last guselkumab dose) for patients randomized to the withdrawal group. And although 89% of the maintenance group maintained their PASI 90 response at 48 weeks, 37% of those in the withdrawal group had still maintained that 90% improvement over baseline by 48 weeks.

“Is this drug opening the door to disease modification? Is it doing something that allows disease control even if we stop the therapy? This is what we see happening when we stop the drug in PASI 90 responders. Yes, the disease is coming back, but the median time to recurrence is more than 3 months.”

The cytokine profiles of these patients appear to support this idea, Dr. Reich contended.

“In the first 28 weeks, when they were all receiving the drug, their IL-23, IL-17A, and IL-17F levels were all going down rapidly. But this is the interesting part. In some patients who maintained their PASI response after withdrawal, those cytokines continued to be suppressed. They rose in patients who lost response. We need to do more tests to understand what’s going on here, but I do think the door is opening to what I would call disease modification.”

SOURCE: Gordon K et al. AAD 2018 Abstract 6748.

msullivan@frontlinemedcom.com

SAN DIEGO – Could some of the monoclonal antibodies posting striking results in psoriasis trials be doing more than quelling symptoms?

At least some researchers think so, as evidenced by a brief discussion during AAD 2018 of the durable responses some guselkumab-treated patients achieved in the VOYAGE 2 trial.

“Isn’t this amazing?” asked Kristian Reich, MD, after listening to several late-breaking, solidly positive trials of monoclonal antibodies for plaque psoriasis. “I think it’s fantastic that we now have drugs that clear 50% or more of a patient’s psoriasis. We should not be taking this for granted.”

Although PASI 90 responses were much better maintained in the guselkumab group that stayed on therapy, they did not fade quickly. The median time to loss of PASI 90 response was 15 weeks (23 weeks after last guselkumab dose) for patients randomized to the withdrawal group. And although 89% of the maintenance group maintained their PASI 90 response at 48 weeks, 37% of those in the withdrawal group had still maintained that 90% improvement over baseline by 48 weeks.

“Is this drug opening the door to disease modification? Is it doing something that allows disease control even if we stop the therapy? This is what we see happening when we stop the drug in PASI 90 responders. Yes, the disease is coming back, but the median time to recurrence is more than 3 months.”

The cytokine profiles of these patients appear to support this idea, Dr. Reich contended.

“In the first 28 weeks, when they were all receiving the drug, their IL-23, IL-17A, and IL-17F levels were all going down rapidly. But this is the interesting part. In some patients who maintained their PASI response after withdrawal, those cytokines continued to be suppressed. They rose in patients who lost response. We need to do more tests to understand what’s going on here, but I do think the door is opening to what I would call disease modification.”

SOURCE: Gordon K et al. AAD 2018 Abstract 6748.

msullivan@frontlinemedcom.com

SAN DIEGO – Could some of the monoclonal antibodies posting striking results in psoriasis trials be doing more than quelling symptoms?

At least some researchers think so, as evidenced by a brief discussion during AAD 2018 of the durable responses some guselkumab-treated patients achieved in the VOYAGE 2 trial.

“Isn’t this amazing?” asked Kristian Reich, MD, after listening to several late-breaking, solidly positive trials of monoclonal antibodies for plaque psoriasis. “I think it’s fantastic that we now have drugs that clear 50% or more of a patient’s psoriasis. We should not be taking this for granted.”

Although PASI 90 responses were much better maintained in the guselkumab group that stayed on therapy, they did not fade quickly. The median time to loss of PASI 90 response was 15 weeks (23 weeks after last guselkumab dose) for patients randomized to the withdrawal group. And although 89% of the maintenance group maintained their PASI 90 response at 48 weeks, 37% of those in the withdrawal group had still maintained that 90% improvement over baseline by 48 weeks.

“Is this drug opening the door to disease modification? Is it doing something that allows disease control even if we stop the therapy? This is what we see happening when we stop the drug in PASI 90 responders. Yes, the disease is coming back, but the median time to recurrence is more than 3 months.”

The cytokine profiles of these patients appear to support this idea, Dr. Reich contended.

“In the first 28 weeks, when they were all receiving the drug, their IL-23, IL-17A, and IL-17F levels were all going down rapidly. But this is the interesting part. In some patients who maintained their PASI response after withdrawal, those cytokines continued to be suppressed. They rose in patients who lost response. We need to do more tests to understand what’s going on here, but I do think the door is opening to what I would call disease modification.”

SOURCE: Gordon K et al. AAD 2018 Abstract 6748.

msullivan@frontlinemedcom.com