Psoriasis

Biologics appear to be associated with a significantly greater rate of total adverse events, withdrawals due to adverse events, and an increased risk of tuberculosis reactivation compared with control agents, based on a meta-analysis involving more than 60,000 patients.

However, there were no significant differences in the rates of serious adverse events, serious infections, lymphoma, and congestive heart failure between biologics and control agents.

"Our review included indirect comparisons of the safety of biologics and should provide some guidance to clinicians and patients until head-to-head comparisons become available," wrote Dr. Jasvinder A. Singh and his coauthors (Cochrane Database Syst. Rev. 2011 [doi: 10.1002/14651858.CD008794.pub2]).

The results come from a network meta-analysis and Cochrane overview of the adverse effects of biologic drugs that are approved for the treatment of rheumatoid arthritis and other conditions in Europe, the United Kingdom, the United States, Canada, and Australia.

The investigators included randomized controlled trials (RCTs), controlled clinical trials, and open-label extension studies that involved one of the nine biologics for use in any indication and that reported this study's prespecified adverse outcomes. The researchers did not include studies on biologics for the treatment of HIV/AIDS. The nine biologics investigated were abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan/MabThera), and tocilizumab (Actemra).

They searched the Cochrane Library, Medline, and Embase (through January 2010). The investigators performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework for the network meta-analysis.

In all, included in the analysis were 163 RCTs with 50,010 adult participants and 46 extension studies with 11,954 adult participants. The median duration was 6 months for the RCTs and 13 months for the extension studies. Given the short duration of the RCTs, all the results should be interpreted as applying to a fairly short time frame.

After the analysis was adjusted for dose, biologics as a group were associated with a significantly greater rate of total adverse events (odds ratio 1.19) and withdrawals due to adverse events (OR 1.32), as well as an increased risk of TB reactivation (OR 4.68), compared with control agents.

Notably, certolizumab pegol was associated with a significantly greater risk of serious infections than was control treatment (OR 3.51). Infliximab was associated with a significantly greater risk of withdrawals due to adverse events compared with the control (OR 2.04).

Heart failure and cancer have been of particular concern with the use of biologic drugs. There appears to be little or no difference in the number of people who experienced heart failure or cancer taking any biologic compared with people who took placebo. However, there were not many cases of congestive heart failure or cancer, so confidence in these results is low.

The researchers also were able to indirectly compare individual biologic drugs. These analyses revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events than were most other biologics. In addition, certolizumab pegol was associated with significantly greater odds of serious infections than were etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab. Abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections; abatacept, adalimumab, etanercept, and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. However, the authors noted that the overall numbers were relatively small and that these comparisons should be interpreted with caution.

The lack of long-term studies of biologics is still a concern, they added. "There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics," they concluded.

Dr. Singh and several of his coauthors reported that they have significant financial relationships with several pharmaceutical companies.

Biologics appear to be associated with a significantly greater rate of total adverse events, withdrawals due to adverse events, and an increased risk of tuberculosis reactivation compared with control agents, based on a meta-analysis involving more than 60,000 patients.

However, there were no significant differences in the rates of serious adverse events, serious infections, lymphoma, and congestive heart failure between biologics and control agents.

"Our review included indirect comparisons of the safety of biologics and should provide some guidance to clinicians and patients until head-to-head comparisons become available," wrote Dr. Jasvinder A. Singh and his coauthors (Cochrane Database Syst. Rev. 2011 [doi: 10.1002/14651858.CD008794.pub2]).

The results come from a network meta-analysis and Cochrane overview of the adverse effects of biologic drugs that are approved for the treatment of rheumatoid arthritis and other conditions in Europe, the United Kingdom, the United States, Canada, and Australia.

The investigators included randomized controlled trials (RCTs), controlled clinical trials, and open-label extension studies that involved one of the nine biologics for use in any indication and that reported this study's prespecified adverse outcomes. The researchers did not include studies on biologics for the treatment of HIV/AIDS. The nine biologics investigated were abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan/MabThera), and tocilizumab (Actemra).

They searched the Cochrane Library, Medline, and Embase (through January 2010). The investigators performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework for the network meta-analysis.

In all, included in the analysis were 163 RCTs with 50,010 adult participants and 46 extension studies with 11,954 adult participants. The median duration was 6 months for the RCTs and 13 months for the extension studies. Given the short duration of the RCTs, all the results should be interpreted as applying to a fairly short time frame.

After the analysis was adjusted for dose, biologics as a group were associated with a significantly greater rate of total adverse events (odds ratio 1.19) and withdrawals due to adverse events (OR 1.32), as well as an increased risk of TB reactivation (OR 4.68), compared with control agents.

Notably, certolizumab pegol was associated with a significantly greater risk of serious infections than was control treatment (OR 3.51). Infliximab was associated with a significantly greater risk of withdrawals due to adverse events compared with the control (OR 2.04).

Heart failure and cancer have been of particular concern with the use of biologic drugs. There appears to be little or no difference in the number of people who experienced heart failure or cancer taking any biologic compared with people who took placebo. However, there were not many cases of congestive heart failure or cancer, so confidence in these results is low.

The researchers also were able to indirectly compare individual biologic drugs. These analyses revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events than were most other biologics. In addition, certolizumab pegol was associated with significantly greater odds of serious infections than were etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab. Abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections; abatacept, adalimumab, etanercept, and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. However, the authors noted that the overall numbers were relatively small and that these comparisons should be interpreted with caution.

The lack of long-term studies of biologics is still a concern, they added. "There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics," they concluded.

Dr. Singh and several of his coauthors reported that they have significant financial relationships with several pharmaceutical companies.

Biologics appear to be associated with a significantly greater rate of total adverse events, withdrawals due to adverse events, and an increased risk of tuberculosis reactivation compared with control agents, based on a meta-analysis involving more than 60,000 patients.

However, there were no significant differences in the rates of serious adverse events, serious infections, lymphoma, and congestive heart failure between biologics and control agents.

"Our review included indirect comparisons of the safety of biologics and should provide some guidance to clinicians and patients until head-to-head comparisons become available," wrote Dr. Jasvinder A. Singh and his coauthors (Cochrane Database Syst. Rev. 2011 [doi: 10.1002/14651858.CD008794.pub2]).

The results come from a network meta-analysis and Cochrane overview of the adverse effects of biologic drugs that are approved for the treatment of rheumatoid arthritis and other conditions in Europe, the United Kingdom, the United States, Canada, and Australia.

The investigators included randomized controlled trials (RCTs), controlled clinical trials, and open-label extension studies that involved one of the nine biologics for use in any indication and that reported this study's prespecified adverse outcomes. The researchers did not include studies on biologics for the treatment of HIV/AIDS. The nine biologics investigated were abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan/MabThera), and tocilizumab (Actemra).

They searched the Cochrane Library, Medline, and Embase (through January 2010). The investigators performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework for the network meta-analysis.

In all, included in the analysis were 163 RCTs with 50,010 adult participants and 46 extension studies with 11,954 adult participants. The median duration was 6 months for the RCTs and 13 months for the extension studies. Given the short duration of the RCTs, all the results should be interpreted as applying to a fairly short time frame.

After the analysis was adjusted for dose, biologics as a group were associated with a significantly greater rate of total adverse events (odds ratio 1.19) and withdrawals due to adverse events (OR 1.32), as well as an increased risk of TB reactivation (OR 4.68), compared with control agents.

Notably, certolizumab pegol was associated with a significantly greater risk of serious infections than was control treatment (OR 3.51). Infliximab was associated with a significantly greater risk of withdrawals due to adverse events compared with the control (OR 2.04).

Heart failure and cancer have been of particular concern with the use of biologic drugs. There appears to be little or no difference in the number of people who experienced heart failure or cancer taking any biologic compared with people who took placebo. However, there were not many cases of congestive heart failure or cancer, so confidence in these results is low.

The researchers also were able to indirectly compare individual biologic drugs. These analyses revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events than were most other biologics. In addition, certolizumab pegol was associated with significantly greater odds of serious infections than were etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab. Abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections; abatacept, adalimumab, etanercept, and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. However, the authors noted that the overall numbers were relatively small and that these comparisons should be interpreted with caution.

The lack of long-term studies of biologics is still a concern, they added. "There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics," they concluded.

Dr. Singh and several of his coauthors reported that they have significant financial relationships with several pharmaceutical companies.

Studies show that severe psoriasis is associated with a 50% increased risk of mortality and up to 5 years of life lost, according to Dr. Joel M. Gelfand.

The leading causes of death in psoriasis patients are cardiovascular disease, infection, and cancer, which account for 34%, 22%, and 21% of deaths, respectively (Br. J. Dermatol. 2010;163:586-92), Dr. Gelfand said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Although there are not yet enough data to confirm a causal effect between psoriasis and these leading causes of death, the findings do have implications for managing patients with psoriasis, he said. Data have consistently demonstrated an association between psoriasis and cardiovascular disease, with numerous published studies linking the two conditions.

Taken together, findings from several of these studies suggest that patients with psoriasis are at increased risk of myocardial infarction, stroke, and cardiovascular death, and that those with severe psoriasis have the greatest risks, said Dr. Gelfand of the department of dermatology at the University of Pennsylvania in Philadelphia.

The clinical significance of these findings is striking; patients with severe psoriasis, for example, are 15 times more likely to die prematurely as a result of cardiovascular disease attributable to psoriasis than they are to develop a melanoma, he said.

One study demonstrated a link between psoriasis and several cardiovascular risk factors, including smoking, obesity, dyslipidemia, hypertension, and diabetes, said Dr. Gelfand, who was one of the authors of the study (J. Am. Acad. Dermatol. 2006;55;829-35).

Furthermore, a population-based cohort study involving more than 130,000 psoriasis patients – including more than 3,800 with severe psoriasis - and up to 5 controls per patient, suggested that psoriasis confers an independent risk for myocardial infarction, particularly in young patients with severe psoriasis. The adjusted relative risk of MI in a 30-year-old patient with mild psoriasis was 1.29, and in a 30-year-old with severe psoriasis was 3.01. The adjusted relative risk of MI in a 60-year old with mild psoriasis was 1.08, and in a 60-year-old with severe psoriasis was 1.36, Dr. Gelfand and his colleagues reported (JAMA 2006;296:1735-41).

That study was conducted using the General Practice Research Database of medical records in the United Kingdom, which includes more than 9 million patients and more than 40 million person-years of follow-up data from 1987 to 2002, he said, adding that at least 12 papers have confirmed an association between psoriasis and cardiovascular disease independent of traditional risk factors for cardiovascular disease.

Although the available data on psoriasis and cardiovascular disease demonstrate the biologic credibility of an association, as well as a plausible time sequence suggesting causation, dose response has been demonstrated in only a few studies, and the strength of the study design has been variable, Dr. Gelfand said.

Although most studies have found an effect – along with a modest but clinically important strength of association similar to the association seen in heart disease, hypertension, and diabetes – data from a randomized controlled trial are needed before a causal relationship between psoriasis and cardiovascular disease can be confirmed, and before a link between aggressive treatment of psoriasis and a reduced risk of cardiovascular disease can be demonstrated, he said in an interview, adding that it currently remains unclear whether aggressive treatment will lower cardiovascular disease risk.

However, the U.S. Preventive Services Task Force, the American Diabetes Association, and the National Cholesterol Education Program recommend that severe psoriasis patients over age 21 years undergo blood pressure screening at each office visit; that those aged 45 years and older undergo fasting blood glucose testing every 3 years (unless they have diabetes risk factors, in which case they should undergo screening earlier and more often); and that those aged 20 years and older undergo cholesterol screening every 5 years.

Existing data also support recommendations for addressing concerns about infection and cancer risk in patients with psoriasis, Dr. Gelfand said.

Patients with severe psoriasis are 65% more likely to die of an infection than are those without psoriasis (Br. J. Dermatol. 2010;163:586-92). Specifically, studies have shown that streptococcal pharyngitis is a risk factor for guttate psoriasis, and that HIV is a risk factor for severe psoriasis, he said, noting that it is recommended that patients be screened for streptococcal infection with guttate flares, and that they be screened for HIV if they have severe psoriasis.

It is also important that patients with psoriasis be routinely vaccinated – prior to initiation of immunosuppressive therapy – against influenza and pneumonia. Vaccination against hepatitis B in patients at risk for infection should also be considered, as well as vaccination against zoster in patients aged 60 and older.

As for cancer, it is a concern in psoriasis patients because of the chronic use of immunosuppressive therapies, comorbid behaviors, and chronic inflammation, Dr. Gelfand said. Patients with severe psoriasis are 41% more likely to die of cancer than are those without psoriasis.

Studies have shown – although not consistently – that psoriasis may be linked with lung, liver, pancreatic, breast, colon, bladder, and kidney cancer. Lymphoma is also a particular concern, with cutaneous T-cell lymphoma having the strongest association.

As with cardiovascular disease, however, findings are not strong or consistent enough to confirm a causal effect of psoriasis on cancer risk, or to clarify whether any association is a disease effect or treatment effect.

Still, the available findings are concerning enough that biopsy should be considered in severe disease, especially if clinical features are not classic, and in those who fail to respond to treatment, because cutaneous T-cell lymphoma may progress rapidly in those on immunosuppressive therapy.

"Always consider a skin biopsy in patients with atypical features of psoriasis and those not responding to treatment," Dr. Gelfand said.

Also, encourage patients to stay up to date on age-appropriate cancer screening. According to Centers for Disease Control guidelines, women aged 21-70 years should undergo cervical cancer screening every 2-3 years, women aged 50-74 years should undergo screening for breast cancer by mammography every 2 years, and men and women aged 50-75 years should undergo screening for colon cancer by fecal occult blood testing every year, by flexible sigmoidoscopy every 5 years, and by colonoscopy every 10 years, he said.

Dr. Gelfand has been an investigator and/or consultant for Amgen, Abbott, Centocor, Pfizer, Celgene, Novartis, and Genentech. He reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.

Studies show that severe psoriasis is associated with a 50% increased risk of mortality and up to 5 years of life lost, according to Dr. Joel M. Gelfand.

The leading causes of death in psoriasis patients are cardiovascular disease, infection, and cancer, which account for 34%, 22%, and 21% of deaths, respectively (Br. J. Dermatol. 2010;163:586-92), Dr. Gelfand said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Although there are not yet enough data to confirm a causal effect between psoriasis and these leading causes of death, the findings do have implications for managing patients with psoriasis, he said. Data have consistently demonstrated an association between psoriasis and cardiovascular disease, with numerous published studies linking the two conditions.

Taken together, findings from several of these studies suggest that patients with psoriasis are at increased risk of myocardial infarction, stroke, and cardiovascular death, and that those with severe psoriasis have the greatest risks, said Dr. Gelfand of the department of dermatology at the University of Pennsylvania in Philadelphia.

The clinical significance of these findings is striking; patients with severe psoriasis, for example, are 15 times more likely to die prematurely as a result of cardiovascular disease attributable to psoriasis than they are to develop a melanoma, he said.

One study demonstrated a link between psoriasis and several cardiovascular risk factors, including smoking, obesity, dyslipidemia, hypertension, and diabetes, said Dr. Gelfand, who was one of the authors of the study (J. Am. Acad. Dermatol. 2006;55;829-35).

Furthermore, a population-based cohort study involving more than 130,000 psoriasis patients – including more than 3,800 with severe psoriasis - and up to 5 controls per patient, suggested that psoriasis confers an independent risk for myocardial infarction, particularly in young patients with severe psoriasis. The adjusted relative risk of MI in a 30-year-old patient with mild psoriasis was 1.29, and in a 30-year-old with severe psoriasis was 3.01. The adjusted relative risk of MI in a 60-year old with mild psoriasis was 1.08, and in a 60-year-old with severe psoriasis was 1.36, Dr. Gelfand and his colleagues reported (JAMA 2006;296:1735-41).

That study was conducted using the General Practice Research Database of medical records in the United Kingdom, which includes more than 9 million patients and more than 40 million person-years of follow-up data from 1987 to 2002, he said, adding that at least 12 papers have confirmed an association between psoriasis and cardiovascular disease independent of traditional risk factors for cardiovascular disease.

Although the available data on psoriasis and cardiovascular disease demonstrate the biologic credibility of an association, as well as a plausible time sequence suggesting causation, dose response has been demonstrated in only a few studies, and the strength of the study design has been variable, Dr. Gelfand said.

Although most studies have found an effect – along with a modest but clinically important strength of association similar to the association seen in heart disease, hypertension, and diabetes – data from a randomized controlled trial are needed before a causal relationship between psoriasis and cardiovascular disease can be confirmed, and before a link between aggressive treatment of psoriasis and a reduced risk of cardiovascular disease can be demonstrated, he said in an interview, adding that it currently remains unclear whether aggressive treatment will lower cardiovascular disease risk.

However, the U.S. Preventive Services Task Force, the American Diabetes Association, and the National Cholesterol Education Program recommend that severe psoriasis patients over age 21 years undergo blood pressure screening at each office visit; that those aged 45 years and older undergo fasting blood glucose testing every 3 years (unless they have diabetes risk factors, in which case they should undergo screening earlier and more often); and that those aged 20 years and older undergo cholesterol screening every 5 years.

Existing data also support recommendations for addressing concerns about infection and cancer risk in patients with psoriasis, Dr. Gelfand said.

Patients with severe psoriasis are 65% more likely to die of an infection than are those without psoriasis (Br. J. Dermatol. 2010;163:586-92). Specifically, studies have shown that streptococcal pharyngitis is a risk factor for guttate psoriasis, and that HIV is a risk factor for severe psoriasis, he said, noting that it is recommended that patients be screened for streptococcal infection with guttate flares, and that they be screened for HIV if they have severe psoriasis.

It is also important that patients with psoriasis be routinely vaccinated – prior to initiation of immunosuppressive therapy – against influenza and pneumonia. Vaccination against hepatitis B in patients at risk for infection should also be considered, as well as vaccination against zoster in patients aged 60 and older.

As for cancer, it is a concern in psoriasis patients because of the chronic use of immunosuppressive therapies, comorbid behaviors, and chronic inflammation, Dr. Gelfand said. Patients with severe psoriasis are 41% more likely to die of cancer than are those without psoriasis.

Studies have shown – although not consistently – that psoriasis may be linked with lung, liver, pancreatic, breast, colon, bladder, and kidney cancer. Lymphoma is also a particular concern, with cutaneous T-cell lymphoma having the strongest association.

As with cardiovascular disease, however, findings are not strong or consistent enough to confirm a causal effect of psoriasis on cancer risk, or to clarify whether any association is a disease effect or treatment effect.

Still, the available findings are concerning enough that biopsy should be considered in severe disease, especially if clinical features are not classic, and in those who fail to respond to treatment, because cutaneous T-cell lymphoma may progress rapidly in those on immunosuppressive therapy.

"Always consider a skin biopsy in patients with atypical features of psoriasis and those not responding to treatment," Dr. Gelfand said.

Also, encourage patients to stay up to date on age-appropriate cancer screening. According to Centers for Disease Control guidelines, women aged 21-70 years should undergo cervical cancer screening every 2-3 years, women aged 50-74 years should undergo screening for breast cancer by mammography every 2 years, and men and women aged 50-75 years should undergo screening for colon cancer by fecal occult blood testing every year, by flexible sigmoidoscopy every 5 years, and by colonoscopy every 10 years, he said.

Dr. Gelfand has been an investigator and/or consultant for Amgen, Abbott, Centocor, Pfizer, Celgene, Novartis, and Genentech. He reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.

Studies show that severe psoriasis is associated with a 50% increased risk of mortality and up to 5 years of life lost, according to Dr. Joel M. Gelfand.

The leading causes of death in psoriasis patients are cardiovascular disease, infection, and cancer, which account for 34%, 22%, and 21% of deaths, respectively (Br. J. Dermatol. 2010;163:586-92), Dr. Gelfand said at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF).

Although there are not yet enough data to confirm a causal effect between psoriasis and these leading causes of death, the findings do have implications for managing patients with psoriasis, he said. Data have consistently demonstrated an association between psoriasis and cardiovascular disease, with numerous published studies linking the two conditions.

Taken together, findings from several of these studies suggest that patients with psoriasis are at increased risk of myocardial infarction, stroke, and cardiovascular death, and that those with severe psoriasis have the greatest risks, said Dr. Gelfand of the department of dermatology at the University of Pennsylvania in Philadelphia.

The clinical significance of these findings is striking; patients with severe psoriasis, for example, are 15 times more likely to die prematurely as a result of cardiovascular disease attributable to psoriasis than they are to develop a melanoma, he said.

One study demonstrated a link between psoriasis and several cardiovascular risk factors, including smoking, obesity, dyslipidemia, hypertension, and diabetes, said Dr. Gelfand, who was one of the authors of the study (J. Am. Acad. Dermatol. 2006;55;829-35).

Furthermore, a population-based cohort study involving more than 130,000 psoriasis patients – including more than 3,800 with severe psoriasis - and up to 5 controls per patient, suggested that psoriasis confers an independent risk for myocardial infarction, particularly in young patients with severe psoriasis. The adjusted relative risk of MI in a 30-year-old patient with mild psoriasis was 1.29, and in a 30-year-old with severe psoriasis was 3.01. The adjusted relative risk of MI in a 60-year old with mild psoriasis was 1.08, and in a 60-year-old with severe psoriasis was 1.36, Dr. Gelfand and his colleagues reported (JAMA 2006;296:1735-41).

That study was conducted using the General Practice Research Database of medical records in the United Kingdom, which includes more than 9 million patients and more than 40 million person-years of follow-up data from 1987 to 2002, he said, adding that at least 12 papers have confirmed an association between psoriasis and cardiovascular disease independent of traditional risk factors for cardiovascular disease.

Although the available data on psoriasis and cardiovascular disease demonstrate the biologic credibility of an association, as well as a plausible time sequence suggesting causation, dose response has been demonstrated in only a few studies, and the strength of the study design has been variable, Dr. Gelfand said.

Although most studies have found an effect – along with a modest but clinically important strength of association similar to the association seen in heart disease, hypertension, and diabetes – data from a randomized controlled trial are needed before a causal relationship between psoriasis and cardiovascular disease can be confirmed, and before a link between aggressive treatment of psoriasis and a reduced risk of cardiovascular disease can be demonstrated, he said in an interview, adding that it currently remains unclear whether aggressive treatment will lower cardiovascular disease risk.

However, the U.S. Preventive Services Task Force, the American Diabetes Association, and the National Cholesterol Education Program recommend that severe psoriasis patients over age 21 years undergo blood pressure screening at each office visit; that those aged 45 years and older undergo fasting blood glucose testing every 3 years (unless they have diabetes risk factors, in which case they should undergo screening earlier and more often); and that those aged 20 years and older undergo cholesterol screening every 5 years.

Existing data also support recommendations for addressing concerns about infection and cancer risk in patients with psoriasis, Dr. Gelfand said.

Patients with severe psoriasis are 65% more likely to die of an infection than are those without psoriasis (Br. J. Dermatol. 2010;163:586-92). Specifically, studies have shown that streptococcal pharyngitis is a risk factor for guttate psoriasis, and that HIV is a risk factor for severe psoriasis, he said, noting that it is recommended that patients be screened for streptococcal infection with guttate flares, and that they be screened for HIV if they have severe psoriasis.

It is also important that patients with psoriasis be routinely vaccinated – prior to initiation of immunosuppressive therapy – against influenza and pneumonia. Vaccination against hepatitis B in patients at risk for infection should also be considered, as well as vaccination against zoster in patients aged 60 and older.

As for cancer, it is a concern in psoriasis patients because of the chronic use of immunosuppressive therapies, comorbid behaviors, and chronic inflammation, Dr. Gelfand said. Patients with severe psoriasis are 41% more likely to die of cancer than are those without psoriasis.

Studies have shown – although not consistently – that psoriasis may be linked with lung, liver, pancreatic, breast, colon, bladder, and kidney cancer. Lymphoma is also a particular concern, with cutaneous T-cell lymphoma having the strongest association.

As with cardiovascular disease, however, findings are not strong or consistent enough to confirm a causal effect of psoriasis on cancer risk, or to clarify whether any association is a disease effect or treatment effect.

Still, the available findings are concerning enough that biopsy should be considered in severe disease, especially if clinical features are not classic, and in those who fail to respond to treatment, because cutaneous T-cell lymphoma may progress rapidly in those on immunosuppressive therapy.

"Always consider a skin biopsy in patients with atypical features of psoriasis and those not responding to treatment," Dr. Gelfand said.

Also, encourage patients to stay up to date on age-appropriate cancer screening. According to Centers for Disease Control guidelines, women aged 21-70 years should undergo cervical cancer screening every 2-3 years, women aged 50-74 years should undergo screening for breast cancer by mammography every 2 years, and men and women aged 50-75 years should undergo screening for colon cancer by fecal occult blood testing every year, by flexible sigmoidoscopy every 5 years, and by colonoscopy every 10 years, he said.

Dr. Gelfand has been an investigator and/or consultant for Amgen, Abbott, Centocor, Pfizer, Celgene, Novartis, and Genentech. He reported having no relevant financial disclosures. SDEF and this news organization are owned by Elsevier.

The limitations of the drug approval process in fully characterizing a new drug's safety profile are clearly illustrated in the dermatologic therapeutics arena and clinicians should keep these limitations in mind when prescribing and counseling patients about a relatively new therapeutic agent, according to Dr. Joel M. Gelfand.

Previously unknown risks of new drugs are routinely identified after Food and Drug Administration approval, when "rare" adverse events are more likely to be detected, said Dr. Gelfand at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). Examples of rare adverse events – those that occur at a rate of less than 1 per 1,000 – include fatal arrhythmias associated with terfenadine and astemizole, lymphomas associated with biologics, and progressive multifocal leukoencephalopathy (PML) associated with efalizumab.

The clinical trials that are the basis of drug approvals evaluate short-term safety only and lack the statistical power to detect rare events, he said, pointing out that a study of 3,000 patients can only detect adverse events that occur at a rate of more than 1 per 1,000.

The types of adverse effects detected pre-approval are pharmacologic side effects, which are common and dose dependent, such as isotretinoin-induced cheilitis, said Dr. Gelfand, of the department of dermatology at the University of Pennsylvania in Philadelphia.

Adverse effects that are detected after approval fall into two categories: idiosyncratic or allergic reactions, which are rare and "occur in close proximity to exposure," he said, such as dapsone-induced agranulocytosis, and new morbidities, which are delayed and uncommon. An example of the latter is skin cancers associated with psoralen and ultraviolet A (PUVA) treatment, which was associated with melanoma in 1997, more than 2 decades after it was found to be effective for treating psoriasis.

There is a need for ongoing risk assessment throughout the life cycle of a drug, Dr. Gelfand said, which includes MedWatch, the FDA's voluntary adverse event reporting program that relies on spontaneous reporting of adverse events. MedWatch's advantages include that it is inexpensive and can identify safety signals; however, it is limited by under-reporting and MedWatch reports usually cannot be used to determine causality, he noted.

The association between efalizumab (Raptiva) and PML, an untreatable and often fatal central nervous system infection that occurs primarily in the setting of immunosuppression, is an example of "signal detection in action," Dr. Gelfand said. Efalizumab was approved in 2003 for psoriasis, based on studies of about 2,700 people, including 218 treated for more than 1 year. By 2008, after 46,000 people had been treated, including 3,000 for at least 2 years, there had been 3 confirmed cases and one suspected case of PML. All four were spontaneous reports, which "can be useful for very rare diseases such as PML," he said.

With efalizumab treatment, the overall estimated risk of PML is 1 in 15,000 patients per year and one in 1,000 patients treated for more than 2 years. These are likely underestimates because of incomplete reporting, and is a relationship that is "likely causal," he said. In the case of efalizumab, the risk was "judged unacceptable given treatment alternatives and disease indication" and the drug was withdrawn from the market in 2009.

A causal association between isotretinoin and inflammatory bowel disease (IBD) has not been established, but the drug's prescribing information includes a warning about the association.

The data on isotretinoin and IBD include a large administrative claims database of over 8,000 cases of IBD, and 21,832 controls published in 2010 (Am. J. Gastroenterol. 2010;105:1986-93). Analysis of the database found that the risk of IBD within 12 months of being treated with isotretinoin was 1.7; for ulcerative colitis, the risk was increased fourfold; for Crohn's disease the risk was slightly reduced.

In that study, which controlled for age, sex, and geographic region, the dose response was evident for ulcerative colitis only, Dr. Gelfand said.

In a review of 85 spontaneous reports of IBD in isotretinoin patients to the FDA between 1997-2002, isotretinoin was considered "highly probable" as the cause in 4 cases (5%), "probable" in 58 cases (68%), and "possible" in 23 cases (27%). These included three cases with a positive dechallenge and rechallenge.

When in comes to ulcerative colitis, the overall data available "suggest a specific association" between isotretinoin and the disease, but the data are conflicting, he said. Studies have not addressed the possibility that patients with severe acne are at an increased risk of ulcerative colitis, or of confounding variables including oral antibiotics and smoking, he said. If the risk is real, it is small, with a number needed to harm that exceeds 3,300.

With these examples in mind, Dr. Gelfand advised clinicians to "use the science of medicine in judging safety... [and] the art of medicine" when communicating the risk of therapies to their patients.

"The benefits of treatments are well-characterized relative to the long-term safety and the risk of rare but serious medical events," he said. "Sir William Osler was the first to recognize the need to be cautious when prescribing new medications advising physicians 'Do not be the first to prescribe a new drug and do not be the last to stop prescribing an old drug.' "

Dr. Gelfand disclosed that he has been an investigator and/or consultant to Amgen, Abbott, Centocor, Pfizer, Celegene, Novartis, and Genentech, and that his presentation was his work only.

SDEF and this news organization are owned by Elsevier.

The limitations of the drug approval process in fully characterizing a new drug's safety profile are clearly illustrated in the dermatologic therapeutics arena and clinicians should keep these limitations in mind when prescribing and counseling patients about a relatively new therapeutic agent, according to Dr. Joel M. Gelfand.

Previously unknown risks of new drugs are routinely identified after Food and Drug Administration approval, when "rare" adverse events are more likely to be detected, said Dr. Gelfand at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). Examples of rare adverse events – those that occur at a rate of less than 1 per 1,000 – include fatal arrhythmias associated with terfenadine and astemizole, lymphomas associated with biologics, and progressive multifocal leukoencephalopathy (PML) associated with efalizumab.

The clinical trials that are the basis of drug approvals evaluate short-term safety only and lack the statistical power to detect rare events, he said, pointing out that a study of 3,000 patients can only detect adverse events that occur at a rate of more than 1 per 1,000.

The types of adverse effects detected pre-approval are pharmacologic side effects, which are common and dose dependent, such as isotretinoin-induced cheilitis, said Dr. Gelfand, of the department of dermatology at the University of Pennsylvania in Philadelphia.

Adverse effects that are detected after approval fall into two categories: idiosyncratic or allergic reactions, which are rare and "occur in close proximity to exposure," he said, such as dapsone-induced agranulocytosis, and new morbidities, which are delayed and uncommon. An example of the latter is skin cancers associated with psoralen and ultraviolet A (PUVA) treatment, which was associated with melanoma in 1997, more than 2 decades after it was found to be effective for treating psoriasis.

There is a need for ongoing risk assessment throughout the life cycle of a drug, Dr. Gelfand said, which includes MedWatch, the FDA's voluntary adverse event reporting program that relies on spontaneous reporting of adverse events. MedWatch's advantages include that it is inexpensive and can identify safety signals; however, it is limited by under-reporting and MedWatch reports usually cannot be used to determine causality, he noted.

The association between efalizumab (Raptiva) and PML, an untreatable and often fatal central nervous system infection that occurs primarily in the setting of immunosuppression, is an example of "signal detection in action," Dr. Gelfand said. Efalizumab was approved in 2003 for psoriasis, based on studies of about 2,700 people, including 218 treated for more than 1 year. By 2008, after 46,000 people had been treated, including 3,000 for at least 2 years, there had been 3 confirmed cases and one suspected case of PML. All four were spontaneous reports, which "can be useful for very rare diseases such as PML," he said.

With efalizumab treatment, the overall estimated risk of PML is 1 in 15,000 patients per year and one in 1,000 patients treated for more than 2 years. These are likely underestimates because of incomplete reporting, and is a relationship that is "likely causal," he said. In the case of efalizumab, the risk was "judged unacceptable given treatment alternatives and disease indication" and the drug was withdrawn from the market in 2009.

A causal association between isotretinoin and inflammatory bowel disease (IBD) has not been established, but the drug's prescribing information includes a warning about the association.

The data on isotretinoin and IBD include a large administrative claims database of over 8,000 cases of IBD, and 21,832 controls published in 2010 (Am. J. Gastroenterol. 2010;105:1986-93). Analysis of the database found that the risk of IBD within 12 months of being treated with isotretinoin was 1.7; for ulcerative colitis, the risk was increased fourfold; for Crohn's disease the risk was slightly reduced.

In that study, which controlled for age, sex, and geographic region, the dose response was evident for ulcerative colitis only, Dr. Gelfand said.

In a review of 85 spontaneous reports of IBD in isotretinoin patients to the FDA between 1997-2002, isotretinoin was considered "highly probable" as the cause in 4 cases (5%), "probable" in 58 cases (68%), and "possible" in 23 cases (27%). These included three cases with a positive dechallenge and rechallenge.

When in comes to ulcerative colitis, the overall data available "suggest a specific association" between isotretinoin and the disease, but the data are conflicting, he said. Studies have not addressed the possibility that patients with severe acne are at an increased risk of ulcerative colitis, or of confounding variables including oral antibiotics and smoking, he said. If the risk is real, it is small, with a number needed to harm that exceeds 3,300.

With these examples in mind, Dr. Gelfand advised clinicians to "use the science of medicine in judging safety... [and] the art of medicine" when communicating the risk of therapies to their patients.

"The benefits of treatments are well-characterized relative to the long-term safety and the risk of rare but serious medical events," he said. "Sir William Osler was the first to recognize the need to be cautious when prescribing new medications advising physicians 'Do not be the first to prescribe a new drug and do not be the last to stop prescribing an old drug.' "

Dr. Gelfand disclosed that he has been an investigator and/or consultant to Amgen, Abbott, Centocor, Pfizer, Celegene, Novartis, and Genentech, and that his presentation was his work only.

SDEF and this news organization are owned by Elsevier.

The limitations of the drug approval process in fully characterizing a new drug's safety profile are clearly illustrated in the dermatologic therapeutics arena and clinicians should keep these limitations in mind when prescribing and counseling patients about a relatively new therapeutic agent, according to Dr. Joel M. Gelfand.

Previously unknown risks of new drugs are routinely identified after Food and Drug Administration approval, when "rare" adverse events are more likely to be detected, said Dr. Gelfand at the Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation (SDEF). Examples of rare adverse events – those that occur at a rate of less than 1 per 1,000 – include fatal arrhythmias associated with terfenadine and astemizole, lymphomas associated with biologics, and progressive multifocal leukoencephalopathy (PML) associated with efalizumab.

The clinical trials that are the basis of drug approvals evaluate short-term safety only and lack the statistical power to detect rare events, he said, pointing out that a study of 3,000 patients can only detect adverse events that occur at a rate of more than 1 per 1,000.

The types of adverse effects detected pre-approval are pharmacologic side effects, which are common and dose dependent, such as isotretinoin-induced cheilitis, said Dr. Gelfand, of the department of dermatology at the University of Pennsylvania in Philadelphia.

Adverse effects that are detected after approval fall into two categories: idiosyncratic or allergic reactions, which are rare and "occur in close proximity to exposure," he said, such as dapsone-induced agranulocytosis, and new morbidities, which are delayed and uncommon. An example of the latter is skin cancers associated with psoralen and ultraviolet A (PUVA) treatment, which was associated with melanoma in 1997, more than 2 decades after it was found to be effective for treating psoriasis.

There is a need for ongoing risk assessment throughout the life cycle of a drug, Dr. Gelfand said, which includes MedWatch, the FDA's voluntary adverse event reporting program that relies on spontaneous reporting of adverse events. MedWatch's advantages include that it is inexpensive and can identify safety signals; however, it is limited by under-reporting and MedWatch reports usually cannot be used to determine causality, he noted.

The association between efalizumab (Raptiva) and PML, an untreatable and often fatal central nervous system infection that occurs primarily in the setting of immunosuppression, is an example of "signal detection in action," Dr. Gelfand said. Efalizumab was approved in 2003 for psoriasis, based on studies of about 2,700 people, including 218 treated for more than 1 year. By 2008, after 46,000 people had been treated, including 3,000 for at least 2 years, there had been 3 confirmed cases and one suspected case of PML. All four were spontaneous reports, which "can be useful for very rare diseases such as PML," he said.

With efalizumab treatment, the overall estimated risk of PML is 1 in 15,000 patients per year and one in 1,000 patients treated for more than 2 years. These are likely underestimates because of incomplete reporting, and is a relationship that is "likely causal," he said. In the case of efalizumab, the risk was "judged unacceptable given treatment alternatives and disease indication" and the drug was withdrawn from the market in 2009.

A causal association between isotretinoin and inflammatory bowel disease (IBD) has not been established, but the drug's prescribing information includes a warning about the association.

The data on isotretinoin and IBD include a large administrative claims database of over 8,000 cases of IBD, and 21,832 controls published in 2010 (Am. J. Gastroenterol. 2010;105:1986-93). Analysis of the database found that the risk of IBD within 12 months of being treated with isotretinoin was 1.7; for ulcerative colitis, the risk was increased fourfold; for Crohn's disease the risk was slightly reduced.

In that study, which controlled for age, sex, and geographic region, the dose response was evident for ulcerative colitis only, Dr. Gelfand said.

In a review of 85 spontaneous reports of IBD in isotretinoin patients to the FDA between 1997-2002, isotretinoin was considered "highly probable" as the cause in 4 cases (5%), "probable" in 58 cases (68%), and "possible" in 23 cases (27%). These included three cases with a positive dechallenge and rechallenge.

When in comes to ulcerative colitis, the overall data available "suggest a specific association" between isotretinoin and the disease, but the data are conflicting, he said. Studies have not addressed the possibility that patients with severe acne are at an increased risk of ulcerative colitis, or of confounding variables including oral antibiotics and smoking, he said. If the risk is real, it is small, with a number needed to harm that exceeds 3,300.

With these examples in mind, Dr. Gelfand advised clinicians to "use the science of medicine in judging safety... [and] the art of medicine" when communicating the risk of therapies to their patients.

"The benefits of treatments are well-characterized relative to the long-term safety and the risk of rare but serious medical events," he said. "Sir William Osler was the first to recognize the need to be cautious when prescribing new medications advising physicians 'Do not be the first to prescribe a new drug and do not be the last to stop prescribing an old drug.' "

Dr. Gelfand disclosed that he has been an investigator and/or consultant to Amgen, Abbott, Centocor, Pfizer, Celegene, Novartis, and Genentech, and that his presentation was his work only.

SDEF and this news organization are owned by Elsevier.

The drug sildenafil reduced the frequency of attacks of Raynaud's phenomenon secondary to limited cutaneous systemic sclerosis in a small, randomized, placebo-controlled trial that was reported in Arthritis & Rheumatism.

The study enrolled 57 men and women aged 18-75 years, all of whom both had a diagnosis of Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis and experienced at least 7 attacks per week. Patients were randomized to receive modified-release sildenafil (100 mg once daily for 3 days, titrated to 200 mg once daily for 25 days) or placebo, reported Dr. Ariane Herrick of the University of Manchester (England) and her associates (Arthritis Rheum. 2011;63:775-82).

Of the 57 people originally enrolled, 20 in the treatment group and 25 controls completed the 28-day study and were entered into analysis. Patients kept treatment diaries before and during the study period, recording the duration and pain intensity of each attack; serum samples were taken on days 1, 7, and 28.

The primary end point was the percent change in the number of weekly RP attacks. Secondary end points measured the severity and duration of attacks.

After 28 days, the mean number of RP attacks per week lessened from 25 at baseline to 19 in the control arm, and from 31 at baseline to 19 in the treatment arm, with a mean percent reduction of 44% in the treatment arm, compared with 18% in the control arm (P = .034). Statistically insignificant differences were noted between the groups for Raynaud’s Condition Score, duration of attacks, pain score, endothelial dysfunction, or serum biomarkers associated with RP. The most frequent adverse events reported were headache and dyspepsia.

Dr. Ulf Müller-Ladner, professor of internal medicine and rheumatology at Justus-Liebig University Giessen (Germany), said in an interview that this "is a very important study, as we do not have too many controlled clinical trials for Raynaud’s, and every controlled study showing efficacy is very helpful for daily practice." The investigators acknowledged the study’s small size and high attrition from the intention-to-treat sildenafil arm as limitations, particularly as the study was no longer powered to detect secondary end points. Also disappointing, they wrote, was that the endothelial dysfunction measures and the serum levels of biomarkers were similar between the groups.

The study's short duration was another possible limitation. The findings from an earlier, longer (5.2-month) study of sildenafil in 16 patients with systemic sclerosis – of whom 7 had limited cutaneous involvement – showed statistically significant lessening of attack pain associated with RP with the maximum tolerated dose of sildenafil (Ann. Rheum. Dis. 2010;69:1475-8).

Finally, they noted, the modified-release formulation of sildenafil may not have provided the most effective dose for the patient population studied.

Dr. Müller-Ladner agreed with the description of the study's design weaknesses: "The shortcomings of the present study are its placebo arm and its short duration. These results must be confirmed through the initiation of a large, multinational, longer-term trial."

The trial was funded by Pfizer, the drug's manufacturer. Dr. Herrick acknowledged financial relationships with Actelion, Mediquest, Pfizer, and United Therapeutics. Several of the coinvestigators also made relevant financial disclosures. Dr. Müller-Ladner had no relevant financial disclosures.

The drug sildenafil reduced the frequency of attacks of Raynaud's phenomenon secondary to limited cutaneous systemic sclerosis in a small, randomized, placebo-controlled trial that was reported in Arthritis & Rheumatism.

The study enrolled 57 men and women aged 18-75 years, all of whom both had a diagnosis of Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis and experienced at least 7 attacks per week. Patients were randomized to receive modified-release sildenafil (100 mg once daily for 3 days, titrated to 200 mg once daily for 25 days) or placebo, reported Dr. Ariane Herrick of the University of Manchester (England) and her associates (Arthritis Rheum. 2011;63:775-82).

Of the 57 people originally enrolled, 20 in the treatment group and 25 controls completed the 28-day study and were entered into analysis. Patients kept treatment diaries before and during the study period, recording the duration and pain intensity of each attack; serum samples were taken on days 1, 7, and 28.

The primary end point was the percent change in the number of weekly RP attacks. Secondary end points measured the severity and duration of attacks.

After 28 days, the mean number of RP attacks per week lessened from 25 at baseline to 19 in the control arm, and from 31 at baseline to 19 in the treatment arm, with a mean percent reduction of 44% in the treatment arm, compared with 18% in the control arm (P = .034). Statistically insignificant differences were noted between the groups for Raynaud’s Condition Score, duration of attacks, pain score, endothelial dysfunction, or serum biomarkers associated with RP. The most frequent adverse events reported were headache and dyspepsia.

Dr. Ulf Müller-Ladner, professor of internal medicine and rheumatology at Justus-Liebig University Giessen (Germany), said in an interview that this "is a very important study, as we do not have too many controlled clinical trials for Raynaud’s, and every controlled study showing efficacy is very helpful for daily practice." The investigators acknowledged the study’s small size and high attrition from the intention-to-treat sildenafil arm as limitations, particularly as the study was no longer powered to detect secondary end points. Also disappointing, they wrote, was that the endothelial dysfunction measures and the serum levels of biomarkers were similar between the groups.

The study's short duration was another possible limitation. The findings from an earlier, longer (5.2-month) study of sildenafil in 16 patients with systemic sclerosis – of whom 7 had limited cutaneous involvement – showed statistically significant lessening of attack pain associated with RP with the maximum tolerated dose of sildenafil (Ann. Rheum. Dis. 2010;69:1475-8).

Finally, they noted, the modified-release formulation of sildenafil may not have provided the most effective dose for the patient population studied.

Dr. Müller-Ladner agreed with the description of the study's design weaknesses: "The shortcomings of the present study are its placebo arm and its short duration. These results must be confirmed through the initiation of a large, multinational, longer-term trial."

The trial was funded by Pfizer, the drug's manufacturer. Dr. Herrick acknowledged financial relationships with Actelion, Mediquest, Pfizer, and United Therapeutics. Several of the coinvestigators also made relevant financial disclosures. Dr. Müller-Ladner had no relevant financial disclosures.

The drug sildenafil reduced the frequency of attacks of Raynaud's phenomenon secondary to limited cutaneous systemic sclerosis in a small, randomized, placebo-controlled trial that was reported in Arthritis & Rheumatism.

The study enrolled 57 men and women aged 18-75 years, all of whom both had a diagnosis of Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis and experienced at least 7 attacks per week. Patients were randomized to receive modified-release sildenafil (100 mg once daily for 3 days, titrated to 200 mg once daily for 25 days) or placebo, reported Dr. Ariane Herrick of the University of Manchester (England) and her associates (Arthritis Rheum. 2011;63:775-82).

Of the 57 people originally enrolled, 20 in the treatment group and 25 controls completed the 28-day study and were entered into analysis. Patients kept treatment diaries before and during the study period, recording the duration and pain intensity of each attack; serum samples were taken on days 1, 7, and 28.

The primary end point was the percent change in the number of weekly RP attacks. Secondary end points measured the severity and duration of attacks.

After 28 days, the mean number of RP attacks per week lessened from 25 at baseline to 19 in the control arm, and from 31 at baseline to 19 in the treatment arm, with a mean percent reduction of 44% in the treatment arm, compared with 18% in the control arm (P = .034). Statistically insignificant differences were noted between the groups for Raynaud’s Condition Score, duration of attacks, pain score, endothelial dysfunction, or serum biomarkers associated with RP. The most frequent adverse events reported were headache and dyspepsia.

Dr. Ulf Müller-Ladner, professor of internal medicine and rheumatology at Justus-Liebig University Giessen (Germany), said in an interview that this "is a very important study, as we do not have too many controlled clinical trials for Raynaud’s, and every controlled study showing efficacy is very helpful for daily practice." The investigators acknowledged the study’s small size and high attrition from the intention-to-treat sildenafil arm as limitations, particularly as the study was no longer powered to detect secondary end points. Also disappointing, they wrote, was that the endothelial dysfunction measures and the serum levels of biomarkers were similar between the groups.

The study's short duration was another possible limitation. The findings from an earlier, longer (5.2-month) study of sildenafil in 16 patients with systemic sclerosis – of whom 7 had limited cutaneous involvement – showed statistically significant lessening of attack pain associated with RP with the maximum tolerated dose of sildenafil (Ann. Rheum. Dis. 2010;69:1475-8).

Finally, they noted, the modified-release formulation of sildenafil may not have provided the most effective dose for the patient population studied.

Dr. Müller-Ladner agreed with the description of the study's design weaknesses: "The shortcomings of the present study are its placebo arm and its short duration. These results must be confirmed through the initiation of a large, multinational, longer-term trial."

The trial was funded by Pfizer, the drug's manufacturer. Dr. Herrick acknowledged financial relationships with Actelion, Mediquest, Pfizer, and United Therapeutics. Several of the coinvestigators also made relevant financial disclosures. Dr. Müller-Ladner had no relevant financial disclosures.

The announcement late on March 9 from the Food and Drug Administration that it had approved belimumab as a treatment for systemic lupus erythematosus, the first new treatment approved for this disease in more than 50 years, produced reaction among lupus specialists that ran the gamut from unrestrained elation to somewhat more restrained enthusiasm.

Regardless of the degree of caution experts might have about the efficacy of belimumab and the consequences of its widespread use, there was no denying that its approval marked a milestone for the management of patients with systemic lupus erythematosus (SLE).

"I've been calling my friends and going yippee. This is a historic day for lupus patients," said Dr. Joan T. Merrill, professor of medicine and chair of the clinical pharmacology research program at the Oklahoma Medical Research Foundation in Oklahoma City, who participated in the belimumab trials and exemplified a more enthusiastic take on the drug's approval.

A more cautious but still welcoming view came from Dr. David Wofsy, who was not involved in the belimumab studies. "I expect the drug will be widely used in lupus, given the great, unmet need for new therapies. But patients and physicians need to remain cognizant of the fact that roughly half of the subjects in the trials did not achieve the desired clinical outcome" a novel measure designed specifically for the two pivotal belimumab trials, the SLE Responder Index, said Dr. Wofsy, a professor of rheumatology at the University of California, San Francisco.

"Moreover, at this point, there is relatively little information about the effect of belimumab in patients with the most serious manifestations of lupus," such as active nephritis and central nervous system manifestations, Dr. Wofsy said in an interview. The majority of patients in the belimumab trials had cutaneous manifestations, musculoskeletal manifestations, or both, so we are beginning to understand the potential benefit of the drug in these patients. It will take time and undoubtedly more trials before we know how the drug will perform in patients with other manifestations.

"There is understandably great excitement about this landmark achievement, but patients and physicians will be well served if they remain realistic in their expectations and cautious in their use of a new agent," Dr. Wofsy said.

Dr. Merrill applied less caution in her assessment of the role belimumab will fill once physicians start prescribing it.

"I believe it will be tried in many [SLE] patients over the next year," she said in an interview. "I will certainly try it in many of my patients. The majority of lupus patients will flare sooner or later on the medicine they're on. If they flare a little, I'd first look to raise the dose of the drug they're on before I go to a brand new biologic such as belimumab. But we have a lot of patients where that [raising the dose] won't work, and they deserve a chance to try" the new drug. "The data from the trials show us that belimumab won't be the perfect drug for every patient, but there may be a substantial number of patients who may be helped. A patient doing well on a less expensive drug is not a candidate for changing treatment to belimumab, but there are many patients who are candidates."

What remains less clear today is the possible role of belimumab as initial therapy. "There are no treatment algorithms in SLE; there is no clinical trial evidence to know which drug to start first," Dr. Merrill said. A patient with SLE and predominant arthritis symptoms might initially get started on methotrexate, but if that is only partially effective, it would be reasonable to use belimumab as the next step, she said. An SLE patient who presents with a significant rash as the predominant symptom might start on methotrexate or another oral immunosuppressant, and again, belimumab could later be added if needed. Or the patient may be intolerant of such drugs as azathioprine or mycophenolate, prompting a faster progression to belimumab. Hydroxychloroquine monotherapy usually can't adequately control substantial SLE symptoms.

Although the two companies that will jointly market belimumab (Benlysta), Human Genome Sciences and GlaxoSmithKline, have not yet announced the drug's pricing, expectations are that it will be high. "There is no such thing as a cheap biologic," especially while it remains on patent, Dr. Merrill noted. But the world of drug options for treating SLE is somewhat unique, because virtually none of the standard-of-care options has labeling for SLE.

"For many years, insurers refused to cover expensive biologics" for SLE patients, Dr. Merrill said. "I've had to fight to get my patients access, even the ones who were very sick. The payer's argument was that the drug was not approved for lupus. Now it's the expensive drug that's approved, but the inexpensive ones aren't. Insurers will have trouble because if they say 'Have you tried azathioprine or methotrexate?' I can say 'But those drugs are not approved for lupus.' "

The United States "is struggling to figure out how to solve the cost of medical care. In the meantime, my strong conviction is that lupus patients, like any other patient, should have access to the best care available. If that proves to be belimumab, then so be it," Dr. Wofsy said.

A notable feature of the FDA's announcement of belimumab's approval was the agency noting that African American SLE patients and those of African heritage "did not appear to respond to treatment with belimumab" in the two pivotal studies. The FDA noted that the companies developing belimumab agreed to run a new study to specifically address this issue in greater detail.

"The trials done were not powered to address the efficacy of belimumab in African Americans, but the lack of an encouraging signal in this population can only be described as very disappointing, given that this population is disproportionately affected by SLE. The company's apparent commitment to answer this question definitely in a new trial is very important and to their credit," Dr. Wofsy said.

But citing the difficulty of presuming a genetic profile in individual patients who might have a particular racial identity, Dr. Merrill drew a different conclusion. "In my opinion, the data do not support any limitation excluding African Americans" from treatment with belimumab. "Everyone has a different genetic mix. Data that focus on race are very unscientific. I think that all patients deserve a chance to be tried on a treatment that's clearly showed widespread safety, compared with other drugs that are used for standard of care but have lots of side effects."

The labeling issued by the companies that will market belimumab lists a recommended dosage for each belimumab infusion as 10 mg/kg, every 2 weeks for the first three doses followed by new doses every 4 weeks, the dosage that gave the best results in the pivotal trials. But physicians will need to take a flexible attitude on dosage as they start treating patients, Dr. Merrill said. Although she will start some patients on 10 mg/kg, she might start with a lower dosage in patients she is nervous about and then slowly raise the dosage, and, if a patient remains symptomatic but well tolerates 10 mg/kg, she would also consider increasing the dosage higher, she said.

Dr. Merrill said that she has been a consultant to and has received research support from Human Genome Sciences and GlaxoSmithKline, as well as from many other companies. Dr. Wofsy has been a consultant to Bristol Myers Squibb and has received research support from several drug companies.

Dr. Wofsy has consulted for Human Genome Sciences and GlaxoSmithKline, as well as other companies involved in lupus drug development.

The announcement late on March 9 from the Food and Drug Administration that it had approved belimumab as a treatment for systemic lupus erythematosus, the first new treatment approved for this disease in more than 50 years, produced reaction among lupus specialists that ran the gamut from unrestrained elation to somewhat more restrained enthusiasm.

Regardless of the degree of caution experts might have about the efficacy of belimumab and the consequences of its widespread use, there was no denying that its approval marked a milestone for the management of patients with systemic lupus erythematosus (SLE).

"I've been calling my friends and going yippee. This is a historic day for lupus patients," said Dr. Joan T. Merrill, professor of medicine and chair of the clinical pharmacology research program at the Oklahoma Medical Research Foundation in Oklahoma City, who participated in the belimumab trials and exemplified a more enthusiastic take on the drug's approval.

A more cautious but still welcoming view came from Dr. David Wofsy, who was not involved in the belimumab studies. "I expect the drug will be widely used in lupus, given the great, unmet need for new therapies. But patients and physicians need to remain cognizant of the fact that roughly half of the subjects in the trials did not achieve the desired clinical outcome" a novel measure designed specifically for the two pivotal belimumab trials, the SLE Responder Index, said Dr. Wofsy, a professor of rheumatology at the University of California, San Francisco.

"Moreover, at this point, there is relatively little information about the effect of belimumab in patients with the most serious manifestations of lupus," such as active nephritis and central nervous system manifestations, Dr. Wofsy said in an interview. The majority of patients in the belimumab trials had cutaneous manifestations, musculoskeletal manifestations, or both, so we are beginning to understand the potential benefit of the drug in these patients. It will take time and undoubtedly more trials before we know how the drug will perform in patients with other manifestations.

"There is understandably great excitement about this landmark achievement, but patients and physicians will be well served if they remain realistic in their expectations and cautious in their use of a new agent," Dr. Wofsy said.

Dr. Merrill applied less caution in her assessment of the role belimumab will fill once physicians start prescribing it.

"I believe it will be tried in many [SLE] patients over the next year," she said in an interview. "I will certainly try it in many of my patients. The majority of lupus patients will flare sooner or later on the medicine they're on. If they flare a little, I'd first look to raise the dose of the drug they're on before I go to a brand new biologic such as belimumab. But we have a lot of patients where that [raising the dose] won't work, and they deserve a chance to try" the new drug. "The data from the trials show us that belimumab won't be the perfect drug for every patient, but there may be a substantial number of patients who may be helped. A patient doing well on a less expensive drug is not a candidate for changing treatment to belimumab, but there are many patients who are candidates."

What remains less clear today is the possible role of belimumab as initial therapy. "There are no treatment algorithms in SLE; there is no clinical trial evidence to know which drug to start first," Dr. Merrill said. A patient with SLE and predominant arthritis symptoms might initially get started on methotrexate, but if that is only partially effective, it would be reasonable to use belimumab as the next step, she said. An SLE patient who presents with a significant rash as the predominant symptom might start on methotrexate or another oral immunosuppressant, and again, belimumab could later be added if needed. Or the patient may be intolerant of such drugs as azathioprine or mycophenolate, prompting a faster progression to belimumab. Hydroxychloroquine monotherapy usually can't adequately control substantial SLE symptoms.

Although the two companies that will jointly market belimumab (Benlysta), Human Genome Sciences and GlaxoSmithKline, have not yet announced the drug's pricing, expectations are that it will be high. "There is no such thing as a cheap biologic," especially while it remains on patent, Dr. Merrill noted. But the world of drug options for treating SLE is somewhat unique, because virtually none of the standard-of-care options has labeling for SLE.

"For many years, insurers refused to cover expensive biologics" for SLE patients, Dr. Merrill said. "I've had to fight to get my patients access, even the ones who were very sick. The payer's argument was that the drug was not approved for lupus. Now it's the expensive drug that's approved, but the inexpensive ones aren't. Insurers will have trouble because if they say 'Have you tried azathioprine or methotrexate?' I can say 'But those drugs are not approved for lupus.' "

The United States "is struggling to figure out how to solve the cost of medical care. In the meantime, my strong conviction is that lupus patients, like any other patient, should have access to the best care available. If that proves to be belimumab, then so be it," Dr. Wofsy said.

A notable feature of the FDA's announcement of belimumab's approval was the agency noting that African American SLE patients and those of African heritage "did not appear to respond to treatment with belimumab" in the two pivotal studies. The FDA noted that the companies developing belimumab agreed to run a new study to specifically address this issue in greater detail.

"The trials done were not powered to address the efficacy of belimumab in African Americans, but the lack of an encouraging signal in this population can only be described as very disappointing, given that this population is disproportionately affected by SLE. The company's apparent commitment to answer this question definitely in a new trial is very important and to their credit," Dr. Wofsy said.

But citing the difficulty of presuming a genetic profile in individual patients who might have a particular racial identity, Dr. Merrill drew a different conclusion. "In my opinion, the data do not support any limitation excluding African Americans" from treatment with belimumab. "Everyone has a different genetic mix. Data that focus on race are very unscientific. I think that all patients deserve a chance to be tried on a treatment that's clearly showed widespread safety, compared with other drugs that are used for standard of care but have lots of side effects."

The labeling issued by the companies that will market belimumab lists a recommended dosage for each belimumab infusion as 10 mg/kg, every 2 weeks for the first three doses followed by new doses every 4 weeks, the dosage that gave the best results in the pivotal trials. But physicians will need to take a flexible attitude on dosage as they start treating patients, Dr. Merrill said. Although she will start some patients on 10 mg/kg, she might start with a lower dosage in patients she is nervous about and then slowly raise the dosage, and, if a patient remains symptomatic but well tolerates 10 mg/kg, she would also consider increasing the dosage higher, she said.

Dr. Merrill said that she has been a consultant to and has received research support from Human Genome Sciences and GlaxoSmithKline, as well as from many other companies. Dr. Wofsy has been a consultant to Bristol Myers Squibb and has received research support from several drug companies.

Dr. Wofsy has consulted for Human Genome Sciences and GlaxoSmithKline, as well as other companies involved in lupus drug development.

The announcement late on March 9 from the Food and Drug Administration that it had approved belimumab as a treatment for systemic lupus erythematosus, the first new treatment approved for this disease in more than 50 years, produced reaction among lupus specialists that ran the gamut from unrestrained elation to somewhat more restrained enthusiasm.

Regardless of the degree of caution experts might have about the efficacy of belimumab and the consequences of its widespread use, there was no denying that its approval marked a milestone for the management of patients with systemic lupus erythematosus (SLE).

"I've been calling my friends and going yippee. This is a historic day for lupus patients," said Dr. Joan T. Merrill, professor of medicine and chair of the clinical pharmacology research program at the Oklahoma Medical Research Foundation in Oklahoma City, who participated in the belimumab trials and exemplified a more enthusiastic take on the drug's approval.

A more cautious but still welcoming view came from Dr. David Wofsy, who was not involved in the belimumab studies. "I expect the drug will be widely used in lupus, given the great, unmet need for new therapies. But patients and physicians need to remain cognizant of the fact that roughly half of the subjects in the trials did not achieve the desired clinical outcome" a novel measure designed specifically for the two pivotal belimumab trials, the SLE Responder Index, said Dr. Wofsy, a professor of rheumatology at the University of California, San Francisco.

"Moreover, at this point, there is relatively little information about the effect of belimumab in patients with the most serious manifestations of lupus," such as active nephritis and central nervous system manifestations, Dr. Wofsy said in an interview. The majority of patients in the belimumab trials had cutaneous manifestations, musculoskeletal manifestations, or both, so we are beginning to understand the potential benefit of the drug in these patients. It will take time and undoubtedly more trials before we know how the drug will perform in patients with other manifestations.

"There is understandably great excitement about this landmark achievement, but patients and physicians will be well served if they remain realistic in their expectations and cautious in their use of a new agent," Dr. Wofsy said.

Dr. Merrill applied less caution in her assessment of the role belimumab will fill once physicians start prescribing it.

"I believe it will be tried in many [SLE] patients over the next year," she said in an interview. "I will certainly try it in many of my patients. The majority of lupus patients will flare sooner or later on the medicine they're on. If they flare a little, I'd first look to raise the dose of the drug they're on before I go to a brand new biologic such as belimumab. But we have a lot of patients where that [raising the dose] won't work, and they deserve a chance to try" the new drug. "The data from the trials show us that belimumab won't be the perfect drug for every patient, but there may be a substantial number of patients who may be helped. A patient doing well on a less expensive drug is not a candidate for changing treatment to belimumab, but there are many patients who are candidates."

What remains less clear today is the possible role of belimumab as initial therapy. "There are no treatment algorithms in SLE; there is no clinical trial evidence to know which drug to start first," Dr. Merrill said. A patient with SLE and predominant arthritis symptoms might initially get started on methotrexate, but if that is only partially effective, it would be reasonable to use belimumab as the next step, she said. An SLE patient who presents with a significant rash as the predominant symptom might start on methotrexate or another oral immunosuppressant, and again, belimumab could later be added if needed. Or the patient may be intolerant of such drugs as azathioprine or mycophenolate, prompting a faster progression to belimumab. Hydroxychloroquine monotherapy usually can't adequately control substantial SLE symptoms.

Although the two companies that will jointly market belimumab (Benlysta), Human Genome Sciences and GlaxoSmithKline, have not yet announced the drug's pricing, expectations are that it will be high. "There is no such thing as a cheap biologic," especially while it remains on patent, Dr. Merrill noted. But the world of drug options for treating SLE is somewhat unique, because virtually none of the standard-of-care options has labeling for SLE.

"For many years, insurers refused to cover expensive biologics" for SLE patients, Dr. Merrill said. "I've had to fight to get my patients access, even the ones who were very sick. The payer's argument was that the drug was not approved for lupus. Now it's the expensive drug that's approved, but the inexpensive ones aren't. Insurers will have trouble because if they say 'Have you tried azathioprine or methotrexate?' I can say 'But those drugs are not approved for lupus.' "

The United States "is struggling to figure out how to solve the cost of medical care. In the meantime, my strong conviction is that lupus patients, like any other patient, should have access to the best care available. If that proves to be belimumab, then so be it," Dr. Wofsy said.

A notable feature of the FDA's announcement of belimumab's approval was the agency noting that African American SLE patients and those of African heritage "did not appear to respond to treatment with belimumab" in the two pivotal studies. The FDA noted that the companies developing belimumab agreed to run a new study to specifically address this issue in greater detail.

"The trials done were not powered to address the efficacy of belimumab in African Americans, but the lack of an encouraging signal in this population can only be described as very disappointing, given that this population is disproportionately affected by SLE. The company's apparent commitment to answer this question definitely in a new trial is very important and to their credit," Dr. Wofsy said.

But citing the difficulty of presuming a genetic profile in individual patients who might have a particular racial identity, Dr. Merrill drew a different conclusion. "In my opinion, the data do not support any limitation excluding African Americans" from treatment with belimumab. "Everyone has a different genetic mix. Data that focus on race are very unscientific. I think that all patients deserve a chance to be tried on a treatment that's clearly showed widespread safety, compared with other drugs that are used for standard of care but have lots of side effects."

The labeling issued by the companies that will market belimumab lists a recommended dosage for each belimumab infusion as 10 mg/kg, every 2 weeks for the first three doses followed by new doses every 4 weeks, the dosage that gave the best results in the pivotal trials. But physicians will need to take a flexible attitude on dosage as they start treating patients, Dr. Merrill said. Although she will start some patients on 10 mg/kg, she might start with a lower dosage in patients she is nervous about and then slowly raise the dosage, and, if a patient remains symptomatic but well tolerates 10 mg/kg, she would also consider increasing the dosage higher, she said.

Dr. Merrill said that she has been a consultant to and has received research support from Human Genome Sciences and GlaxoSmithKline, as well as from many other companies. Dr. Wofsy has been a consultant to Bristol Myers Squibb and has received research support from several drug companies.

Dr. Wofsy has consulted for Human Genome Sciences and GlaxoSmithKline, as well as other companies involved in lupus drug development.

NEW ORLEANS – Clinically successful biologic therapy for psoriasis reverses roughly 70% of the molecular disease profile, leaving behind more than 1,200 dysregulated genes whose expression is either markedly increased or reduced, compared with nonlesional skin.

"Even highly effective treatments for psoriasis don't restore gene expression to levels seen in control skin biopsies. This suggests the possibility of a 'molecular scar' of psoriasis, even in clinically resolved psoriatic lesions," Dr. James G. Krueger said at the annual meeting of the American Academy of Dermatology.

Many of these residual dysregulated genes are involved in promoting what he called "smoldering inflammation."

"This could be the reason why psoriasis tends to recur in focal clinical regions. It's very common if you have bad plaque psoriasis that it comes back in the same spot after it’s effectively treated," noted Dr. Krueger, professor and head of the laboratory of investigative dermatology at Rockefeller University in New York.

He reported on 85 patients with moderate to severe plaque psoriasis who participated in a larger randomized clinical trial and underwent skin biopsies of lesional and nonlesional skin at baseline and again after 12 weeks of etanercept therapy. Another 85 patients were biopsied before and after 12 weeks on ustekinumab. In all, 21 etanercept-treated patients achieved a PASI 75 score (a 75% improvement over baseline on the Psoriasis Area and Severity Index), as did 19 on ustekinumab. In addition, skin biopsies were obtained from 25 normal, healthy volunteers. The specimens from all subjects were subjected to gene microarray analysis.

In all, 4,175 genes were differentially expressed (that is, either upregulated or downregulated) at baseline in lesional – compared with nonlesional – skin from psoriasis patients. Following 12 weeks of successful biologic therapy in patients who achieved a PASI 75 response, 2,922 of these genes were essentially normalized in lesions that were resolved clinically and histologically on hematoxylin and eosin stain, meaning that the genes' activity improved by at least 75% with treatment.

For the most part, both biologic agents normalized the same dysregulated genes; however, 7.7% of dysregulated genes were uniquely normalized by ustekinumab, and 14.7% were modulated only by etanercept.

Most of the dysregulated genes that were present in lesional skin whose functionality improved after 12 weeks of treatment were involved in keratinization, cyclin production, and formation of structural proteins. They were largely responsible for creating the classic hyperplasia phenotype of psoriasis which melts away both clinically and histologically in biologic therapy responders. But in addition, there was a high rate of improvement in genes that were involved in inflammatory pathways.

The molecular disease remnant that remained unchanged by the two biologics – that is, the 30% of dysregulated genes that were not normalized in response to clinically successful treatment – were to a considerable extent concerned with interferon pathway suppression and other residual inflammatory pathways. A probing of the tissue structure of these clinically resolved psoriatic lesions demonstrated subtle pathology, specifically in the lymphatics, which were "completely collapsed," according to Dr. Krueger.

"The idea that there is altered tissue structure caused by psoriasis perhaps puts it into the same category of scarring diseases as psoriatic arthritis and rheumatoid arthritis in that we don’t have totally benign and reversible disease of the skin," he said.

Further analysis of the molecular disease remnants that are present after clinically successful biologic therapy, and the pathways in which the involved genes lie, may lead to identification of novel therapeutic targets in psoriasis, Dr. Krueger added.

Nonlesional skin of patients with psoriasis contained roughly 2,000 genes that were significantly dysregulated, compared with their activity in normal skin from healthy controls.

Dr. Krueger said that he plans to rebiopsy patients again as they continue on etanercept or ustekinumab.

"It becomes really important to know whether we need to treat this disease for a very long time to maximize benefit," he noted. "With gene microarray analysis, we now have a tool set where we can ask if we can improve treatment ... by starting earlier, treating longer, or using smart combinations of agents."

Dr. Krueger said that this study was supported by Centocor, a company with which he holds an intellectual property arrangement.

NEW ORLEANS – Clinically successful biologic therapy for psoriasis reverses roughly 70% of the molecular disease profile, leaving behind more than 1,200 dysregulated genes whose expression is either markedly increased or reduced, compared with nonlesional skin.

"Even highly effective treatments for psoriasis don't restore gene expression to levels seen in control skin biopsies. This suggests the possibility of a 'molecular scar' of psoriasis, even in clinically resolved psoriatic lesions," Dr. James G. Krueger said at the annual meeting of the American Academy of Dermatology.

Many of these residual dysregulated genes are involved in promoting what he called "smoldering inflammation."

"This could be the reason why psoriasis tends to recur in focal clinical regions. It's very common if you have bad plaque psoriasis that it comes back in the same spot after it’s effectively treated," noted Dr. Krueger, professor and head of the laboratory of investigative dermatology at Rockefeller University in New York.

He reported on 85 patients with moderate to severe plaque psoriasis who participated in a larger randomized clinical trial and underwent skin biopsies of lesional and nonlesional skin at baseline and again after 12 weeks of etanercept therapy. Another 85 patients were biopsied before and after 12 weeks on ustekinumab. In all, 21 etanercept-treated patients achieved a PASI 75 score (a 75% improvement over baseline on the Psoriasis Area and Severity Index), as did 19 on ustekinumab. In addition, skin biopsies were obtained from 25 normal, healthy volunteers. The specimens from all subjects were subjected to gene microarray analysis.

In all, 4,175 genes were differentially expressed (that is, either upregulated or downregulated) at baseline in lesional – compared with nonlesional – skin from psoriasis patients. Following 12 weeks of successful biologic therapy in patients who achieved a PASI 75 response, 2,922 of these genes were essentially normalized in lesions that were resolved clinically and histologically on hematoxylin and eosin stain, meaning that the genes' activity improved by at least 75% with treatment.

For the most part, both biologic agents normalized the same dysregulated genes; however, 7.7% of dysregulated genes were uniquely normalized by ustekinumab, and 14.7% were modulated only by etanercept.

Most of the dysregulated genes that were present in lesional skin whose functionality improved after 12 weeks of treatment were involved in keratinization, cyclin production, and formation of structural proteins. They were largely responsible for creating the classic hyperplasia phenotype of psoriasis which melts away both clinically and histologically in biologic therapy responders. But in addition, there was a high rate of improvement in genes that were involved in inflammatory pathways.

The molecular disease remnant that remained unchanged by the two biologics – that is, the 30% of dysregulated genes that were not normalized in response to clinically successful treatment – were to a considerable extent concerned with interferon pathway suppression and other residual inflammatory pathways. A probing of the tissue structure of these clinically resolved psoriatic lesions demonstrated subtle pathology, specifically in the lymphatics, which were "completely collapsed," according to Dr. Krueger.

"The idea that there is altered tissue structure caused by psoriasis perhaps puts it into the same category of scarring diseases as psoriatic arthritis and rheumatoid arthritis in that we don’t have totally benign and reversible disease of the skin," he said.

Further analysis of the molecular disease remnants that are present after clinically successful biologic therapy, and the pathways in which the involved genes lie, may lead to identification of novel therapeutic targets in psoriasis, Dr. Krueger added.

Nonlesional skin of patients with psoriasis contained roughly 2,000 genes that were significantly dysregulated, compared with their activity in normal skin from healthy controls.

Dr. Krueger said that he plans to rebiopsy patients again as they continue on etanercept or ustekinumab.

"It becomes really important to know whether we need to treat this disease for a very long time to maximize benefit," he noted. "With gene microarray analysis, we now have a tool set where we can ask if we can improve treatment ... by starting earlier, treating longer, or using smart combinations of agents."

Dr. Krueger said that this study was supported by Centocor, a company with which he holds an intellectual property arrangement.

NEW ORLEANS – Clinically successful biologic therapy for psoriasis reverses roughly 70% of the molecular disease profile, leaving behind more than 1,200 dysregulated genes whose expression is either markedly increased or reduced, compared with nonlesional skin.

"Even highly effective treatments for psoriasis don't restore gene expression to levels seen in control skin biopsies. This suggests the possibility of a 'molecular scar' of psoriasis, even in clinically resolved psoriatic lesions," Dr. James G. Krueger said at the annual meeting of the American Academy of Dermatology.

Many of these residual dysregulated genes are involved in promoting what he called "smoldering inflammation."

"This could be the reason why psoriasis tends to recur in focal clinical regions. It's very common if you have bad plaque psoriasis that it comes back in the same spot after it’s effectively treated," noted Dr. Krueger, professor and head of the laboratory of investigative dermatology at Rockefeller University in New York.

He reported on 85 patients with moderate to severe plaque psoriasis who participated in a larger randomized clinical trial and underwent skin biopsies of lesional and nonlesional skin at baseline and again after 12 weeks of etanercept therapy. Another 85 patients were biopsied before and after 12 weeks on ustekinumab. In all, 21 etanercept-treated patients achieved a PASI 75 score (a 75% improvement over baseline on the Psoriasis Area and Severity Index), as did 19 on ustekinumab. In addition, skin biopsies were obtained from 25 normal, healthy volunteers. The specimens from all subjects were subjected to gene microarray analysis.

In all, 4,175 genes were differentially expressed (that is, either upregulated or downregulated) at baseline in lesional – compared with nonlesional – skin from psoriasis patients. Following 12 weeks of successful biologic therapy in patients who achieved a PASI 75 response, 2,922 of these genes were essentially normalized in lesions that were resolved clinically and histologically on hematoxylin and eosin stain, meaning that the genes' activity improved by at least 75% with treatment.

For the most part, both biologic agents normalized the same dysregulated genes; however, 7.7% of dysregulated genes were uniquely normalized by ustekinumab, and 14.7% were modulated only by etanercept.

Most of the dysregulated genes that were present in lesional skin whose functionality improved after 12 weeks of treatment were involved in keratinization, cyclin production, and formation of structural proteins. They were largely responsible for creating the classic hyperplasia phenotype of psoriasis which melts away both clinically and histologically in biologic therapy responders. But in addition, there was a high rate of improvement in genes that were involved in inflammatory pathways.

The molecular disease remnant that remained unchanged by the two biologics – that is, the 30% of dysregulated genes that were not normalized in response to clinically successful treatment – were to a considerable extent concerned with interferon pathway suppression and other residual inflammatory pathways. A probing of the tissue structure of these clinically resolved psoriatic lesions demonstrated subtle pathology, specifically in the lymphatics, which were "completely collapsed," according to Dr. Krueger.

"The idea that there is altered tissue structure caused by psoriasis perhaps puts it into the same category of scarring diseases as psoriatic arthritis and rheumatoid arthritis in that we don’t have totally benign and reversible disease of the skin," he said.

Further analysis of the molecular disease remnants that are present after clinically successful biologic therapy, and the pathways in which the involved genes lie, may lead to identification of novel therapeutic targets in psoriasis, Dr. Krueger added.

Nonlesional skin of patients with psoriasis contained roughly 2,000 genes that were significantly dysregulated, compared with their activity in normal skin from healthy controls.

Dr. Krueger said that he plans to rebiopsy patients again as they continue on etanercept or ustekinumab.

"It becomes really important to know whether we need to treat this disease for a very long time to maximize benefit," he noted. "With gene microarray analysis, we now have a tool set where we can ask if we can improve treatment ... by starting earlier, treating longer, or using smart combinations of agents."

Dr. Krueger said that this study was supported by Centocor, a company with which he holds an intellectual property arrangement.

NEW ORLEANS – Apremilast, tofacitinib, and a drug for now known as AMG-627 are three novel investigational medications for psoriasis worth keeping an eye on.

The efficacy of these three agents is beyond question, ranging from good to great. Whether they ultimately reach the market will depend upon the answers to tolerability and safety questions that should be provided in phase III clinical trials, Dr. Bruce E. Strober said at the annual meeting of the American Academy of Dermatology.

Here's the low-down on these exciting agents, several of which also are being developed for rheumatoid arthritis and other autoimmune diseases, according to Dr. Strober of New York University.

• Apremilast. This oral small molecule inhibitor of phosphodiesterase type 4 is now entering phase III testing for psoriasis.

"You might see this drug on the market in 3-4 years," the dermatologist said.

By inhibiting phosphodiesterase type 4, apremilast curbs formation of multiple cytokines important in inflammatory pathways, including interleukins-12 and -17 as well as tumor necrosis factor–alpha. These pathways are important not only in the pathophysiology of psoriasis, but also for rheumatoid arthritis and other autoimmune diseases as well. For this reason, apremilast's developer, Celgene, is interested in pursuing other indications in addition to psoriasis.

A 16-week, double-blind, placebo-controlled, phase II study conducted in 352 patients with moderate-to-severe plaque-type psoriasis showed an unequivocal dose-response relationship. A 75% reduction from baseline in Psoriasis Area and Severity Index scores, or PASI 75, occurred in 41% of patients randomized to 30 mg of apremilast b.i.d., 29% on 20 mg b.i.d., 11% on 10 mg b.i.d., and 5.7% on placebo.

Tolerability issues came up in this study, especially in patients on the highest dose of apremilast. One-third of them reported headaches, 18% nausea, 16% urinary tract infections, and 16% diarrhea, all rates substantially higher than in controls. The discontinuation rate in the highest-dose group was 14%, compared with 6% in controls.

Nevertheless, this is an oral drug with enough efficacy that it might find a role as first-line therapy after a failure on topical therapy, Dr. Strober predicted.

"It's left to be seen in phase III how safe it is, but I think there will be a place for such an intermediately acting small molecule. Keep your eyes open for this one," he continued.

• Tofacitinib. This oral Janus kinase (JAK) inhibitor just underwent a name change. It was formerly known as tasocitinib. Like apremilast, it's now entering phase III testing for psoriasis.

Tofacitinib is best thought of a broadly acting immunosuppressive agent. By inhibiting JAK kinase, it's likely to affect transcription of genes important in inflammation, red blood cell development, and innate and adaptive immunity. Tofacitinib is also under study for rheumatoid arthritis and other immunologic diseases.

In a 12-week, phase IIb study of 197 patients, psoriasis patients randomized to tofacitinib at 15 mg b.i.d. achieved a 67% PASI 75, compared with a PASI 75 of 41% with 5 mg b.i.d., 25% with 2 mg b.i.d., and 2% for placebo.

Dr. Strober predicted that Pfizer will take the 5 mg b.i.d. dosing forward into phase III because it provides the best combination of efficacy and safety. Dose-related safety issues that emerged in the phase IIb study were a slight reduction in hemoglobin, a decrease in neutrophil count that normalized during the course of the study, and increases in both HDL cholesterol and LDL cholesterol.

"This is a drug that in all likelihood will require monitoring by clinicians during therapy," he concluded.

• AMG-627. This Amgen drug blocks the interleukin-17 receptor. In contrast, Novartis and Lilly are working on drugs that block interleukin-17m which is believed to be a pivotal cytokine in the pathogenesis of psoriasis.

AMG-627 is not as far along the developmental pipeline as apremilast and tofacitinib, but the early clinical studies make one thing clear, in Dr. Strober's view: "The efficacy of this approach will be fairly unequalled. It will come down, as usual, to the safety of the class."

Dr. Strober disclosed that he serves as an investigator for, and consultant to, Pfizer, Amgen, and other pharmaceutical companies having an interest in psoriasis treatment.

NEW ORLEANS – Apremilast, tofacitinib, and a drug for now known as AMG-627 are three novel investigational medications for psoriasis worth keeping an eye on.

The efficacy of these three agents is beyond question, ranging from good to great. Whether they ultimately reach the market will depend upon the answers to tolerability and safety questions that should be provided in phase III clinical trials, Dr. Bruce E. Strober said at the annual meeting of the American Academy of Dermatology.

Here's the low-down on these exciting agents, several of which also are being developed for rheumatoid arthritis and other autoimmune diseases, according to Dr. Strober of New York University.

• Apremilast. This oral small molecule inhibitor of phosphodiesterase type 4 is now entering phase III testing for psoriasis.

"You might see this drug on the market in 3-4 years," the dermatologist said.

By inhibiting phosphodiesterase type 4, apremilast curbs formation of multiple cytokines important in inflammatory pathways, including interleukins-12 and -17 as well as tumor necrosis factor–alpha. These pathways are important not only in the pathophysiology of psoriasis, but also for rheumatoid arthritis and other autoimmune diseases as well. For this reason, apremilast's developer, Celgene, is interested in pursuing other indications in addition to psoriasis.

A 16-week, double-blind, placebo-controlled, phase II study conducted in 352 patients with moderate-to-severe plaque-type psoriasis showed an unequivocal dose-response relationship. A 75% reduction from baseline in Psoriasis Area and Severity Index scores, or PASI 75, occurred in 41% of patients randomized to 30 mg of apremilast b.i.d., 29% on 20 mg b.i.d., 11% on 10 mg b.i.d., and 5.7% on placebo.

Tolerability issues came up in this study, especially in patients on the highest dose of apremilast. One-third of them reported headaches, 18% nausea, 16% urinary tract infections, and 16% diarrhea, all rates substantially higher than in controls. The discontinuation rate in the highest-dose group was 14%, compared with 6% in controls.

Nevertheless, this is an oral drug with enough efficacy that it might find a role as first-line therapy after a failure on topical therapy, Dr. Strober predicted.

"It's left to be seen in phase III how safe it is, but I think there will be a place for such an intermediately acting small molecule. Keep your eyes open for this one," he continued.

• Tofacitinib. This oral Janus kinase (JAK) inhibitor just underwent a name change. It was formerly known as tasocitinib. Like apremilast, it's now entering phase III testing for psoriasis.

Tofacitinib is best thought of a broadly acting immunosuppressive agent. By inhibiting JAK kinase, it's likely to affect transcription of genes important in inflammation, red blood cell development, and innate and adaptive immunity. Tofacitinib is also under study for rheumatoid arthritis and other immunologic diseases.

In a 12-week, phase IIb study of 197 patients, psoriasis patients randomized to tofacitinib at 15 mg b.i.d. achieved a 67% PASI 75, compared with a PASI 75 of 41% with 5 mg b.i.d., 25% with 2 mg b.i.d., and 2% for placebo.

Dr. Strober predicted that Pfizer will take the 5 mg b.i.d. dosing forward into phase III because it provides the best combination of efficacy and safety. Dose-related safety issues that emerged in the phase IIb study were a slight reduction in hemoglobin, a decrease in neutrophil count that normalized during the course of the study, and increases in both HDL cholesterol and LDL cholesterol.

"This is a drug that in all likelihood will require monitoring by clinicians during therapy," he concluded.

• AMG-627. This Amgen drug blocks the interleukin-17 receptor. In contrast, Novartis and Lilly are working on drugs that block interleukin-17m which is believed to be a pivotal cytokine in the pathogenesis of psoriasis.

AMG-627 is not as far along the developmental pipeline as apremilast and tofacitinib, but the early clinical studies make one thing clear, in Dr. Strober's view: "The efficacy of this approach will be fairly unequalled. It will come down, as usual, to the safety of the class."

Dr. Strober disclosed that he serves as an investigator for, and consultant to, Pfizer, Amgen, and other pharmaceutical companies having an interest in psoriasis treatment.

NEW ORLEANS – Apremilast, tofacitinib, and a drug for now known as AMG-627 are three novel investigational medications for psoriasis worth keeping an eye on.

The efficacy of these three agents is beyond question, ranging from good to great. Whether they ultimately reach the market will depend upon the answers to tolerability and safety questions that should be provided in phase III clinical trials, Dr. Bruce E. Strober said at the annual meeting of the American Academy of Dermatology.

Here's the low-down on these exciting agents, several of which also are being developed for rheumatoid arthritis and other autoimmune diseases, according to Dr. Strober of New York University.

• Apremilast. This oral small molecule inhibitor of phosphodiesterase type 4 is now entering phase III testing for psoriasis.

"You might see this drug on the market in 3-4 years," the dermatologist said.

By inhibiting phosphodiesterase type 4, apremilast curbs formation of multiple cytokines important in inflammatory pathways, including interleukins-12 and -17 as well as tumor necrosis factor–alpha. These pathways are important not only in the pathophysiology of psoriasis, but also for rheumatoid arthritis and other autoimmune diseases as well. For this reason, apremilast's developer, Celgene, is interested in pursuing other indications in addition to psoriasis.

A 16-week, double-blind, placebo-controlled, phase II study conducted in 352 patients with moderate-to-severe plaque-type psoriasis showed an unequivocal dose-response relationship. A 75% reduction from baseline in Psoriasis Area and Severity Index scores, or PASI 75, occurred in 41% of patients randomized to 30 mg of apremilast b.i.d., 29% on 20 mg b.i.d., 11% on 10 mg b.i.d., and 5.7% on placebo.

Tolerability issues came up in this study, especially in patients on the highest dose of apremilast. One-third of them reported headaches, 18% nausea, 16% urinary tract infections, and 16% diarrhea, all rates substantially higher than in controls. The discontinuation rate in the highest-dose group was 14%, compared with 6% in controls.

Nevertheless, this is an oral drug with enough efficacy that it might find a role as first-line therapy after a failure on topical therapy, Dr. Strober predicted.

"It's left to be seen in phase III how safe it is, but I think there will be a place for such an intermediately acting small molecule. Keep your eyes open for this one," he continued.

• Tofacitinib. This oral Janus kinase (JAK) inhibitor just underwent a name change. It was formerly known as tasocitinib. Like apremilast, it's now entering phase III testing for psoriasis.

Tofacitinib is best thought of a broadly acting immunosuppressive agent. By inhibiting JAK kinase, it's likely to affect transcription of genes important in inflammation, red blood cell development, and innate and adaptive immunity. Tofacitinib is also under study for rheumatoid arthritis and other immunologic diseases.

In a 12-week, phase IIb study of 197 patients, psoriasis patients randomized to tofacitinib at 15 mg b.i.d. achieved a 67% PASI 75, compared with a PASI 75 of 41% with 5 mg b.i.d., 25% with 2 mg b.i.d., and 2% for placebo.

Dr. Strober predicted that Pfizer will take the 5 mg b.i.d. dosing forward into phase III because it provides the best combination of efficacy and safety. Dose-related safety issues that emerged in the phase IIb study were a slight reduction in hemoglobin, a decrease in neutrophil count that normalized during the course of the study, and increases in both HDL cholesterol and LDL cholesterol.

"This is a drug that in all likelihood will require monitoring by clinicians during therapy," he concluded.

• AMG-627. This Amgen drug blocks the interleukin-17 receptor. In contrast, Novartis and Lilly are working on drugs that block interleukin-17m which is believed to be a pivotal cytokine in the pathogenesis of psoriasis.

AMG-627 is not as far along the developmental pipeline as apremilast and tofacitinib, but the early clinical studies make one thing clear, in Dr. Strober's view: "The efficacy of this approach will be fairly unequalled. It will come down, as usual, to the safety of the class."

Dr. Strober disclosed that he serves as an investigator for, and consultant to, Pfizer, Amgen, and other pharmaceutical companies having an interest in psoriasis treatment.

NEW ORLEANS – Think of psoriasis as a systemic disease whose key extracutaneous sites of involvement include the eyes, joints, and perhaps the coronary arteries, although that remains controversial.

"Psoriasis is an inflammatory condition that flows far beyond the skin," Dr. Brian F. Mandell stressed at the annual meeting of the American Academy of Dermatology.

Dr. Mandell, professor and chairman of the department of medicine at the Cleveland Clinic, offered a rheumatologist's perspective on a disease whose full range of expression extends well afield of daily dermatologic practice.

Psoriatic uveitis. This uncommon disease manifestation affects only about 2% of psoriasis patients, but it's often insidious in onset and can result in irreversible loss of vision.

Psoriasis-associated uveitis can be either anterior or posterior. The anterior uveitis tends to be painful and often produces a minimally red and irritated eye. In contrast, posterior uveitis is often essentially devoid of symptoms other than perhaps floaters or a bit of blurring. Psoriasis-associated uveitis is more like the uveitis associated with inflammatory bowel disease than the classic HLA-B27-associated form of uveitis.

"Be wary of any eye complaints, and be very liberal in referring to ophthalmology for a slit-lamp exam," he advised.

Psoriatic joint disease. Two forms of joint disease are of particular relevance to the psoriatic population. One is the increased incidence of gouty arthritis in patients with the skin disease.

"The challenge here is to distinguish between gout and what appears to be a totally typical flare of psoriatic monoarticular arthritis. As a dermatologist, what you should expect from a rheumatology colleague in that setting is for us to stick a needle in the joint and make that distinction, because otherwise there's no way that distinction can be made with certainty. Patients tend to be hyperuricemic when they have psoriasis, so you can't use a laboratory test to make the distinction," Dr. Mandell explained.

The occurrence of psoriatic arthritis is, rather surprisingly, unrelated to the severity of the skin disease. Nor is psoriatic arthritis strongly associated with nail involvement. The most important patterns of psoriatic arthritis include spondylitis, enthesitis, and peripheral arthritides.

The hallmark of spondylitis is morning stiffness and pain lasting for several hours. That's the key distinguishing feature separating inflammatory from mechanical back pain – and it's a complaint that definitely warrants sending a psoriasis patient to a rheumatologist, in Dr. Mandell's view.

Enthesitis involves inflammation where tendons and ligaments join to the bone. Common manifestations in patients with psoriatic arthritis include hip pain or pain on the outside of the knee. The onset is often subtle. Successful treatment requires high-intensity anti-inflammatory therapy; enthesitis does'’t respond well to pain medications.

In contrast to the subtleties of psoriatic enthesitis, psoriatic peripheral arthritis is generally a dramatic condition marked by impressive fluid accumulation. In dactylitis, the entire digit, not just a joint, is swollen and strikingly painful; this is the sausage digit. And unlike rheumatoid arthritis, psoriatic dactylitis occurs asymmetrically.

"Rheumatoid arthritis just doesn't do this. There are very few 'nevers' in medicine. But I've never seen rheumatoid arthritis take the form of a true dactylitis. When you see it in the absence of skin disease, as a rheumatologist I'm actually going to undress the patient and go looking for skin disease," Dr. Mandell said.

Like psoriatic enthesitis, psoriatic dactylitis responds well to full-dose anti-inflammatory medication, he added.

Very few inflammatory arthritides target the distal interphalangeal joints. Psoriatic arthritis is far and away the most common one. This is an exceedingly destructive disease process over time, and it warrants very aggressive treatment.

Methotrexate is "reasonably effective" for all forms of psoriatic arthritis except spondylitis, according to Dr. Mandell. Anti–tumor necrosis factor biologics are strikingly effective for all manifestations of psoriatic arthritis; often lower doses are required than for treatment of skin disease.

Coronary artery disease. There's no question that psoriasis patients have an increased prevalence of the metabolic syndrome. And epidemiologic studies also demonstrate that they are at increased risk for CAD and cardiovascular events. But whether psoriasis constitutes an independent risk factor for acute ischemic heart disease or the increased risk is due to the high prevalence of traditional coronary risk factors in psoriasis patients remains a topic of active debate in both the dermatologic and internal medicine literature.

"Whether psoriasis is directly causative or merely an association I don't think really matters," Dr. Mandell asserted. "When you have a patient with psoriasis in front of you, you need to take advantage of a teaching moment. They're naked, they’re glowing in the dark from their psoriasis, and this is an opportunity to let them know there probably is a cardiovascular risk and they should be seeing their primary care provider to make sure their modifiable cardiovascular risk factors like lipids, hypertension, and smoking have been addressed. In that way you've done your job the same way I’ll do my job in similar settings when I see a patient with rheumatoid arthritis or psoriatic arthritis."

Dr. Mandell said that he has no relevant financial interests.

NEW ORLEANS – Think of psoriasis as a systemic disease whose key extracutaneous sites of involvement include the eyes, joints, and perhaps the coronary arteries, although that remains controversial.

"Psoriasis is an inflammatory condition that flows far beyond the skin," Dr. Brian F. Mandell stressed at the annual meeting of the American Academy of Dermatology.

Dr. Mandell, professor and chairman of the department of medicine at the Cleveland Clinic, offered a rheumatologist's perspective on a disease whose full range of expression extends well afield of daily dermatologic practice.

Psoriatic uveitis. This uncommon disease manifestation affects only about 2% of psoriasis patients, but it's often insidious in onset and can result in irreversible loss of vision.

Psoriasis-associated uveitis can be either anterior or posterior. The anterior uveitis tends to be painful and often produces a minimally red and irritated eye. In contrast, posterior uveitis is often essentially devoid of symptoms other than perhaps floaters or a bit of blurring. Psoriasis-associated uveitis is more like the uveitis associated with inflammatory bowel disease than the classic HLA-B27-associated form of uveitis.

"Be wary of any eye complaints, and be very liberal in referring to ophthalmology for a slit-lamp exam," he advised.

Psoriatic joint disease. Two forms of joint disease are of particular relevance to the psoriatic population. One is the increased incidence of gouty arthritis in patients with the skin disease.

"The challenge here is to distinguish between gout and what appears to be a totally typical flare of psoriatic monoarticular arthritis. As a dermatologist, what you should expect from a rheumatology colleague in that setting is for us to stick a needle in the joint and make that distinction, because otherwise there's no way that distinction can be made with certainty. Patients tend to be hyperuricemic when they have psoriasis, so you can't use a laboratory test to make the distinction," Dr. Mandell explained.

The occurrence of psoriatic arthritis is, rather surprisingly, unrelated to the severity of the skin disease. Nor is psoriatic arthritis strongly associated with nail involvement. The most important patterns of psoriatic arthritis include spondylitis, enthesitis, and peripheral arthritides.

The hallmark of spondylitis is morning stiffness and pain lasting for several hours. That's the key distinguishing feature separating inflammatory from mechanical back pain – and it's a complaint that definitely warrants sending a psoriasis patient to a rheumatologist, in Dr. Mandell's view.

Enthesitis involves inflammation where tendons and ligaments join to the bone. Common manifestations in patients with psoriatic arthritis include hip pain or pain on the outside of the knee. The onset is often subtle. Successful treatment requires high-intensity anti-inflammatory therapy; enthesitis does'’t respond well to pain medications.

In contrast to the subtleties of psoriatic enthesitis, psoriatic peripheral arthritis is generally a dramatic condition marked by impressive fluid accumulation. In dactylitis, the entire digit, not just a joint, is swollen and strikingly painful; this is the sausage digit. And unlike rheumatoid arthritis, psoriatic dactylitis occurs asymmetrically.

"Rheumatoid arthritis just doesn't do this. There are very few 'nevers' in medicine. But I've never seen rheumatoid arthritis take the form of a true dactylitis. When you see it in the absence of skin disease, as a rheumatologist I'm actually going to undress the patient and go looking for skin disease," Dr. Mandell said.

Like psoriatic enthesitis, psoriatic dactylitis responds well to full-dose anti-inflammatory medication, he added.

Very few inflammatory arthritides target the distal interphalangeal joints. Psoriatic arthritis is far and away the most common one. This is an exceedingly destructive disease process over time, and it warrants very aggressive treatment.

Methotrexate is "reasonably effective" for all forms of psoriatic arthritis except spondylitis, according to Dr. Mandell. Anti–tumor necrosis factor biologics are strikingly effective for all manifestations of psoriatic arthritis; often lower doses are required than for treatment of skin disease.

Coronary artery disease. There's no question that psoriasis patients have an increased prevalence of the metabolic syndrome. And epidemiologic studies also demonstrate that they are at increased risk for CAD and cardiovascular events. But whether psoriasis constitutes an independent risk factor for acute ischemic heart disease or the increased risk is due to the high prevalence of traditional coronary risk factors in psoriasis patients remains a topic of active debate in both the dermatologic and internal medicine literature.

"Whether psoriasis is directly causative or merely an association I don't think really matters," Dr. Mandell asserted. "When you have a patient with psoriasis in front of you, you need to take advantage of a teaching moment. They're naked, they’re glowing in the dark from their psoriasis, and this is an opportunity to let them know there probably is a cardiovascular risk and they should be seeing their primary care provider to make sure their modifiable cardiovascular risk factors like lipids, hypertension, and smoking have been addressed. In that way you've done your job the same way I’ll do my job in similar settings when I see a patient with rheumatoid arthritis or psoriatic arthritis."

Dr. Mandell said that he has no relevant financial interests.

NEW ORLEANS – Think of psoriasis as a systemic disease whose key extracutaneous sites of involvement include the eyes, joints, and perhaps the coronary arteries, although that remains controversial.

"Psoriasis is an inflammatory condition that flows far beyond the skin," Dr. Brian F. Mandell stressed at the annual meeting of the American Academy of Dermatology.

Dr. Mandell, professor and chairman of the department of medicine at the Cleveland Clinic, offered a rheumatologist's perspective on a disease whose full range of expression extends well afield of daily dermatologic practice.

Psoriatic uveitis. This uncommon disease manifestation affects only about 2% of psoriasis patients, but it's often insidious in onset and can result in irreversible loss of vision.

Psoriasis-associated uveitis can be either anterior or posterior. The anterior uveitis tends to be painful and often produces a minimally red and irritated eye. In contrast, posterior uveitis is often essentially devoid of symptoms other than perhaps floaters or a bit of blurring. Psoriasis-associated uveitis is more like the uveitis associated with inflammatory bowel disease than the classic HLA-B27-associated form of uveitis.

"Be wary of any eye complaints, and be very liberal in referring to ophthalmology for a slit-lamp exam," he advised.

Psoriatic joint disease. Two forms of joint disease are of particular relevance to the psoriatic population. One is the increased incidence of gouty arthritis in patients with the skin disease.

"The challenge here is to distinguish between gout and what appears to be a totally typical flare of psoriatic monoarticular arthritis. As a dermatologist, what you should expect from a rheumatology colleague in that setting is for us to stick a needle in the joint and make that distinction, because otherwise there's no way that distinction can be made with certainty. Patients tend to be hyperuricemic when they have psoriasis, so you can't use a laboratory test to make the distinction," Dr. Mandell explained.

The occurrence of psoriatic arthritis is, rather surprisingly, unrelated to the severity of the skin disease. Nor is psoriatic arthritis strongly associated with nail involvement. The most important patterns of psoriatic arthritis include spondylitis, enthesitis, and peripheral arthritides.

The hallmark of spondylitis is morning stiffness and pain lasting for several hours. That's the key distinguishing feature separating inflammatory from mechanical back pain – and it's a complaint that definitely warrants sending a psoriasis patient to a rheumatologist, in Dr. Mandell's view.

Enthesitis involves inflammation where tendons and ligaments join to the bone. Common manifestations in patients with psoriatic arthritis include hip pain or pain on the outside of the knee. The onset is often subtle. Successful treatment requires high-intensity anti-inflammatory therapy; enthesitis does'’t respond well to pain medications.

In contrast to the subtleties of psoriatic enthesitis, psoriatic peripheral arthritis is generally a dramatic condition marked by impressive fluid accumulation. In dactylitis, the entire digit, not just a joint, is swollen and strikingly painful; this is the sausage digit. And unlike rheumatoid arthritis, psoriatic dactylitis occurs asymmetrically.

"Rheumatoid arthritis just doesn't do this. There are very few 'nevers' in medicine. But I've never seen rheumatoid arthritis take the form of a true dactylitis. When you see it in the absence of skin disease, as a rheumatologist I'm actually going to undress the patient and go looking for skin disease," Dr. Mandell said.

Like psoriatic enthesitis, psoriatic dactylitis responds well to full-dose anti-inflammatory medication, he added.

Very few inflammatory arthritides target the distal interphalangeal joints. Psoriatic arthritis is far and away the most common one. This is an exceedingly destructive disease process over time, and it warrants very aggressive treatment.

Methotrexate is "reasonably effective" for all forms of psoriatic arthritis except spondylitis, according to Dr. Mandell. Anti–tumor necrosis factor biologics are strikingly effective for all manifestations of psoriatic arthritis; often lower doses are required than for treatment of skin disease.

Coronary artery disease. There's no question that psoriasis patients have an increased prevalence of the metabolic syndrome. And epidemiologic studies also demonstrate that they are at increased risk for CAD and cardiovascular events. But whether psoriasis constitutes an independent risk factor for acute ischemic heart disease or the increased risk is due to the high prevalence of traditional coronary risk factors in psoriasis patients remains a topic of active debate in both the dermatologic and internal medicine literature.

"Whether psoriasis is directly causative or merely an association I don't think really matters," Dr. Mandell asserted. "When you have a patient with psoriasis in front of you, you need to take advantage of a teaching moment. They're naked, they’re glowing in the dark from their psoriasis, and this is an opportunity to let them know there probably is a cardiovascular risk and they should be seeing their primary care provider to make sure their modifiable cardiovascular risk factors like lipids, hypertension, and smoking have been addressed. In that way you've done your job the same way I’ll do my job in similar settings when I see a patient with rheumatoid arthritis or psoriatic arthritis."

Dr. Mandell said that he has no relevant financial interests.

NEW ORLEANS – The use of potent or very potent topical corticosteroids in pregnancy is associated with a significantly increased risk of fetal growth retardation, according to a very large population-based cohort study.

Fortunately, maternal exposure to topical corticosteroids was not associated with any other adverse outcomes, including miscarriage, stillbirth, preterm delivery, or orofacial cleft, Dr. Linda F. Stein said in highlighting the study findings at the annual meeting of the American Academy of Dermatology.

Dr. Stein, director of dermatology research at Henry Ford Hospital in Detroit, singled out the study for special attention because its unusually large size makes for convincingly strong conclusions regarding an issue for which there has been a dearth of data: the safety of topical steroids in pregnancy.

Investigators at Chang Gung University in Taoyuan, Taiwan, and the University of Oxford (England) used the U.K. General Practice Research Database to identify 35,503 women who had been prescribed topical corticosteroids during or shortly before pregnancy, and a control group comprising 48,630 unexposed pregnant women.

Maternal exposure to potent or very potent topical steroids was associated with an adjusted 2.1-fold increased relative risk of fetal growth restriction. Moreover, a significant dose-response relationship was found, such that for every 30 g of prescribed potent or very potent topical steroids, the risk of fetal growth retardation climbed by about 3%. The risk rose with the increasing potency of the topical medication.

The investigators estimated that 168 pregnant women would have to receive potent or very potent topical steroids in order to result in one additional case of fetal growth restriction (J. Invest. Dermatol. 2010 Dec. 30 [doi:10.1038/jid.2010.392]).

Dr. Stein had no relevant financial interests.

NEW ORLEANS – The use of potent or very potent topical corticosteroids in pregnancy is associated with a significantly increased risk of fetal growth retardation, according to a very large population-based cohort study.

Fortunately, maternal exposure to topical corticosteroids was not associated with any other adverse outcomes, including miscarriage, stillbirth, preterm delivery, or orofacial cleft, Dr. Linda F. Stein said in highlighting the study findings at the annual meeting of the American Academy of Dermatology.

Dr. Stein, director of dermatology research at Henry Ford Hospital in Detroit, singled out the study for special attention because its unusually large size makes for convincingly strong conclusions regarding an issue for which there has been a dearth of data: the safety of topical steroids in pregnancy.

Investigators at Chang Gung University in Taoyuan, Taiwan, and the University of Oxford (England) used the U.K. General Practice Research Database to identify 35,503 women who had been prescribed topical corticosteroids during or shortly before pregnancy, and a control group comprising 48,630 unexposed pregnant women.

Maternal exposure to potent or very potent topical steroids was associated with an adjusted 2.1-fold increased relative risk of fetal growth restriction. Moreover, a significant dose-response relationship was found, such that for every 30 g of prescribed potent or very potent topical steroids, the risk of fetal growth retardation climbed by about 3%. The risk rose with the increasing potency of the topical medication.

The investigators estimated that 168 pregnant women would have to receive potent or very potent topical steroids in order to result in one additional case of fetal growth restriction (J. Invest. Dermatol. 2010 Dec. 30 [doi:10.1038/jid.2010.392]).

Dr. Stein had no relevant financial interests.

NEW ORLEANS – The use of potent or very potent topical corticosteroids in pregnancy is associated with a significantly increased risk of fetal growth retardation, according to a very large population-based cohort study.

Fortunately, maternal exposure to topical corticosteroids was not associated with any other adverse outcomes, including miscarriage, stillbirth, preterm delivery, or orofacial cleft, Dr. Linda F. Stein said in highlighting the study findings at the annual meeting of the American Academy of Dermatology.

Dr. Stein, director of dermatology research at Henry Ford Hospital in Detroit, singled out the study for special attention because its unusually large size makes for convincingly strong conclusions regarding an issue for which there has been a dearth of data: the safety of topical steroids in pregnancy.

Investigators at Chang Gung University in Taoyuan, Taiwan, and the University of Oxford (England) used the U.K. General Practice Research Database to identify 35,503 women who had been prescribed topical corticosteroids during or shortly before pregnancy, and a control group comprising 48,630 unexposed pregnant women.

Maternal exposure to potent or very potent topical steroids was associated with an adjusted 2.1-fold increased relative risk of fetal growth restriction. Moreover, a significant dose-response relationship was found, such that for every 30 g of prescribed potent or very potent topical steroids, the risk of fetal growth retardation climbed by about 3%. The risk rose with the increasing potency of the topical medication.

The investigators estimated that 168 pregnant women would have to receive potent or very potent topical steroids in order to result in one additional case of fetal growth restriction (J. Invest. Dermatol. 2010 Dec. 30 [doi:10.1038/jid.2010.392]).

Dr. Stein had no relevant financial interests.

LAS VEGAS – If you think of biologic therapies for psoriasis as cars, some are sturdy but pedestrian while others are racy sports cars.

"Etanercept is like a Volvo. It's not a fast car, it's not a flashy car, but it's a good, solid car that will probably work for you. Some of the other biologics are more like Ferraris – very fast but more difficult to steer," Dr. Francisco A. Kerdel said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Infliximab would be a Ferrari. "This is a high-performance vehicle, but you need to know what you're doing," said Dr. Kerdel, director of the dermatology inpatient service at University of Miami Hospital.

Golimumab is "like one of those European cars that look fantastic, but you're probably never going to own one," he said. Dr. Kerdel believes that golimumab probably will not win an indication specifically to treat psoriasis. It is approved for treating rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

He offered several driver's tips for getting the best performance out of infliximab.

Unlike the other biologics, infliximab is administered intravenously. It's "very, very efficacious and very fast" for treating psoriasis, he said. With the 5-mg/kg dose being marketed, 56% of patients achieved a 75% improvement in Psoriasis Area and Severity Index (PASI 75) score after 6 weeks in a phase III clinical trial. By week 10, 57% achieved a PASI 90.

Because infliximab is given on a mg/kg basis, the patient’s weight doesn’t seem to have as much effect on responses. Improvements are similar in patients who are normal weight, overweight, or obese.

Approximately 4% of patients receiving infliximab develop infusion reactions, compared with 2% who get placebo infusions. "The vast majority of these reactions are mild, and they can be managed in the office," Dr. Kerdel said. Less than 1% of patients will develop an infusion reaction severe enough to stop the drug.

Infusion reactions are more common in patients who receive episodic treatment (regardless of dose), making them more likely to develop antibodies to infliximab. Sticking to scheduled infusions every 8-10 weeks reduces those risks.

Tell patients to fasten their seat belts and prepare for a regular commute. "Adherence to this therapy is very, very, very important," Dr. Kerdel said. "In those patients in whom you are considering this agent, you have to explain to them that they have to come for their scheduled visits."

Patients who keep to the every-8-weeks maintenance schedule after induction are less likely to have undetectable serum concentrations of infliximab when they return for treatment and more likely to respond to treatment. "Even though the drug is approved for every 8 weeks after the initial induction phase, some patients may have to receive the infusions every 4 or 6 weeks. The interval may have to be shortened for them to get an adequate response," he said.

If psoriasis relapses during long-term maintenance therapy with infliximab, repeating the induction phase may help, a small retrospective study suggests. Of 22 patients who lost their PASI 50 response and underwent re-induction, 20 regained a PASI 50 and 9 achieved a PASI 75 (Dermatol. Ther. 2010;23:199-202).

Keep safety in mind from the start, Dr. Kerdel said. Infliximab is contraindicated in patients with sepsis or serious infections. Get a tuberculosis skin test before starting infliximab and every year thereafter. Take precautions for patients with demyelinating disorders, congestive heart failure, liver function test abnormalities, or hepatitis B.

SDEF and this news organization are owned by Elsevier. Dr. Kerdel has been an adviser or speaker for, or has received grants from, Centocor Ortho Biotech (which markets infliximab and golimumab), Amgen (which markets etanercept), Abbott, Merck, Eisai, Astellas, Genentech, Stiefel, Novartis, and Wyeth.

LAS VEGAS – If you think of biologic therapies for psoriasis as cars, some are sturdy but pedestrian while others are racy sports cars.

"Etanercept is like a Volvo. It's not a fast car, it's not a flashy car, but it's a good, solid car that will probably work for you. Some of the other biologics are more like Ferraris – very fast but more difficult to steer," Dr. Francisco A. Kerdel said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Infliximab would be a Ferrari. "This is a high-performance vehicle, but you need to know what you're doing," said Dr. Kerdel, director of the dermatology inpatient service at University of Miami Hospital.

Golimumab is "like one of those European cars that look fantastic, but you're probably never going to own one," he said. Dr. Kerdel believes that golimumab probably will not win an indication specifically to treat psoriasis. It is approved for treating rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

He offered several driver's tips for getting the best performance out of infliximab.

Unlike the other biologics, infliximab is administered intravenously. It's "very, very efficacious and very fast" for treating psoriasis, he said. With the 5-mg/kg dose being marketed, 56% of patients achieved a 75% improvement in Psoriasis Area and Severity Index (PASI 75) score after 6 weeks in a phase III clinical trial. By week 10, 57% achieved a PASI 90.

Because infliximab is given on a mg/kg basis, the patient’s weight doesn’t seem to have as much effect on responses. Improvements are similar in patients who are normal weight, overweight, or obese.

Approximately 4% of patients receiving infliximab develop infusion reactions, compared with 2% who get placebo infusions. "The vast majority of these reactions are mild, and they can be managed in the office," Dr. Kerdel said. Less than 1% of patients will develop an infusion reaction severe enough to stop the drug.

Infusion reactions are more common in patients who receive episodic treatment (regardless of dose), making them more likely to develop antibodies to infliximab. Sticking to scheduled infusions every 8-10 weeks reduces those risks.

Tell patients to fasten their seat belts and prepare for a regular commute. "Adherence to this therapy is very, very, very important," Dr. Kerdel said. "In those patients in whom you are considering this agent, you have to explain to them that they have to come for their scheduled visits."

Patients who keep to the every-8-weeks maintenance schedule after induction are less likely to have undetectable serum concentrations of infliximab when they return for treatment and more likely to respond to treatment. "Even though the drug is approved for every 8 weeks after the initial induction phase, some patients may have to receive the infusions every 4 or 6 weeks. The interval may have to be shortened for them to get an adequate response," he said.

If psoriasis relapses during long-term maintenance therapy with infliximab, repeating the induction phase may help, a small retrospective study suggests. Of 22 patients who lost their PASI 50 response and underwent re-induction, 20 regained a PASI 50 and 9 achieved a PASI 75 (Dermatol. Ther. 2010;23:199-202).

Keep safety in mind from the start, Dr. Kerdel said. Infliximab is contraindicated in patients with sepsis or serious infections. Get a tuberculosis skin test before starting infliximab and every year thereafter. Take precautions for patients with demyelinating disorders, congestive heart failure, liver function test abnormalities, or hepatitis B.

SDEF and this news organization are owned by Elsevier. Dr. Kerdel has been an adviser or speaker for, or has received grants from, Centocor Ortho Biotech (which markets infliximab and golimumab), Amgen (which markets etanercept), Abbott, Merck, Eisai, Astellas, Genentech, Stiefel, Novartis, and Wyeth.

LAS VEGAS – If you think of biologic therapies for psoriasis as cars, some are sturdy but pedestrian while others are racy sports cars.

"Etanercept is like a Volvo. It's not a fast car, it's not a flashy car, but it's a good, solid car that will probably work for you. Some of the other biologics are more like Ferraris – very fast but more difficult to steer," Dr. Francisco A. Kerdel said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Infliximab would be a Ferrari. "This is a high-performance vehicle, but you need to know what you're doing," said Dr. Kerdel, director of the dermatology inpatient service at University of Miami Hospital.

Golimumab is "like one of those European cars that look fantastic, but you're probably never going to own one," he said. Dr. Kerdel believes that golimumab probably will not win an indication specifically to treat psoriasis. It is approved for treating rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

He offered several driver's tips for getting the best performance out of infliximab.

Unlike the other biologics, infliximab is administered intravenously. It's "very, very efficacious and very fast" for treating psoriasis, he said. With the 5-mg/kg dose being marketed, 56% of patients achieved a 75% improvement in Psoriasis Area and Severity Index (PASI 75) score after 6 weeks in a phase III clinical trial. By week 10, 57% achieved a PASI 90.

Because infliximab is given on a mg/kg basis, the patient’s weight doesn’t seem to have as much effect on responses. Improvements are similar in patients who are normal weight, overweight, or obese.

Approximately 4% of patients receiving infliximab develop infusion reactions, compared with 2% who get placebo infusions. "The vast majority of these reactions are mild, and they can be managed in the office," Dr. Kerdel said. Less than 1% of patients will develop an infusion reaction severe enough to stop the drug.

Infusion reactions are more common in patients who receive episodic treatment (regardless of dose), making them more likely to develop antibodies to infliximab. Sticking to scheduled infusions every 8-10 weeks reduces those risks.

Tell patients to fasten their seat belts and prepare for a regular commute. "Adherence to this therapy is very, very, very important," Dr. Kerdel said. "In those patients in whom you are considering this agent, you have to explain to them that they have to come for their scheduled visits."

Patients who keep to the every-8-weeks maintenance schedule after induction are less likely to have undetectable serum concentrations of infliximab when they return for treatment and more likely to respond to treatment. "Even though the drug is approved for every 8 weeks after the initial induction phase, some patients may have to receive the infusions every 4 or 6 weeks. The interval may have to be shortened for them to get an adequate response," he said.

If psoriasis relapses during long-term maintenance therapy with infliximab, repeating the induction phase may help, a small retrospective study suggests. Of 22 patients who lost their PASI 50 response and underwent re-induction, 20 regained a PASI 50 and 9 achieved a PASI 75 (Dermatol. Ther. 2010;23:199-202).

Keep safety in mind from the start, Dr. Kerdel said. Infliximab is contraindicated in patients with sepsis or serious infections. Get a tuberculosis skin test before starting infliximab and every year thereafter. Take precautions for patients with demyelinating disorders, congestive heart failure, liver function test abnormalities, or hepatitis B.

SDEF and this news organization are owned by Elsevier. Dr. Kerdel has been an adviser or speaker for, or has received grants from, Centocor Ortho Biotech (which markets infliximab and golimumab), Amgen (which markets etanercept), Abbott, Merck, Eisai, Astellas, Genentech, Stiefel, Novartis, and Wyeth.