The Journal of Family Practice

CASE › A 43-year-old woman arrives at your office with persistent itching on her arms and legs. For some time, she has used moisturizing lotions and herbal preparations suggested by her mother, but they have provided no relief. You note multiple 0.5- to 2-cm firm, excoriated nodules symmetrically distributed on her elbows and knees bilaterally. She has seasonal allergies and a history of childhood asthma. How would you care for this patient?

Treating prurigo nodularis (PN) can be a daunting task for even the most experienced clinician. Prurigo nodules are cutaneous lesions often produced by repetitive scratching—hence the nickname “picker’s nodules”—which may occur as sequelae of chronic pruritus or neurotic excoriations. Thus, PN can be classified as a subtype of neurodermatitis. The nodules can be intensely pruritic, resulting in an itch-scratch cycle that can be difficult to break.^1,2 In this review, we examine evidence-based therapies for PN.

Key findings with prurigo nodularis

Typically, prurigo nodules are firm, hyperkeratotic, pruritic papules or nodules that range in diameter from a few millimeters to several centimeters. The lesions usually have eroded or ulcerated components secondary to repeated excoriation, which can eventually lead to scarring and changes in pigmentation. Patients can have one nodule or hundreds of lesions, depending on disease severity. The lesions tend to be distributed symmetrically and have a predilection for the extensor surfaces of the upper and lower limbs. The abdomen, posterior neck, upper and lower back, and buttocks are also commonly affected, whereas the face, palms, and flexural areas are rarely involved^2-5 (FIGURE 1).

The differential diagnosis for PN includes dermatitis herpetiformis, scabies, lichen simplex chronicus, hypertrophic lichen planus, perforating disorders, atopic dermatitis, allergic contact dermatitis, neurotic excoriations, and multiple keratoacanthomas.^4,5

PN prevalence and etiology are unknown. Although PN can occur at any age, the typical age range is 20 to 60 years, with middle-aged women most commonly affected. Patients who develop PN at a younger age are more likely to have an atopic diathesis.^3,4

There is ongoing debate regarding whether PN is a primary cutaneous disease or a response to repetitive scratching provoked by a separate cause. PN has been associated with a variety of diseases, such as psychiatric disorders, atopic dermatitis, chronic renal failure, hyperthyroidism, iron-deficiency anemia, obstructive biliary disease, gastric malignancy, lymphoma, leukemia, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C.^2,3

Use the diagnostic work-up to focus on management decisions

When taking the history, first determine why patients are picking or scratching. If the lesions are pruritic or painful, look for a potential underlying cause of pruritic symptoms.⁶ If you identify an underlying dermatologic or systemic condition, treat that disorder first.¹ For example, adequately treating a patient’s atopic dermatitis or hyperthyroidism may quell the pruritic symptoms and potentially make the prurigo nodules more responsive to symptomatic treatment or even obviate the need for such measures.

Consider obtaining a biopsy of a non-traumatized lesion, which can help uncover scabies, atopic dermatitis, lichenoid drug eruption, or simple xerosis.

If treating the underlying cause of PN does not provide adequate relief, or if no cause for pruritic nodules can be found, the nodules may yet respond to symptomatic treatments targeted at decreasing pruritus and inflammation. In contrast, with patients who habitually scratch lesions they describe as non-pruritic, neurotic excoriations could be the source of PN, making the nodules less likely to respond to antipruritic therapies.^4,7

Patient insights. Assessing whether patients have insight into their condition is also important. Some patients may be unaware that they are repetitively picking and scratching the affected areas and causing the development and perpetuation of the nodules. In cases associated with an underlying psychiatric component, such as delusional parasitosis, patients often lack insight into their condition and thus may benefit from treatment of psychiatric comorbidities.^4,7

On physical exam, try to find lesions that have not been traumatized by patients. They can be useful in uncovering a primary cause, such as scabies, atopic dermatitis, lichenoid drug eruption, or simple xerosis.

If a diagnosis cannot be made clinically, consider obtaining a biopsy of a nontraumatized lesion. Traumatized lesions are typically unrevealing on histopathology. If the clinical assessment of pruritic lesions is indeterminate, laboratory tests that may prove helpful include, but are not limited to, thyroid-stimulating hormone levels, liver function tests, kidney function, a hepatitis panel, and HIV screening.

With severe refractory pruritus in which a primary cutaneous or systemic cause cannot be determined, evaluate for malignancy—especially polycythemia, lymphoma, or multiple myeloma—by ordering liver function tests (including lactate dehydrogenase), a complete blood count with differential, a basic metabolic panel, a chest x-ray, and possibly a serum protein electrophoresis.⁷

Available treatments

If the patient’s pruritic symptoms do not resolve and an underlying cause cannot be determined, direct treatment at decreasing pruritus either locally or systemically. Topical therapies, typically associated with fewer adverse effects, are preferable in localized cases of PN. In more severe, widespread, or recalcitrant disease, systemic agents may be necessary. Typical first-line treatments for PN aimed at decreasing pruritic symptoms include:

• topical antipruritics, such as ointments containing menthol or camphor; topical corticosteroids, with increased efficacy under occlusion as seen with flurandrenolide tape (Cordran tape)
• oral antihistamines, such as promethazine hydrochloride; oral antidepressants, such as doxepin
• intralesional corticosteroids—eg, triamcinolone acetonide (the concentration
  used depends on the thickness of the lesion and how well the lesion responded to prior injections)
• a short course of systemic corticosteroids, unless the patient has a comorbid condition that could be exacerbated by rapid tapering of corticosteroids (eg, psoriasis).

For patients with concomitant depression or anxiety, treatment with a selective serotonin reuptake inhibitor or anxiolytic, respectively, may be indicated.^2-4 With the exception of topical corticosteroids^8,9 and oral antihistamines,¹⁰ the aforementioned first-line treatments for PN are mostly based on clinical experience and anecdotal success with no studies to support their use.³ Furthermore, these treatments may be ineffective for many patients.^11,12 We present our review of several studies in the literature examining potential therapies for PN.

Topical therapies
Calcipotriol vs betamethasone. A prospective, randomized, double-blind study that ran right/left comparisons of calcipotriol ointment (a vitamin D₃ analog) and betamethasone ointment as treatment for PN in 9 patients showed that calcipotriol and betamethasone were both effective. However, calcipotriol ointment 50 mcg/g was more effective in reducing the number and size of nodules compared with 0.1% betamethasone valerate ointment.⁸

Topical corticosteroids have long been viewed as a first-line therapy for PN.² However, given their potential for adverse effects with long-term use, such as skin atrophy, steroidsparing agents are preferred. Calcipotriol ointment can be useful as both a steroid-sparing and a keratolytic agent, as it inhibits keratinocyte proliferation.^4,13 Corticosteroids and calcipotriol possess anti-inflammatory and antipruritic properties, likely explaining their efficacy in treating PN.⁴

Pimecrolimus and tacrolimus. The topical calcineurin inhibitors pimecrolimus and tacrolimus have been used successfully as steroid-sparing agents in treating atopic dermatitis.¹⁴ Their antipruritic effect, likely related to their influence on cutaneous sensory nerve fibers and inhibition of inflammatory cytokines, could also explain their efficacy in treating PN.^15,16

A randomized, hydrocortisone-controlled, double-blind phase II trial sponsored by Novartis was designed as a right/left comparison study between pimecrolimus 1% cream and hydrocortisone 1% cream in 30 patients with non-atopic PN. When applied twice daily, each agent decreased pruritic symptoms and resolved scratch lesions to degrees that were statistically significant. However, an intention-to-treat analysis revealed no significant differences between pimecrolimus and hydrocortisone.¹⁵ In a prospective case series of 11 patients with PN, 2 out of 4 patients (50%) receiving tacrolimus 0.1% ointment and 5 out of 7 patients (71%) using pimecrolimus 1% cream experienced a reduction in pruritic symptoms and improvement of lesions by 50% or greater with twice daily application of their assigned calcineurin inhibitor.¹⁶

Before prescribing topical calcineurin inhibitors, inform patients of the black-box warning issued by the US Food and Drug Administration (FDA) regarding the theoretical increased risk of developing cutaneous malignancy and lymphoma. This warning is controversial because in clinical databases, the incidences of malignancy and lymphoma associated with topical calcineurin inhibitors are less than those observed in the general population.¹⁴

Capsaicin. Based on a prospective study of 33 patients with PN, topical capsaicin may be an effective treatment if administered 4 to 6 times daily for at least 2 weeks and up to 10 months.¹⁷ Patients may require up to 0.3% concentration for total resolution of pruritus. Importantly, capsaicin use may be limited by the high application frequency.

Systemic therapies
Fexofenadine and montelukast. Oral antihistamines have long been used as a first-line treatment for PN. Although clinical experience and anecdotal success support the use of various antihistamines, evidence-based literature exists only for fexofenadine and the leukotriene receptor antagonist montelukast. These oral agents also avoid potential unwanted effects of topical antihistamines, which may sensitize skin and increase the risk of developing allergic contact dermatitis.¹

Whereas antihistamines exert their antipruritic effect by blocking histamine H1-receptors, montelukast decreases pruritic symptoms by antagonizing leukotriene receptors.¹⁰ In a prospective study of 12 patients with PN receiving fexofenadine 240 mg twice daily and montelukast 10 mg daily for 4 weeks, 9 of the 12 patients (75%) reported some degree of improvement.¹⁰ However, 5 of these 9 patients (56%) achieved only slight improvement. Level of improvement was based on how well the agents reduced the pruritus and lesion number.

Naltrexone. As an opioid antagonist, naltrexone is able to block endogenous opiates from binding to central opioid receptors and causing the sensation of pruritus. Accordingly, oral naltrexone can be used to treat PN, as shown in an open-label clinical trial in which 9 out of 17 patients (53%) achieved high antipruritic effect, defined as a reduction of pruritic symptoms by at least half.¹⁸

When selecting naltrexone to treat PN, prescribe a daily dose of 50 mg for an average of 4.7 months; up to 20 months of treatment may be required. If tachyphylaxis occurs, consider increasing the dose to 50 mg twice a day. Most patients should notice some level of antipruritic efficacy and varying degrees of lesion flattening, softening, or healing. However, exacerbation after therapy discontinuation may occur in 41% of patients. Adverse medication effects include fatigue, nausea, and dizziness.¹⁸

Oral naltrexone, gabapentin, or pregabalin may be needed for widespread or treatment-resistant prurigo nodularis.

Gabapentin and pregabalin. In response to a report of a case series in which 4 patients with PN responded well to gabapentin,¹⁹ Mazza et al²⁰ conducted a prospective study of pregabalin treatment for 30 patients with PN. Both gabapentin and pregabalin inhibit calcium influx and subsequent excitatory neurotransmitter release, the mechanism by which they likely decrease pruritus in patients with PN.²⁰ In the pregabalin study, 23 out of 30 patients (77%) experienced complete resolution of pruritic symptoms and a reduction of prurigo nodules in number or flattening. The recommended dosage of pregabalin is 25 mg 3 times daily for 3 months, after which time clinical progress is assessed. If a patient is not lesion-free, continue pregabalin at a maintenance dose of 50 mg/d for up to 2 years. Adverse effects typically include headache, sedation, and dizziness.²⁰

When to refer a dermatologist

Refer patients to a dermatologist if initial clinical findings suggest a need for further work-up to rule out primary cutaneous diseases, or if the therapies discussed (TABLE^8-10,15-20) yield unsatisfactory results. Dermatologists can provide more advanced treatments that require close monitoring, such as phototherapy,^21-24 cyclosporine,²⁵ or thalidomide.^26-28 Based on multiple case series and case reports, as well as our own personal experience (FIGURE 2), thalidomide is efficacious in treating PN. However, thalidomide is typically reserved for cases that are severe and treatment-recalcitrant due to the drug’s high cost, teratogenicity (pregnancy category X), and potentially irreversible peripheral neuropathy.²⁹

Putting Tx options into practice

In addition to ruling out potential causes of pruritus and determining the best treatment for each individual with PN, assess for and appropriately treat any psychiatric comorbidities, which are often a psychological component of PN.

Localized PN. Start with topical corticosteroids under occlusion for localized PN. To avoid complications of long-term topical corticosteroid use, including dermal atrophy, periodically switch to a steroid-sparing agent, such as calcipotriol ointment or topical pimecrolimus. Less evidence is available to support the efficacy of tacrolimus ointment in PN treatment. Topical capsaicin is not as practical as other topical treatments since it needs to be applied 4 to 6 times daily. Oral antihistamines and montelukast may be added to the therapeutic regimen if there is a chronic pruritic component related to the lesions themselves or an underlying atopic diathesis fueling the itch-scratch cycle.

Widespread or treatment-resistant PN. Prescribe naltrexone, gabapentin, or pregabalin for more widespread disease or lesions resistant to conservative therapies. If you suspect a primary cutaneous disease as the underlying cause of pruritus or if topical and oral therapies do not achieve the desired therapeutic effect, refer to a dermatologist for further work-up and treatment.

How we would manage the case presented in the introduction. We would start the 43-year-old on topical corticosteroids under occlusion and periodically substitute calcipotriol ointment. (Given the unease that some patients might feel with the black-box warning on topical calcineurin inhibitors, we would likely try calcipotriol ointment as a courtesy before suggesting topical calcineurin inhibitors.) We would also prescribe an oral antihistamine at the start, given that her history of seasonal allergies and childhood asthma increases her chances of having an atopic component causing or exacerbating her disease. However, assessing her response to topical therapies before initiating an oral antihistamine would also be an appropriate strategy.

Unfortunately, PN is typically a chronic and often treatment-resistant disease with disappointing recurrence rates. As we learn more about the pathophysiology of PN, more effective therapies will hopefully emerge to improve the quality of life for these patients.

CORRESPONDENCE
Michael Saco, MD, Department of Dermatology & Cutaneous Surgery, University of South Florida, 13330 Laurel Drive, Tampa, FL 33612; ms20142018@aol.com

CASE › A 43-year-old woman arrives at your office with persistent itching on her arms and legs. For some time, she has used moisturizing lotions and herbal preparations suggested by her mother, but they have provided no relief. You note multiple 0.5- to 2-cm firm, excoriated nodules symmetrically distributed on her elbows and knees bilaterally. She has seasonal allergies and a history of childhood asthma. How would you care for this patient?

Treating prurigo nodularis (PN) can be a daunting task for even the most experienced clinician. Prurigo nodules are cutaneous lesions often produced by repetitive scratching—hence the nickname “picker’s nodules”—which may occur as sequelae of chronic pruritus or neurotic excoriations. Thus, PN can be classified as a subtype of neurodermatitis. The nodules can be intensely pruritic, resulting in an itch-scratch cycle that can be difficult to break.^1,2 In this review, we examine evidence-based therapies for PN.

Key findings with prurigo nodularis

Typically, prurigo nodules are firm, hyperkeratotic, pruritic papules or nodules that range in diameter from a few millimeters to several centimeters. The lesions usually have eroded or ulcerated components secondary to repeated excoriation, which can eventually lead to scarring and changes in pigmentation. Patients can have one nodule or hundreds of lesions, depending on disease severity. The lesions tend to be distributed symmetrically and have a predilection for the extensor surfaces of the upper and lower limbs. The abdomen, posterior neck, upper and lower back, and buttocks are also commonly affected, whereas the face, palms, and flexural areas are rarely involved^2-5 (FIGURE 1).

The differential diagnosis for PN includes dermatitis herpetiformis, scabies, lichen simplex chronicus, hypertrophic lichen planus, perforating disorders, atopic dermatitis, allergic contact dermatitis, neurotic excoriations, and multiple keratoacanthomas.^4,5

PN prevalence and etiology are unknown. Although PN can occur at any age, the typical age range is 20 to 60 years, with middle-aged women most commonly affected. Patients who develop PN at a younger age are more likely to have an atopic diathesis.^3,4

There is ongoing debate regarding whether PN is a primary cutaneous disease or a response to repetitive scratching provoked by a separate cause. PN has been associated with a variety of diseases, such as psychiatric disorders, atopic dermatitis, chronic renal failure, hyperthyroidism, iron-deficiency anemia, obstructive biliary disease, gastric malignancy, lymphoma, leukemia, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C.^2,3

Use the diagnostic work-up to focus on management decisions

When taking the history, first determine why patients are picking or scratching. If the lesions are pruritic or painful, look for a potential underlying cause of pruritic symptoms.⁶ If you identify an underlying dermatologic or systemic condition, treat that disorder first.¹ For example, adequately treating a patient’s atopic dermatitis or hyperthyroidism may quell the pruritic symptoms and potentially make the prurigo nodules more responsive to symptomatic treatment or even obviate the need for such measures.

Consider obtaining a biopsy of a non-traumatized lesion, which can help uncover scabies, atopic dermatitis, lichenoid drug eruption, or simple xerosis.

If treating the underlying cause of PN does not provide adequate relief, or if no cause for pruritic nodules can be found, the nodules may yet respond to symptomatic treatments targeted at decreasing pruritus and inflammation. In contrast, with patients who habitually scratch lesions they describe as non-pruritic, neurotic excoriations could be the source of PN, making the nodules less likely to respond to antipruritic therapies.^4,7

Patient insights. Assessing whether patients have insight into their condition is also important. Some patients may be unaware that they are repetitively picking and scratching the affected areas and causing the development and perpetuation of the nodules. In cases associated with an underlying psychiatric component, such as delusional parasitosis, patients often lack insight into their condition and thus may benefit from treatment of psychiatric comorbidities.^4,7

On physical exam, try to find lesions that have not been traumatized by patients. They can be useful in uncovering a primary cause, such as scabies, atopic dermatitis, lichenoid drug eruption, or simple xerosis.

If a diagnosis cannot be made clinically, consider obtaining a biopsy of a nontraumatized lesion. Traumatized lesions are typically unrevealing on histopathology. If the clinical assessment of pruritic lesions is indeterminate, laboratory tests that may prove helpful include, but are not limited to, thyroid-stimulating hormone levels, liver function tests, kidney function, a hepatitis panel, and HIV screening.

With severe refractory pruritus in which a primary cutaneous or systemic cause cannot be determined, evaluate for malignancy—especially polycythemia, lymphoma, or multiple myeloma—by ordering liver function tests (including lactate dehydrogenase), a complete blood count with differential, a basic metabolic panel, a chest x-ray, and possibly a serum protein electrophoresis.⁷

Available treatments

If the patient’s pruritic symptoms do not resolve and an underlying cause cannot be determined, direct treatment at decreasing pruritus either locally or systemically. Topical therapies, typically associated with fewer adverse effects, are preferable in localized cases of PN. In more severe, widespread, or recalcitrant disease, systemic agents may be necessary. Typical first-line treatments for PN aimed at decreasing pruritic symptoms include:

• topical antipruritics, such as ointments containing menthol or camphor; topical corticosteroids, with increased efficacy under occlusion as seen with flurandrenolide tape (Cordran tape)
• oral antihistamines, such as promethazine hydrochloride; oral antidepressants, such as doxepin
• intralesional corticosteroids—eg, triamcinolone acetonide (the concentration
  used depends on the thickness of the lesion and how well the lesion responded to prior injections)
• a short course of systemic corticosteroids, unless the patient has a comorbid condition that could be exacerbated by rapid tapering of corticosteroids (eg, psoriasis).

For patients with concomitant depression or anxiety, treatment with a selective serotonin reuptake inhibitor or anxiolytic, respectively, may be indicated.^2-4 With the exception of topical corticosteroids^8,9 and oral antihistamines,¹⁰ the aforementioned first-line treatments for PN are mostly based on clinical experience and anecdotal success with no studies to support their use.³ Furthermore, these treatments may be ineffective for many patients.^11,12 We present our review of several studies in the literature examining potential therapies for PN.

Topical therapies
Calcipotriol vs betamethasone. A prospective, randomized, double-blind study that ran right/left comparisons of calcipotriol ointment (a vitamin D₃ analog) and betamethasone ointment as treatment for PN in 9 patients showed that calcipotriol and betamethasone were both effective. However, calcipotriol ointment 50 mcg/g was more effective in reducing the number and size of nodules compared with 0.1% betamethasone valerate ointment.⁸

Topical corticosteroids have long been viewed as a first-line therapy for PN.² However, given their potential for adverse effects with long-term use, such as skin atrophy, steroidsparing agents are preferred. Calcipotriol ointment can be useful as both a steroid-sparing and a keratolytic agent, as it inhibits keratinocyte proliferation.^4,13 Corticosteroids and calcipotriol possess anti-inflammatory and antipruritic properties, likely explaining their efficacy in treating PN.⁴

Pimecrolimus and tacrolimus. The topical calcineurin inhibitors pimecrolimus and tacrolimus have been used successfully as steroid-sparing agents in treating atopic dermatitis.¹⁴ Their antipruritic effect, likely related to their influence on cutaneous sensory nerve fibers and inhibition of inflammatory cytokines, could also explain their efficacy in treating PN.^15,16

A randomized, hydrocortisone-controlled, double-blind phase II trial sponsored by Novartis was designed as a right/left comparison study between pimecrolimus 1% cream and hydrocortisone 1% cream in 30 patients with non-atopic PN. When applied twice daily, each agent decreased pruritic symptoms and resolved scratch lesions to degrees that were statistically significant. However, an intention-to-treat analysis revealed no significant differences between pimecrolimus and hydrocortisone.¹⁵ In a prospective case series of 11 patients with PN, 2 out of 4 patients (50%) receiving tacrolimus 0.1% ointment and 5 out of 7 patients (71%) using pimecrolimus 1% cream experienced a reduction in pruritic symptoms and improvement of lesions by 50% or greater with twice daily application of their assigned calcineurin inhibitor.¹⁶

Before prescribing topical calcineurin inhibitors, inform patients of the black-box warning issued by the US Food and Drug Administration (FDA) regarding the theoretical increased risk of developing cutaneous malignancy and lymphoma. This warning is controversial because in clinical databases, the incidences of malignancy and lymphoma associated with topical calcineurin inhibitors are less than those observed in the general population.¹⁴

Capsaicin. Based on a prospective study of 33 patients with PN, topical capsaicin may be an effective treatment if administered 4 to 6 times daily for at least 2 weeks and up to 10 months.¹⁷ Patients may require up to 0.3% concentration for total resolution of pruritus. Importantly, capsaicin use may be limited by the high application frequency.

Systemic therapies
Fexofenadine and montelukast. Oral antihistamines have long been used as a first-line treatment for PN. Although clinical experience and anecdotal success support the use of various antihistamines, evidence-based literature exists only for fexofenadine and the leukotriene receptor antagonist montelukast. These oral agents also avoid potential unwanted effects of topical antihistamines, which may sensitize skin and increase the risk of developing allergic contact dermatitis.¹

Whereas antihistamines exert their antipruritic effect by blocking histamine H1-receptors, montelukast decreases pruritic symptoms by antagonizing leukotriene receptors.¹⁰ In a prospective study of 12 patients with PN receiving fexofenadine 240 mg twice daily and montelukast 10 mg daily for 4 weeks, 9 of the 12 patients (75%) reported some degree of improvement.¹⁰ However, 5 of these 9 patients (56%) achieved only slight improvement. Level of improvement was based on how well the agents reduced the pruritus and lesion number.

Naltrexone. As an opioid antagonist, naltrexone is able to block endogenous opiates from binding to central opioid receptors and causing the sensation of pruritus. Accordingly, oral naltrexone can be used to treat PN, as shown in an open-label clinical trial in which 9 out of 17 patients (53%) achieved high antipruritic effect, defined as a reduction of pruritic symptoms by at least half.¹⁸

When selecting naltrexone to treat PN, prescribe a daily dose of 50 mg for an average of 4.7 months; up to 20 months of treatment may be required. If tachyphylaxis occurs, consider increasing the dose to 50 mg twice a day. Most patients should notice some level of antipruritic efficacy and varying degrees of lesion flattening, softening, or healing. However, exacerbation after therapy discontinuation may occur in 41% of patients. Adverse medication effects include fatigue, nausea, and dizziness.¹⁸

Oral naltrexone, gabapentin, or pregabalin may be needed for widespread or treatment-resistant prurigo nodularis.

Gabapentin and pregabalin. In response to a report of a case series in which 4 patients with PN responded well to gabapentin,¹⁹ Mazza et al²⁰ conducted a prospective study of pregabalin treatment for 30 patients with PN. Both gabapentin and pregabalin inhibit calcium influx and subsequent excitatory neurotransmitter release, the mechanism by which they likely decrease pruritus in patients with PN.²⁰ In the pregabalin study, 23 out of 30 patients (77%) experienced complete resolution of pruritic symptoms and a reduction of prurigo nodules in number or flattening. The recommended dosage of pregabalin is 25 mg 3 times daily for 3 months, after which time clinical progress is assessed. If a patient is not lesion-free, continue pregabalin at a maintenance dose of 50 mg/d for up to 2 years. Adverse effects typically include headache, sedation, and dizziness.²⁰

When to refer a dermatologist

Refer patients to a dermatologist if initial clinical findings suggest a need for further work-up to rule out primary cutaneous diseases, or if the therapies discussed (TABLE^8-10,15-20) yield unsatisfactory results. Dermatologists can provide more advanced treatments that require close monitoring, such as phototherapy,^21-24 cyclosporine,²⁵ or thalidomide.^26-28 Based on multiple case series and case reports, as well as our own personal experience (FIGURE 2), thalidomide is efficacious in treating PN. However, thalidomide is typically reserved for cases that are severe and treatment-recalcitrant due to the drug’s high cost, teratogenicity (pregnancy category X), and potentially irreversible peripheral neuropathy.²⁹

Putting Tx options into practice

In addition to ruling out potential causes of pruritus and determining the best treatment for each individual with PN, assess for and appropriately treat any psychiatric comorbidities, which are often a psychological component of PN.

Localized PN. Start with topical corticosteroids under occlusion for localized PN. To avoid complications of long-term topical corticosteroid use, including dermal atrophy, periodically switch to a steroid-sparing agent, such as calcipotriol ointment or topical pimecrolimus. Less evidence is available to support the efficacy of tacrolimus ointment in PN treatment. Topical capsaicin is not as practical as other topical treatments since it needs to be applied 4 to 6 times daily. Oral antihistamines and montelukast may be added to the therapeutic regimen if there is a chronic pruritic component related to the lesions themselves or an underlying atopic diathesis fueling the itch-scratch cycle.

Widespread or treatment-resistant PN. Prescribe naltrexone, gabapentin, or pregabalin for more widespread disease or lesions resistant to conservative therapies. If you suspect a primary cutaneous disease as the underlying cause of pruritus or if topical and oral therapies do not achieve the desired therapeutic effect, refer to a dermatologist for further work-up and treatment.

How we would manage the case presented in the introduction. We would start the 43-year-old on topical corticosteroids under occlusion and periodically substitute calcipotriol ointment. (Given the unease that some patients might feel with the black-box warning on topical calcineurin inhibitors, we would likely try calcipotriol ointment as a courtesy before suggesting topical calcineurin inhibitors.) We would also prescribe an oral antihistamine at the start, given that her history of seasonal allergies and childhood asthma increases her chances of having an atopic component causing or exacerbating her disease. However, assessing her response to topical therapies before initiating an oral antihistamine would also be an appropriate strategy.

Unfortunately, PN is typically a chronic and often treatment-resistant disease with disappointing recurrence rates. As we learn more about the pathophysiology of PN, more effective therapies will hopefully emerge to improve the quality of life for these patients.

CORRESPONDENCE
Michael Saco, MD, Department of Dermatology & Cutaneous Surgery, University of South Florida, 13330 Laurel Drive, Tampa, FL 33612; ms20142018@aol.com

CASE › A 43-year-old woman arrives at your office with persistent itching on her arms and legs. For some time, she has used moisturizing lotions and herbal preparations suggested by her mother, but they have provided no relief. You note multiple 0.5- to 2-cm firm, excoriated nodules symmetrically distributed on her elbows and knees bilaterally. She has seasonal allergies and a history of childhood asthma. How would you care for this patient?

Treating prurigo nodularis (PN) can be a daunting task for even the most experienced clinician. Prurigo nodules are cutaneous lesions often produced by repetitive scratching—hence the nickname “picker’s nodules”—which may occur as sequelae of chronic pruritus or neurotic excoriations. Thus, PN can be classified as a subtype of neurodermatitis. The nodules can be intensely pruritic, resulting in an itch-scratch cycle that can be difficult to break.^1,2 In this review, we examine evidence-based therapies for PN.

Key findings with prurigo nodularis

Typically, prurigo nodules are firm, hyperkeratotic, pruritic papules or nodules that range in diameter from a few millimeters to several centimeters. The lesions usually have eroded or ulcerated components secondary to repeated excoriation, which can eventually lead to scarring and changes in pigmentation. Patients can have one nodule or hundreds of lesions, depending on disease severity. The lesions tend to be distributed symmetrically and have a predilection for the extensor surfaces of the upper and lower limbs. The abdomen, posterior neck, upper and lower back, and buttocks are also commonly affected, whereas the face, palms, and flexural areas are rarely involved^2-5 (FIGURE 1).

The differential diagnosis for PN includes dermatitis herpetiformis, scabies, lichen simplex chronicus, hypertrophic lichen planus, perforating disorders, atopic dermatitis, allergic contact dermatitis, neurotic excoriations, and multiple keratoacanthomas.^4,5

PN prevalence and etiology are unknown. Although PN can occur at any age, the typical age range is 20 to 60 years, with middle-aged women most commonly affected. Patients who develop PN at a younger age are more likely to have an atopic diathesis.^3,4

There is ongoing debate regarding whether PN is a primary cutaneous disease or a response to repetitive scratching provoked by a separate cause. PN has been associated with a variety of diseases, such as psychiatric disorders, atopic dermatitis, chronic renal failure, hyperthyroidism, iron-deficiency anemia, obstructive biliary disease, gastric malignancy, lymphoma, leukemia, human immunodeficiency virus (HIV), hepatitis B, and hepatitis C.^2,3

Use the diagnostic work-up to focus on management decisions

When taking the history, first determine why patients are picking or scratching. If the lesions are pruritic or painful, look for a potential underlying cause of pruritic symptoms.⁶ If you identify an underlying dermatologic or systemic condition, treat that disorder first.¹ For example, adequately treating a patient’s atopic dermatitis or hyperthyroidism may quell the pruritic symptoms and potentially make the prurigo nodules more responsive to symptomatic treatment or even obviate the need for such measures.

Consider obtaining a biopsy of a non-traumatized lesion, which can help uncover scabies, atopic dermatitis, lichenoid drug eruption, or simple xerosis.

If treating the underlying cause of PN does not provide adequate relief, or if no cause for pruritic nodules can be found, the nodules may yet respond to symptomatic treatments targeted at decreasing pruritus and inflammation. In contrast, with patients who habitually scratch lesions they describe as non-pruritic, neurotic excoriations could be the source of PN, making the nodules less likely to respond to antipruritic therapies.^4,7

Patient insights. Assessing whether patients have insight into their condition is also important. Some patients may be unaware that they are repetitively picking and scratching the affected areas and causing the development and perpetuation of the nodules. In cases associated with an underlying psychiatric component, such as delusional parasitosis, patients often lack insight into their condition and thus may benefit from treatment of psychiatric comorbidities.^4,7

On physical exam, try to find lesions that have not been traumatized by patients. They can be useful in uncovering a primary cause, such as scabies, atopic dermatitis, lichenoid drug eruption, or simple xerosis.

If a diagnosis cannot be made clinically, consider obtaining a biopsy of a nontraumatized lesion. Traumatized lesions are typically unrevealing on histopathology. If the clinical assessment of pruritic lesions is indeterminate, laboratory tests that may prove helpful include, but are not limited to, thyroid-stimulating hormone levels, liver function tests, kidney function, a hepatitis panel, and HIV screening.

With severe refractory pruritus in which a primary cutaneous or systemic cause cannot be determined, evaluate for malignancy—especially polycythemia, lymphoma, or multiple myeloma—by ordering liver function tests (including lactate dehydrogenase), a complete blood count with differential, a basic metabolic panel, a chest x-ray, and possibly a serum protein electrophoresis.⁷

Available treatments

If the patient’s pruritic symptoms do not resolve and an underlying cause cannot be determined, direct treatment at decreasing pruritus either locally or systemically. Topical therapies, typically associated with fewer adverse effects, are preferable in localized cases of PN. In more severe, widespread, or recalcitrant disease, systemic agents may be necessary. Typical first-line treatments for PN aimed at decreasing pruritic symptoms include:

• topical antipruritics, such as ointments containing menthol or camphor; topical corticosteroids, with increased efficacy under occlusion as seen with flurandrenolide tape (Cordran tape)
• oral antihistamines, such as promethazine hydrochloride; oral antidepressants, such as doxepin
• intralesional corticosteroids—eg, triamcinolone acetonide (the concentration
  used depends on the thickness of the lesion and how well the lesion responded to prior injections)
• a short course of systemic corticosteroids, unless the patient has a comorbid condition that could be exacerbated by rapid tapering of corticosteroids (eg, psoriasis).

For patients with concomitant depression or anxiety, treatment with a selective serotonin reuptake inhibitor or anxiolytic, respectively, may be indicated.^2-4 With the exception of topical corticosteroids^8,9 and oral antihistamines,¹⁰ the aforementioned first-line treatments for PN are mostly based on clinical experience and anecdotal success with no studies to support their use.³ Furthermore, these treatments may be ineffective for many patients.^11,12 We present our review of several studies in the literature examining potential therapies for PN.

Topical therapies
Calcipotriol vs betamethasone. A prospective, randomized, double-blind study that ran right/left comparisons of calcipotriol ointment (a vitamin D₃ analog) and betamethasone ointment as treatment for PN in 9 patients showed that calcipotriol and betamethasone were both effective. However, calcipotriol ointment 50 mcg/g was more effective in reducing the number and size of nodules compared with 0.1% betamethasone valerate ointment.⁸

Topical corticosteroids have long been viewed as a first-line therapy for PN.² However, given their potential for adverse effects with long-term use, such as skin atrophy, steroidsparing agents are preferred. Calcipotriol ointment can be useful as both a steroid-sparing and a keratolytic agent, as it inhibits keratinocyte proliferation.^4,13 Corticosteroids and calcipotriol possess anti-inflammatory and antipruritic properties, likely explaining their efficacy in treating PN.⁴

Pimecrolimus and tacrolimus. The topical calcineurin inhibitors pimecrolimus and tacrolimus have been used successfully as steroid-sparing agents in treating atopic dermatitis.¹⁴ Their antipruritic effect, likely related to their influence on cutaneous sensory nerve fibers and inhibition of inflammatory cytokines, could also explain their efficacy in treating PN.^15,16

A randomized, hydrocortisone-controlled, double-blind phase II trial sponsored by Novartis was designed as a right/left comparison study between pimecrolimus 1% cream and hydrocortisone 1% cream in 30 patients with non-atopic PN. When applied twice daily, each agent decreased pruritic symptoms and resolved scratch lesions to degrees that were statistically significant. However, an intention-to-treat analysis revealed no significant differences between pimecrolimus and hydrocortisone.¹⁵ In a prospective case series of 11 patients with PN, 2 out of 4 patients (50%) receiving tacrolimus 0.1% ointment and 5 out of 7 patients (71%) using pimecrolimus 1% cream experienced a reduction in pruritic symptoms and improvement of lesions by 50% or greater with twice daily application of their assigned calcineurin inhibitor.¹⁶

Before prescribing topical calcineurin inhibitors, inform patients of the black-box warning issued by the US Food and Drug Administration (FDA) regarding the theoretical increased risk of developing cutaneous malignancy and lymphoma. This warning is controversial because in clinical databases, the incidences of malignancy and lymphoma associated with topical calcineurin inhibitors are less than those observed in the general population.¹⁴

Capsaicin. Based on a prospective study of 33 patients with PN, topical capsaicin may be an effective treatment if administered 4 to 6 times daily for at least 2 weeks and up to 10 months.¹⁷ Patients may require up to 0.3% concentration for total resolution of pruritus. Importantly, capsaicin use may be limited by the high application frequency.

Systemic therapies
Fexofenadine and montelukast. Oral antihistamines have long been used as a first-line treatment for PN. Although clinical experience and anecdotal success support the use of various antihistamines, evidence-based literature exists only for fexofenadine and the leukotriene receptor antagonist montelukast. These oral agents also avoid potential unwanted effects of topical antihistamines, which may sensitize skin and increase the risk of developing allergic contact dermatitis.¹

Whereas antihistamines exert their antipruritic effect by blocking histamine H1-receptors, montelukast decreases pruritic symptoms by antagonizing leukotriene receptors.¹⁰ In a prospective study of 12 patients with PN receiving fexofenadine 240 mg twice daily and montelukast 10 mg daily for 4 weeks, 9 of the 12 patients (75%) reported some degree of improvement.¹⁰ However, 5 of these 9 patients (56%) achieved only slight improvement. Level of improvement was based on how well the agents reduced the pruritus and lesion number.

Naltrexone. As an opioid antagonist, naltrexone is able to block endogenous opiates from binding to central opioid receptors and causing the sensation of pruritus. Accordingly, oral naltrexone can be used to treat PN, as shown in an open-label clinical trial in which 9 out of 17 patients (53%) achieved high antipruritic effect, defined as a reduction of pruritic symptoms by at least half.¹⁸

When selecting naltrexone to treat PN, prescribe a daily dose of 50 mg for an average of 4.7 months; up to 20 months of treatment may be required. If tachyphylaxis occurs, consider increasing the dose to 50 mg twice a day. Most patients should notice some level of antipruritic efficacy and varying degrees of lesion flattening, softening, or healing. However, exacerbation after therapy discontinuation may occur in 41% of patients. Adverse medication effects include fatigue, nausea, and dizziness.¹⁸

Oral naltrexone, gabapentin, or pregabalin may be needed for widespread or treatment-resistant prurigo nodularis.

Gabapentin and pregabalin. In response to a report of a case series in which 4 patients with PN responded well to gabapentin,¹⁹ Mazza et al²⁰ conducted a prospective study of pregabalin treatment for 30 patients with PN. Both gabapentin and pregabalin inhibit calcium influx and subsequent excitatory neurotransmitter release, the mechanism by which they likely decrease pruritus in patients with PN.²⁰ In the pregabalin study, 23 out of 30 patients (77%) experienced complete resolution of pruritic symptoms and a reduction of prurigo nodules in number or flattening. The recommended dosage of pregabalin is 25 mg 3 times daily for 3 months, after which time clinical progress is assessed. If a patient is not lesion-free, continue pregabalin at a maintenance dose of 50 mg/d for up to 2 years. Adverse effects typically include headache, sedation, and dizziness.²⁰

When to refer a dermatologist

Refer patients to a dermatologist if initial clinical findings suggest a need for further work-up to rule out primary cutaneous diseases, or if the therapies discussed (TABLE^8-10,15-20) yield unsatisfactory results. Dermatologists can provide more advanced treatments that require close monitoring, such as phototherapy,^21-24 cyclosporine,²⁵ or thalidomide.^26-28 Based on multiple case series and case reports, as well as our own personal experience (FIGURE 2), thalidomide is efficacious in treating PN. However, thalidomide is typically reserved for cases that are severe and treatment-recalcitrant due to the drug’s high cost, teratogenicity (pregnancy category X), and potentially irreversible peripheral neuropathy.²⁹

Putting Tx options into practice

In addition to ruling out potential causes of pruritus and determining the best treatment for each individual with PN, assess for and appropriately treat any psychiatric comorbidities, which are often a psychological component of PN.

Localized PN. Start with topical corticosteroids under occlusion for localized PN. To avoid complications of long-term topical corticosteroid use, including dermal atrophy, periodically switch to a steroid-sparing agent, such as calcipotriol ointment or topical pimecrolimus. Less evidence is available to support the efficacy of tacrolimus ointment in PN treatment. Topical capsaicin is not as practical as other topical treatments since it needs to be applied 4 to 6 times daily. Oral antihistamines and montelukast may be added to the therapeutic regimen if there is a chronic pruritic component related to the lesions themselves or an underlying atopic diathesis fueling the itch-scratch cycle.

Widespread or treatment-resistant PN. Prescribe naltrexone, gabapentin, or pregabalin for more widespread disease or lesions resistant to conservative therapies. If you suspect a primary cutaneous disease as the underlying cause of pruritus or if topical and oral therapies do not achieve the desired therapeutic effect, refer to a dermatologist for further work-up and treatment.

How we would manage the case presented in the introduction. We would start the 43-year-old on topical corticosteroids under occlusion and periodically substitute calcipotriol ointment. (Given the unease that some patients might feel with the black-box warning on topical calcineurin inhibitors, we would likely try calcipotriol ointment as a courtesy before suggesting topical calcineurin inhibitors.) We would also prescribe an oral antihistamine at the start, given that her history of seasonal allergies and childhood asthma increases her chances of having an atopic component causing or exacerbating her disease. However, assessing her response to topical therapies before initiating an oral antihistamine would also be an appropriate strategy.

Unfortunately, PN is typically a chronic and often treatment-resistant disease with disappointing recurrence rates. As we learn more about the pathophysiology of PN, more effective therapies will hopefully emerge to improve the quality of life for these patients.

CORRESPONDENCE
Michael Saco, MD, Department of Dermatology & Cutaneous Surgery, University of South Florida, 13330 Laurel Drive, Tampa, FL 33612; ms20142018@aol.com

A 38-year-old African American man with no significant medical history presented to our dermatology clinic with a 5-month history of nodules on the right side of his nose (FIGURE 1). For several years, he’d also had nodules that gradually appeared on several red-inked tattoos shortly after he received each tattoo (FIGURE 2). He also had a 5-year history of nontender swelling of his fingers.

The patient denied any trauma to the areas with nodules or being in contact with anyone who was sick. He had no respiratory complaints, but chest x-rays from recent and past records showed stable bilateral intrathoracic lymphadenopathy without any lobar infiltration or pleural effusion.

Physical examination revealed 3 reddish-brown soft nodules on the nasal ala and multiple, nontender, 3- to 5-mm firm nodules located in the red-inked areas of tattoos on his arms and neck. The tattoo nodules were asymptomatic and stable in size. He had clubbing of multiple digits and nail dystrophy. His distal fingers were edematous, but nontender. X-rays revealed lytic, lace-like lucencies of the middle and distal phalanges and erosions of the distal phalanges on both hands (FIGURE 3).

We biopsied the nodules on his nose and on one of his tattoos.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Sarcoidosis

Based on his clinical presentation and skin biopsy results, the patient was given a diagnosis of cutaneous sarcoidosis. A biopsy from the right side of his nose demonstrated sarcoidal granulomas. Acid-fast bacilli and periodic acid-Schiff stains were negative. A biopsy of one of the tattoo nodules showed sarcoidal granulomas, and close inspection revealed red tattoo pigment within the granulomatous inflammation.

X-rays showed bilateral hilar lymphadenopathy, which was consistent with pulmonary sarcoidosis, and the lace-like appearance of the middle and distal phalanges was consistent with skeletal sarcoidosis.

Systemic sarcoidosis is an idiopathic, granulomatous disease that affects multiple organ systems but primarily the lungs and lymphatic system.¹ The estimated prevalence of systemic sarcoidosis ranges from less than 1 to 40 cases per 100,000 people, and the condition is more common among African Americans.¹

Skin manifestations may be the first—and only—sign of systemic sarcoidosis.

Cutaneous sarcoidosis can occur as a manifestation of systemic sarcoidosis. It occurs in 20% to 35% of patients with systemic sarcoidosis² and may present as asymptomatic red or skin-colored papules and firm nodules within tattoos, old scars, or permanent makeup. Cutaneous sarcoidosis in tattoos may be the first manifestation of sarcoidosis, and the time between acquiring the tattoo and developing sarcoidal nodules varies widely.

It is not clear why sarcoidal granulomas occur in tattoos. One possibility is that chronic low-grade exposure of the immune system to foreign materials such as tattoo ink leads to granulomatous hypersensitivity.^2,3 Sarcoidosis usually occurs in red (cinnabar), black (ferric oxide), or blue-black areas of tattoos,⁴ in which the pigment acts as a nidus for granuloma formation.

A skin biopsy is helpful in making a diagnosis of cutaneous sarcoidosis. The histopathology shows noncaseating epithelioid granulomas.

Because skin manifestations may be the first and only sign of systemic sarcoidosis, patients with cutaneous sarcoidosis should be evaluated for systemic disease. Cutaneous sarcoidosis has been associated with bilateral hilar lymphadenopathy, pulmonary sarcoidosis, uveitis, arthritis, and dactylitis.³

Foreign-body reactions, syphilis are part of the differential Dx

Nonsarcoidal tattoo granulomas are a foreignbody reaction to the pigment used in tattooing and are characterized by lesions occurring only at the site of tattoos. This type of granulomatous reaction is most commonly seen in redpigmented tattoos, but can be seen in other tattoo colors as well. Macrophages containing pigment and “naked” granulomas are seen on histology.

Atypical mycobacterial skin infection can occur in tattoos that were created with contaminated ink or ink diluted with nonsterile water.⁵ Mycobacterial species such as Mycobacterium chelonae have been isolated from skin biopsies taken from the margins of new tattoos that developed a persistent erythematous eruption.⁵

Granuloma annulare is characterized by red or skin-colored plaques in annular and rope-like patterns with central clearing and nonscaly borders. A localized variant is frequently found on the extremities.⁶ There are associations between granuloma annulare, diabetes mellitus, and internal malignancy.⁷

Secondary syphilis classically presents with symmetric macules or papules distributed on the trunk and extremities. However, cutaneous manifestations vary widely. Lesions involving the palms and soles are important clues to a syphilis diagnosis, and patients often have malaise and fever.

Treatment includes topical, intralesional corticosteroids

The evidence for the treatment of cutaneous sarcoidosis is largely drawn from uncontrolled case series; there have been few double-blind, placebo-controlled studies.⁸ The first-line treatment for limited papules is a high-potency topical corticosteroid (eg, clobetasol 0.05% ointment applied twice weekly) and an intralesional corticosteroid (eg, triamcinolone, one 5-10 mg/mL injection every 4 weeks).⁸

For most cutaneous lesions, intralesional corticosteroids and/or hydroxychloroquine followed by methotrexate can be effective.

Antimalarials such as hydroxychloroquine (200 mg twice a day for at least 6 months) or methotrexate (10-15 mg/week taken at once orally or as a subcutaneous or intramuscular injection) can also be helpful. Treatment with a midpotency topical corticosteroid such as triamcinolone 0.1% cream twice a day and doxycycline hyclate (100 mg twice a day for 4 months) has been reported to clear cutaneous lesions in tattoos.³

Oral corticosteroids are the gold standard for severe cutaneous sarcoidosis, but their multiple adverse effects, such as diabetes and adrenal suppression, may prevent prolonged use.⁸ For most cutaneous lesions, intralesional corticosteroids and/or hydroxychloroquine followed by methotrexate can be effective.⁸

The nodules on our patient’s nose were successfully treated with intralesional triamcinolone 5 mg/mL. No treatment was initiated for the tattoo nodules because they were asymptomatic and the patient was not concerned about their appearance. He continues to get new tattoos, but is minimizing the use of red ink.

The patient was also started on prednisone 10 mg/d, which improved his hand swelling. Rheumatologists were considering a steroidsparing immunosuppressive agent such as methotrexate; however, the patient was lost to follow-up.

CORRESPONDENCE
Jinmeng Zhang, MD, Division of Dermatology, Washington University School of Medicine, St. Louis, MO 63110; jinmeng.zhang1@gmail.com

A 38-year-old African American man with no significant medical history presented to our dermatology clinic with a 5-month history of nodules on the right side of his nose (FIGURE 1). For several years, he’d also had nodules that gradually appeared on several red-inked tattoos shortly after he received each tattoo (FIGURE 2). He also had a 5-year history of nontender swelling of his fingers.

The patient denied any trauma to the areas with nodules or being in contact with anyone who was sick. He had no respiratory complaints, but chest x-rays from recent and past records showed stable bilateral intrathoracic lymphadenopathy without any lobar infiltration or pleural effusion.

Physical examination revealed 3 reddish-brown soft nodules on the nasal ala and multiple, nontender, 3- to 5-mm firm nodules located in the red-inked areas of tattoos on his arms and neck. The tattoo nodules were asymptomatic and stable in size. He had clubbing of multiple digits and nail dystrophy. His distal fingers were edematous, but nontender. X-rays revealed lytic, lace-like lucencies of the middle and distal phalanges and erosions of the distal phalanges on both hands (FIGURE 3).

We biopsied the nodules on his nose and on one of his tattoos.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Sarcoidosis

Based on his clinical presentation and skin biopsy results, the patient was given a diagnosis of cutaneous sarcoidosis. A biopsy from the right side of his nose demonstrated sarcoidal granulomas. Acid-fast bacilli and periodic acid-Schiff stains were negative. A biopsy of one of the tattoo nodules showed sarcoidal granulomas, and close inspection revealed red tattoo pigment within the granulomatous inflammation.

X-rays showed bilateral hilar lymphadenopathy, which was consistent with pulmonary sarcoidosis, and the lace-like appearance of the middle and distal phalanges was consistent with skeletal sarcoidosis.

Systemic sarcoidosis is an idiopathic, granulomatous disease that affects multiple organ systems but primarily the lungs and lymphatic system.¹ The estimated prevalence of systemic sarcoidosis ranges from less than 1 to 40 cases per 100,000 people, and the condition is more common among African Americans.¹

Skin manifestations may be the first—and only—sign of systemic sarcoidosis.

Cutaneous sarcoidosis can occur as a manifestation of systemic sarcoidosis. It occurs in 20% to 35% of patients with systemic sarcoidosis² and may present as asymptomatic red or skin-colored papules and firm nodules within tattoos, old scars, or permanent makeup. Cutaneous sarcoidosis in tattoos may be the first manifestation of sarcoidosis, and the time between acquiring the tattoo and developing sarcoidal nodules varies widely.

It is not clear why sarcoidal granulomas occur in tattoos. One possibility is that chronic low-grade exposure of the immune system to foreign materials such as tattoo ink leads to granulomatous hypersensitivity.^2,3 Sarcoidosis usually occurs in red (cinnabar), black (ferric oxide), or blue-black areas of tattoos,⁴ in which the pigment acts as a nidus for granuloma formation.

A skin biopsy is helpful in making a diagnosis of cutaneous sarcoidosis. The histopathology shows noncaseating epithelioid granulomas.

Because skin manifestations may be the first and only sign of systemic sarcoidosis, patients with cutaneous sarcoidosis should be evaluated for systemic disease. Cutaneous sarcoidosis has been associated with bilateral hilar lymphadenopathy, pulmonary sarcoidosis, uveitis, arthritis, and dactylitis.³

Foreign-body reactions, syphilis are part of the differential Dx

Nonsarcoidal tattoo granulomas are a foreignbody reaction to the pigment used in tattooing and are characterized by lesions occurring only at the site of tattoos. This type of granulomatous reaction is most commonly seen in redpigmented tattoos, but can be seen in other tattoo colors as well. Macrophages containing pigment and “naked” granulomas are seen on histology.

Atypical mycobacterial skin infection can occur in tattoos that were created with contaminated ink or ink diluted with nonsterile water.⁵ Mycobacterial species such as Mycobacterium chelonae have been isolated from skin biopsies taken from the margins of new tattoos that developed a persistent erythematous eruption.⁵

Granuloma annulare is characterized by red or skin-colored plaques in annular and rope-like patterns with central clearing and nonscaly borders. A localized variant is frequently found on the extremities.⁶ There are associations between granuloma annulare, diabetes mellitus, and internal malignancy.⁷

Secondary syphilis classically presents with symmetric macules or papules distributed on the trunk and extremities. However, cutaneous manifestations vary widely. Lesions involving the palms and soles are important clues to a syphilis diagnosis, and patients often have malaise and fever.

Treatment includes topical, intralesional corticosteroids

The evidence for the treatment of cutaneous sarcoidosis is largely drawn from uncontrolled case series; there have been few double-blind, placebo-controlled studies.⁸ The first-line treatment for limited papules is a high-potency topical corticosteroid (eg, clobetasol 0.05% ointment applied twice weekly) and an intralesional corticosteroid (eg, triamcinolone, one 5-10 mg/mL injection every 4 weeks).⁸

For most cutaneous lesions, intralesional corticosteroids and/or hydroxychloroquine followed by methotrexate can be effective.

Antimalarials such as hydroxychloroquine (200 mg twice a day for at least 6 months) or methotrexate (10-15 mg/week taken at once orally or as a subcutaneous or intramuscular injection) can also be helpful. Treatment with a midpotency topical corticosteroid such as triamcinolone 0.1% cream twice a day and doxycycline hyclate (100 mg twice a day for 4 months) has been reported to clear cutaneous lesions in tattoos.³

Oral corticosteroids are the gold standard for severe cutaneous sarcoidosis, but their multiple adverse effects, such as diabetes and adrenal suppression, may prevent prolonged use.⁸ For most cutaneous lesions, intralesional corticosteroids and/or hydroxychloroquine followed by methotrexate can be effective.⁸

The nodules on our patient’s nose were successfully treated with intralesional triamcinolone 5 mg/mL. No treatment was initiated for the tattoo nodules because they were asymptomatic and the patient was not concerned about their appearance. He continues to get new tattoos, but is minimizing the use of red ink.

The patient was also started on prednisone 10 mg/d, which improved his hand swelling. Rheumatologists were considering a steroidsparing immunosuppressive agent such as methotrexate; however, the patient was lost to follow-up.

CORRESPONDENCE
Jinmeng Zhang, MD, Division of Dermatology, Washington University School of Medicine, St. Louis, MO 63110; jinmeng.zhang1@gmail.com

A 38-year-old African American man with no significant medical history presented to our dermatology clinic with a 5-month history of nodules on the right side of his nose (FIGURE 1). For several years, he’d also had nodules that gradually appeared on several red-inked tattoos shortly after he received each tattoo (FIGURE 2). He also had a 5-year history of nontender swelling of his fingers.

The patient denied any trauma to the areas with nodules or being in contact with anyone who was sick. He had no respiratory complaints, but chest x-rays from recent and past records showed stable bilateral intrathoracic lymphadenopathy without any lobar infiltration or pleural effusion.

Physical examination revealed 3 reddish-brown soft nodules on the nasal ala and multiple, nontender, 3- to 5-mm firm nodules located in the red-inked areas of tattoos on his arms and neck. The tattoo nodules were asymptomatic and stable in size. He had clubbing of multiple digits and nail dystrophy. His distal fingers were edematous, but nontender. X-rays revealed lytic, lace-like lucencies of the middle and distal phalanges and erosions of the distal phalanges on both hands (FIGURE 3).

We biopsied the nodules on his nose and on one of his tattoos.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Sarcoidosis

Based on his clinical presentation and skin biopsy results, the patient was given a diagnosis of cutaneous sarcoidosis. A biopsy from the right side of his nose demonstrated sarcoidal granulomas. Acid-fast bacilli and periodic acid-Schiff stains were negative. A biopsy of one of the tattoo nodules showed sarcoidal granulomas, and close inspection revealed red tattoo pigment within the granulomatous inflammation.

X-rays showed bilateral hilar lymphadenopathy, which was consistent with pulmonary sarcoidosis, and the lace-like appearance of the middle and distal phalanges was consistent with skeletal sarcoidosis.

Systemic sarcoidosis is an idiopathic, granulomatous disease that affects multiple organ systems but primarily the lungs and lymphatic system.¹ The estimated prevalence of systemic sarcoidosis ranges from less than 1 to 40 cases per 100,000 people, and the condition is more common among African Americans.¹

Skin manifestations may be the first—and only—sign of systemic sarcoidosis.

Cutaneous sarcoidosis can occur as a manifestation of systemic sarcoidosis. It occurs in 20% to 35% of patients with systemic sarcoidosis² and may present as asymptomatic red or skin-colored papules and firm nodules within tattoos, old scars, or permanent makeup. Cutaneous sarcoidosis in tattoos may be the first manifestation of sarcoidosis, and the time between acquiring the tattoo and developing sarcoidal nodules varies widely.

It is not clear why sarcoidal granulomas occur in tattoos. One possibility is that chronic low-grade exposure of the immune system to foreign materials such as tattoo ink leads to granulomatous hypersensitivity.^2,3 Sarcoidosis usually occurs in red (cinnabar), black (ferric oxide), or blue-black areas of tattoos,⁴ in which the pigment acts as a nidus for granuloma formation.

A skin biopsy is helpful in making a diagnosis of cutaneous sarcoidosis. The histopathology shows noncaseating epithelioid granulomas.

Because skin manifestations may be the first and only sign of systemic sarcoidosis, patients with cutaneous sarcoidosis should be evaluated for systemic disease. Cutaneous sarcoidosis has been associated with bilateral hilar lymphadenopathy, pulmonary sarcoidosis, uveitis, arthritis, and dactylitis.³

Foreign-body reactions, syphilis are part of the differential Dx

Nonsarcoidal tattoo granulomas are a foreignbody reaction to the pigment used in tattooing and are characterized by lesions occurring only at the site of tattoos. This type of granulomatous reaction is most commonly seen in redpigmented tattoos, but can be seen in other tattoo colors as well. Macrophages containing pigment and “naked” granulomas are seen on histology.

Atypical mycobacterial skin infection can occur in tattoos that were created with contaminated ink or ink diluted with nonsterile water.⁵ Mycobacterial species such as Mycobacterium chelonae have been isolated from skin biopsies taken from the margins of new tattoos that developed a persistent erythematous eruption.⁵

Granuloma annulare is characterized by red or skin-colored plaques in annular and rope-like patterns with central clearing and nonscaly borders. A localized variant is frequently found on the extremities.⁶ There are associations between granuloma annulare, diabetes mellitus, and internal malignancy.⁷

Secondary syphilis classically presents with symmetric macules or papules distributed on the trunk and extremities. However, cutaneous manifestations vary widely. Lesions involving the palms and soles are important clues to a syphilis diagnosis, and patients often have malaise and fever.

Treatment includes topical, intralesional corticosteroids

The evidence for the treatment of cutaneous sarcoidosis is largely drawn from uncontrolled case series; there have been few double-blind, placebo-controlled studies.⁸ The first-line treatment for limited papules is a high-potency topical corticosteroid (eg, clobetasol 0.05% ointment applied twice weekly) and an intralesional corticosteroid (eg, triamcinolone, one 5-10 mg/mL injection every 4 weeks).⁸

For most cutaneous lesions, intralesional corticosteroids and/or hydroxychloroquine followed by methotrexate can be effective.

Antimalarials such as hydroxychloroquine (200 mg twice a day for at least 6 months) or methotrexate (10-15 mg/week taken at once orally or as a subcutaneous or intramuscular injection) can also be helpful. Treatment with a midpotency topical corticosteroid such as triamcinolone 0.1% cream twice a day and doxycycline hyclate (100 mg twice a day for 4 months) has been reported to clear cutaneous lesions in tattoos.³

Oral corticosteroids are the gold standard for severe cutaneous sarcoidosis, but their multiple adverse effects, such as diabetes and adrenal suppression, may prevent prolonged use.⁸ For most cutaneous lesions, intralesional corticosteroids and/or hydroxychloroquine followed by methotrexate can be effective.⁸

The nodules on our patient’s nose were successfully treated with intralesional triamcinolone 5 mg/mL. No treatment was initiated for the tattoo nodules because they were asymptomatic and the patient was not concerned about their appearance. He continues to get new tattoos, but is minimizing the use of red ink.

The patient was also started on prednisone 10 mg/d, which improved his hand swelling. Rheumatologists were considering a steroidsparing immunosuppressive agent such as methotrexate; however, the patient was lost to follow-up.

CORRESPONDENCE
Jinmeng Zhang, MD, Division of Dermatology, Washington University School of Medicine, St. Louis, MO 63110; jinmeng.zhang1@gmail.com

Diabetes mellitus is a complex, progressive disease that affects every family physician’s practice. Major diabetes organizations recommend that treatment be ongoing and progressive in order to control the disease. The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the American Association of Clinical Endocrinologists recommend that patients be assessed every 2 to 3 months after diagnosis and that treatment should be intensified if the patient is not meeting treatment goals.^1,2 Using this approach, all people with type 2 diabetes could be on insulin one year after diagnosis.^1,2 

While many family physicians have become comfortable with using once-daily basal insulin such as glargine or detemir, what to do after basal insulin is much more complex. This review builds upon an earlier article in this journal, “Insulin for type 2 diabetes: How and when to get started,”³ by explaining 3 strategies to consider when basal insulin alone isn't enough.

3 main strategies for intensifying treatment

Basal insulin is indicated for patients who have glucose toxicity and persistently elevated hemoglobin A1c (HbA1c) despite using 2 or more oral agents, or for those who have not achieved glucose goals one year into treatment.^3,4 ADA/EASD recommends initiating a weight-based approach for basal insulin therapy based on initial HbA1c levels >7% or >8%.⁴ Instructing and encouraging patients to titrate their own insulin dose based on fasting glucose readings provides greater and faster glucose control.^1,2

Despite these attempts, some patients will not reach their glucose goals with basal insulin. When intensifying treatment beyond basal insulin therapy, patient preference, cost-effectiveness, safety, tolerability, glycemic efficacy, risk of hypoglycemia, effects on cardiovascular risk factors, and other non-glycemic effects should be considered in the shared decision-making process. There are 3 main strategies for intensifying treatment:
1. Basal plus incretin therapy. Add a newer injectable agent such as a glucagon-like peptide 1 receptor agonist (GLP-1RA).
2. Basal plus one strategy. Add prandial insulin prior to the largest meal of the day.
3. Basal-bolus combination. Add insulin prior to all meals.

TABLE 1^5-8 provides details of several studies that have documented the efficacy of these 3 strategies.

CLICK IMAGE TO ENLARGE

Monitoring blood glucose to guide the way
Blood glucose monitoring using either a 7-point glucose monitoring technique or staggered glucose checks should guide insulin intensification. A 7-point glucose profile includes pre-meal and post-meal readings for 3 meals a day and an additional bedtime reading.⁹ This is typically performed for 3 to 7 days prior to an appointment and provides an estimate of a typical full day’s glucose pattern.

Staggered monitoring includes a pair of glucose checks taken immediately before and typically 90 minutes after a meal. This is assigned to a different meal each day in order to obtain the same information as is achieved with 7-point monitoring, but with fewer checks on any given day. It may take up to 2 to 3 weeks to gather the necessary information using the staggered monitoring technique.

In order to optimize insulin strategies for tighter glycemic control, it is important to review blood glucose logs at each office visit with either of the above techniques.

Basal plus incretin therapy

GLP-1RAs are subcutaneously administered injectable incretin agents. They mimic the action of endogenous GLP-1 hormones, which are normally secreted in response to meals by the cells of the small intestine.¹⁰ GLP-1 stimulates glucose-dependent insulin secretion, suppresses postprandial glucagon release from pancreatic alpha cells, signals satiety, and slows gastric emptying.¹⁰ In other words, GLP-1 appears to be a physiologic regulator of appetite and food intake. GLP-1 is rapidly metabolized and inactivated by dipeptidyl peptidase-4 (DPP-4) enzymes.¹⁰ The amplification of insulin secretion elicited by hormones secreted from the gastrointestinal (GI) tract is called the “incretin effect.”¹⁰ Obesity, insulin resistance, and type 2 diabetes greatly reduce the incretin effect.¹⁰

Insulin intensification should be guided by glucose monitoring using the 7-point technique or staggered glucose checks.

GLP-1RAs mimic the incretin effect and are not degraded by endogenous DPP-4 enzymes.¹⁰ They provide a pharmacologic level of GLP-1 activity, including beneficial glucose effects (via insulin secretion and glucagon suppression), but they also increase GI adverse effects, such as nausea and vomiting.^11-15 Further, they can suppress appetite and contribute to weight loss.^11-15

GLP-1RAs can be considered as an add-on therapy for patients whose HbA1c exceeds 7% and whose fasting blood glucose ranges from 80 to 130 mg/dL, or for patients with a basal insulin dose >0.5 unit/kg/d. The 5 currently available GLP-1RAs (exenatide, exenatide extended-release, liraglutide, albiglutide, and dulaglutide) are compared in TABLE 2.^11-15

Dosing varies with each agent and includes twice daily before meals for exenatide, once daily (independent of meals) for liraglutide, and once weekly for exenatide extended-release, albiglutide, and dulaglutide. These agents should not be used for patients with a history of pancreatitis or a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2. Because exenatide is cleared through the kidneys, its use is contraindicated in patients with a creatinine clearance <30 mL/min or end-stage renal disease. Caution is advised for its use in patients with a creatinine clearance of 30 to 50 mL/min.¹¹

Basal plus one strategy

To best utilize prandial insulin, it is important to know what the patient’s glucose readings are before and after meals as assessed by the 7-point or staggered blood glucose monitoring techniques described earlier. Once you have clarified which meal(s) are raising the patient’s glucose levels, selecting appropriate treatment becomes easier. To reduce the glucose-monitoring burden for the patient, it may be acceptable to allow the patient to omit the fasting glucose measurement (if stable).

The first major decision is whether to treat one meal per day (basal plus one) or all meals (basal-bolus). Adding a rapid-acting insulin prior to one meal a day (usually the largest meal) is a reasonable starting point.¹⁶

The meal that produces the highest postprandial glucose readings can be considered the meal of greatest glycemic impact. The “delta” value—the difference between pre-meal glucose and 2-hour postprandial glucose readings—also helps to determine the largest meal of the day.¹⁷ The average physiologic delta is ≤50 mg/dL.¹⁷ If the delta for a meal is >75 mg/dL, consider initiating prandial insulin prior to that meal and titrating the dose to achieve a target glucose level of <130 mg/dL before the next meal.

A GLP-1RA can be considered for patients with an HbA1c >7% and a fasting glucose ranging from 80 to 130 mg/dL.

Using 4 to 6 units of a rapid-acting insulin per meal is a good initial regimen for a basal plus one (as well as for a basal-bolus) approach.¹⁶ If the patient experiences significantly increased insulin demands as indicated by glucose patterns where the post-meal glucose is still consistently above 180 mg/dL, the initial regimen may be modified to 0.1 unit per kg per meal,^17-19 and then titrated up to a maximum of 50% of the total daily insulin dose (TDD) for basal plus one¹⁶ (or 10%-20% of TDD per meal for basal-bolus).

Consider the timing of administration. Rapid-acting insulin analogs exhibit peak pharmacodynamic activity 60 minutes after injection (TABLE 3).²⁰

Peak carbohydrate absorption following a meal occurs approximately 75 to 90 minutes after eating begins.^17,21 Thus, to synchronize the action of insulin with carbohydrate digestion, the analog should be injected 15 minutes before meals. This can be increased by titrating prandial insulin by 1 unit/d to a goal of either a 90-minute to 2-hour postprandial glucose of <140 to 180 mg/dL or the next preprandial glucose of <130 mg/dL.¹⁶ The goal is to obtain a near-normal physiologic delta of <50 mg/dL. The drop in delta noted with every unit of insulin added to the current dose can provide a rough approximation of how many additional insulin titrations will be needed to achieve a delta of <50 mg/dL.

Basal-bolus combination

A gradual increase from one injection before a single meal each day to as-needed multiple daily injections (MDIs) is the next step in hyperglycemia management. Starting slow and building up to insulin therapy prior to each meal offers structure, simplicity, and physician-patient confidence in diabetes management. The slow progression from basal plus one to basal-bolus combination allows the patient ease into a complex, labor-intensive regimen of MDIs. Additionally, the stepwise reduction of postprandial hyperglycemia with this slow approach often reduces the incidence of hypoglycemia (more on this in a moment).⁸

Advanced insulin users can calculate an “insulin-to-carbohydrate ratio” (ICR) to estimate the amount of insulin they need to accommodate the amount of carbohydrates they ingest per meal. An ICR of 1:10 implies that the patient administers 1 unit of insulin for every 10 grams of carbohydrates ingested. For example, if a patient with an ICR of 1:10 concludes that his meal contains a total of 60 grams of carbohydrates, then he would administer 6 units of insulin prior to this meal to address the anticipated post-meal hyperglycemia.

In order to use the ICR regimen, a patient would need to be able to accurately determine the nutritional content of his meals (starch, protein, carbohydrates, and fat) and calculate the appropriate insulin dosage. For successful diabetes management, it is essential to evaluate the patient’s skills in these areas before starting an ICR regimen, and to routinely assess hypoglycemic episodes at follow-up visits.

An ICR approach is usually reserved for patients who require tighter glucose control than that obtained from fixed prandial insulin doses, such as patients with type 1 diabetes, those with variable meal schedules and content, those with a malabsorption syndrome that requires consuming meals with a specific amount of carbohydrates, athletes on a structured diet with specific carbohydrate content, and patients who want flexibility with carbohydrate intake with meals.

The risk of hypoglycemia is a major barrier to initiating basal-bolus insulin therapy. Hypoglycemia is classified as a blood glucose level of <70 mg/dL, and severe hypoglycemia as <50 mg/dL, regardless of whether the patient develops symptoms.²² Symptoms of hypoglycemia include dizziness, difficulty speaking, anxiety, confusion, and lethargy. Hypoglycemia can result in loss of consciousness or even death.²²

A patient who has frequent hypoglycemic episodes may lose the protective physiologic response and may not recognize that he is experiencing a hypoglycemic episode (“hypoglycemia unawareness”). This is why it is crucial to ask patients if they have had symptoms of hypoglycemia, and to correlate the timing of these symptoms with blood glucose logs. For example, it is possible for a patient to experience hypoglycemic symptoms for blood glucose readings in the 100 to 200 mg/dL range if his or her average blood glucose has been in the 250 to 300 mg/dL range. Such patient may not realize he is experiencing hypoglycemia until he develops severe symptoms, such as loss of consciousness.

Adding a rapid-acting insulin prior to one meal a day is a reasonable starting point for intensifying insulin therapy.

Hypoglycemia unawareness must be addressed immediately by reducing insulin dosing to prevent all hypoglycemic episodes for 2 to 3 weeks. This has been shown to “reset” the normal physiologic response to hypoglycemia, regardless of how long the patient has had diabetes.^23,24 Even if your patient is aware of the warning signs of a hypoglycemic episode, it is important to routinely ask about hypoglycemia at all diabetes visits because patients may reduce insulin doses, skip doses, or eat defensively to prevent hypoglycemia.

Other than the risk of hypoglycemia, insulin typically has fewer adverse effects than oral medications used to treat diabetes. Most common concerns include weight gain, hypoglycemia, injection site reactions and, rarely, allergy to insulin or its vehicle.¹⁶

CORRESPONDENCE
Jay Shubrook, DO, FAAF P, FACOF P, BC-ADM, Touro University College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; jay.shubrook@tu.edu

Diabetes mellitus is a complex, progressive disease that affects every family physician’s practice. Major diabetes organizations recommend that treatment be ongoing and progressive in order to control the disease. The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the American Association of Clinical Endocrinologists recommend that patients be assessed every 2 to 3 months after diagnosis and that treatment should be intensified if the patient is not meeting treatment goals.^1,2 Using this approach, all people with type 2 diabetes could be on insulin one year after diagnosis.^1,2 

While many family physicians have become comfortable with using once-daily basal insulin such as glargine or detemir, what to do after basal insulin is much more complex. This review builds upon an earlier article in this journal, “Insulin for type 2 diabetes: How and when to get started,”³ by explaining 3 strategies to consider when basal insulin alone isn't enough.

3 main strategies for intensifying treatment

Basal insulin is indicated for patients who have glucose toxicity and persistently elevated hemoglobin A1c (HbA1c) despite using 2 or more oral agents, or for those who have not achieved glucose goals one year into treatment.^3,4 ADA/EASD recommends initiating a weight-based approach for basal insulin therapy based on initial HbA1c levels >7% or >8%.⁴ Instructing and encouraging patients to titrate their own insulin dose based on fasting glucose readings provides greater and faster glucose control.^1,2

Despite these attempts, some patients will not reach their glucose goals with basal insulin. When intensifying treatment beyond basal insulin therapy, patient preference, cost-effectiveness, safety, tolerability, glycemic efficacy, risk of hypoglycemia, effects on cardiovascular risk factors, and other non-glycemic effects should be considered in the shared decision-making process. There are 3 main strategies for intensifying treatment:
1. Basal plus incretin therapy. Add a newer injectable agent such as a glucagon-like peptide 1 receptor agonist (GLP-1RA).
2. Basal plus one strategy. Add prandial insulin prior to the largest meal of the day.
3. Basal-bolus combination. Add insulin prior to all meals.

TABLE 1^5-8 provides details of several studies that have documented the efficacy of these 3 strategies.

CLICK IMAGE TO ENLARGE

Monitoring blood glucose to guide the way
Blood glucose monitoring using either a 7-point glucose monitoring technique or staggered glucose checks should guide insulin intensification. A 7-point glucose profile includes pre-meal and post-meal readings for 3 meals a day and an additional bedtime reading.⁹ This is typically performed for 3 to 7 days prior to an appointment and provides an estimate of a typical full day’s glucose pattern.

Staggered monitoring includes a pair of glucose checks taken immediately before and typically 90 minutes after a meal. This is assigned to a different meal each day in order to obtain the same information as is achieved with 7-point monitoring, but with fewer checks on any given day. It may take up to 2 to 3 weeks to gather the necessary information using the staggered monitoring technique.

In order to optimize insulin strategies for tighter glycemic control, it is important to review blood glucose logs at each office visit with either of the above techniques.

Basal plus incretin therapy

GLP-1RAs are subcutaneously administered injectable incretin agents. They mimic the action of endogenous GLP-1 hormones, which are normally secreted in response to meals by the cells of the small intestine.¹⁰ GLP-1 stimulates glucose-dependent insulin secretion, suppresses postprandial glucagon release from pancreatic alpha cells, signals satiety, and slows gastric emptying.¹⁰ In other words, GLP-1 appears to be a physiologic regulator of appetite and food intake. GLP-1 is rapidly metabolized and inactivated by dipeptidyl peptidase-4 (DPP-4) enzymes.¹⁰ The amplification of insulin secretion elicited by hormones secreted from the gastrointestinal (GI) tract is called the “incretin effect.”¹⁰ Obesity, insulin resistance, and type 2 diabetes greatly reduce the incretin effect.¹⁰

Insulin intensification should be guided by glucose monitoring using the 7-point technique or staggered glucose checks.

GLP-1RAs mimic the incretin effect and are not degraded by endogenous DPP-4 enzymes.¹⁰ They provide a pharmacologic level of GLP-1 activity, including beneficial glucose effects (via insulin secretion and glucagon suppression), but they also increase GI adverse effects, such as nausea and vomiting.^11-15 Further, they can suppress appetite and contribute to weight loss.^11-15

GLP-1RAs can be considered as an add-on therapy for patients whose HbA1c exceeds 7% and whose fasting blood glucose ranges from 80 to 130 mg/dL, or for patients with a basal insulin dose >0.5 unit/kg/d. The 5 currently available GLP-1RAs (exenatide, exenatide extended-release, liraglutide, albiglutide, and dulaglutide) are compared in TABLE 2.^11-15

Dosing varies with each agent and includes twice daily before meals for exenatide, once daily (independent of meals) for liraglutide, and once weekly for exenatide extended-release, albiglutide, and dulaglutide. These agents should not be used for patients with a history of pancreatitis or a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2. Because exenatide is cleared through the kidneys, its use is contraindicated in patients with a creatinine clearance <30 mL/min or end-stage renal disease. Caution is advised for its use in patients with a creatinine clearance of 30 to 50 mL/min.¹¹

Basal plus one strategy

To best utilize prandial insulin, it is important to know what the patient’s glucose readings are before and after meals as assessed by the 7-point or staggered blood glucose monitoring techniques described earlier. Once you have clarified which meal(s) are raising the patient’s glucose levels, selecting appropriate treatment becomes easier. To reduce the glucose-monitoring burden for the patient, it may be acceptable to allow the patient to omit the fasting glucose measurement (if stable).

The first major decision is whether to treat one meal per day (basal plus one) or all meals (basal-bolus). Adding a rapid-acting insulin prior to one meal a day (usually the largest meal) is a reasonable starting point.¹⁶

The meal that produces the highest postprandial glucose readings can be considered the meal of greatest glycemic impact. The “delta” value—the difference between pre-meal glucose and 2-hour postprandial glucose readings—also helps to determine the largest meal of the day.¹⁷ The average physiologic delta is ≤50 mg/dL.¹⁷ If the delta for a meal is >75 mg/dL, consider initiating prandial insulin prior to that meal and titrating the dose to achieve a target glucose level of <130 mg/dL before the next meal.

A GLP-1RA can be considered for patients with an HbA1c >7% and a fasting glucose ranging from 80 to 130 mg/dL.

Using 4 to 6 units of a rapid-acting insulin per meal is a good initial regimen for a basal plus one (as well as for a basal-bolus) approach.¹⁶ If the patient experiences significantly increased insulin demands as indicated by glucose patterns where the post-meal glucose is still consistently above 180 mg/dL, the initial regimen may be modified to 0.1 unit per kg per meal,^17-19 and then titrated up to a maximum of 50% of the total daily insulin dose (TDD) for basal plus one¹⁶ (or 10%-20% of TDD per meal for basal-bolus).

Consider the timing of administration. Rapid-acting insulin analogs exhibit peak pharmacodynamic activity 60 minutes after injection (TABLE 3).²⁰

Peak carbohydrate absorption following a meal occurs approximately 75 to 90 minutes after eating begins.^17,21 Thus, to synchronize the action of insulin with carbohydrate digestion, the analog should be injected 15 minutes before meals. This can be increased by titrating prandial insulin by 1 unit/d to a goal of either a 90-minute to 2-hour postprandial glucose of <140 to 180 mg/dL or the next preprandial glucose of <130 mg/dL.¹⁶ The goal is to obtain a near-normal physiologic delta of <50 mg/dL. The drop in delta noted with every unit of insulin added to the current dose can provide a rough approximation of how many additional insulin titrations will be needed to achieve a delta of <50 mg/dL.

Basal-bolus combination

A gradual increase from one injection before a single meal each day to as-needed multiple daily injections (MDIs) is the next step in hyperglycemia management. Starting slow and building up to insulin therapy prior to each meal offers structure, simplicity, and physician-patient confidence in diabetes management. The slow progression from basal plus one to basal-bolus combination allows the patient ease into a complex, labor-intensive regimen of MDIs. Additionally, the stepwise reduction of postprandial hyperglycemia with this slow approach often reduces the incidence of hypoglycemia (more on this in a moment).⁸

Advanced insulin users can calculate an “insulin-to-carbohydrate ratio” (ICR) to estimate the amount of insulin they need to accommodate the amount of carbohydrates they ingest per meal. An ICR of 1:10 implies that the patient administers 1 unit of insulin for every 10 grams of carbohydrates ingested. For example, if a patient with an ICR of 1:10 concludes that his meal contains a total of 60 grams of carbohydrates, then he would administer 6 units of insulin prior to this meal to address the anticipated post-meal hyperglycemia.

In order to use the ICR regimen, a patient would need to be able to accurately determine the nutritional content of his meals (starch, protein, carbohydrates, and fat) and calculate the appropriate insulin dosage. For successful diabetes management, it is essential to evaluate the patient’s skills in these areas before starting an ICR regimen, and to routinely assess hypoglycemic episodes at follow-up visits.

An ICR approach is usually reserved for patients who require tighter glucose control than that obtained from fixed prandial insulin doses, such as patients with type 1 diabetes, those with variable meal schedules and content, those with a malabsorption syndrome that requires consuming meals with a specific amount of carbohydrates, athletes on a structured diet with specific carbohydrate content, and patients who want flexibility with carbohydrate intake with meals.

The risk of hypoglycemia is a major barrier to initiating basal-bolus insulin therapy. Hypoglycemia is classified as a blood glucose level of <70 mg/dL, and severe hypoglycemia as <50 mg/dL, regardless of whether the patient develops symptoms.²² Symptoms of hypoglycemia include dizziness, difficulty speaking, anxiety, confusion, and lethargy. Hypoglycemia can result in loss of consciousness or even death.²²

A patient who has frequent hypoglycemic episodes may lose the protective physiologic response and may not recognize that he is experiencing a hypoglycemic episode (“hypoglycemia unawareness”). This is why it is crucial to ask patients if they have had symptoms of hypoglycemia, and to correlate the timing of these symptoms with blood glucose logs. For example, it is possible for a patient to experience hypoglycemic symptoms for blood glucose readings in the 100 to 200 mg/dL range if his or her average blood glucose has been in the 250 to 300 mg/dL range. Such patient may not realize he is experiencing hypoglycemia until he develops severe symptoms, such as loss of consciousness.

Adding a rapid-acting insulin prior to one meal a day is a reasonable starting point for intensifying insulin therapy.

Hypoglycemia unawareness must be addressed immediately by reducing insulin dosing to prevent all hypoglycemic episodes for 2 to 3 weeks. This has been shown to “reset” the normal physiologic response to hypoglycemia, regardless of how long the patient has had diabetes.^23,24 Even if your patient is aware of the warning signs of a hypoglycemic episode, it is important to routinely ask about hypoglycemia at all diabetes visits because patients may reduce insulin doses, skip doses, or eat defensively to prevent hypoglycemia.

Other than the risk of hypoglycemia, insulin typically has fewer adverse effects than oral medications used to treat diabetes. Most common concerns include weight gain, hypoglycemia, injection site reactions and, rarely, allergy to insulin or its vehicle.¹⁶

CORRESPONDENCE
Jay Shubrook, DO, FAAF P, FACOF P, BC-ADM, Touro University College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; jay.shubrook@tu.edu

Diabetes mellitus is a complex, progressive disease that affects every family physician’s practice. Major diabetes organizations recommend that treatment be ongoing and progressive in order to control the disease. The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the American Association of Clinical Endocrinologists recommend that patients be assessed every 2 to 3 months after diagnosis and that treatment should be intensified if the patient is not meeting treatment goals.^1,2 Using this approach, all people with type 2 diabetes could be on insulin one year after diagnosis.^1,2 

While many family physicians have become comfortable with using once-daily basal insulin such as glargine or detemir, what to do after basal insulin is much more complex. This review builds upon an earlier article in this journal, “Insulin for type 2 diabetes: How and when to get started,”³ by explaining 3 strategies to consider when basal insulin alone isn't enough.

3 main strategies for intensifying treatment

Basal insulin is indicated for patients who have glucose toxicity and persistently elevated hemoglobin A1c (HbA1c) despite using 2 or more oral agents, or for those who have not achieved glucose goals one year into treatment.^3,4 ADA/EASD recommends initiating a weight-based approach for basal insulin therapy based on initial HbA1c levels >7% or >8%.⁴ Instructing and encouraging patients to titrate their own insulin dose based on fasting glucose readings provides greater and faster glucose control.^1,2

Despite these attempts, some patients will not reach their glucose goals with basal insulin. When intensifying treatment beyond basal insulin therapy, patient preference, cost-effectiveness, safety, tolerability, glycemic efficacy, risk of hypoglycemia, effects on cardiovascular risk factors, and other non-glycemic effects should be considered in the shared decision-making process. There are 3 main strategies for intensifying treatment:
1. Basal plus incretin therapy. Add a newer injectable agent such as a glucagon-like peptide 1 receptor agonist (GLP-1RA).
2. Basal plus one strategy. Add prandial insulin prior to the largest meal of the day.
3. Basal-bolus combination. Add insulin prior to all meals.

TABLE 1^5-8 provides details of several studies that have documented the efficacy of these 3 strategies.

CLICK IMAGE TO ENLARGE

Monitoring blood glucose to guide the way
Blood glucose monitoring using either a 7-point glucose monitoring technique or staggered glucose checks should guide insulin intensification. A 7-point glucose profile includes pre-meal and post-meal readings for 3 meals a day and an additional bedtime reading.⁹ This is typically performed for 3 to 7 days prior to an appointment and provides an estimate of a typical full day’s glucose pattern.

Staggered monitoring includes a pair of glucose checks taken immediately before and typically 90 minutes after a meal. This is assigned to a different meal each day in order to obtain the same information as is achieved with 7-point monitoring, but with fewer checks on any given day. It may take up to 2 to 3 weeks to gather the necessary information using the staggered monitoring technique.

In order to optimize insulin strategies for tighter glycemic control, it is important to review blood glucose logs at each office visit with either of the above techniques.

Basal plus incretin therapy

GLP-1RAs are subcutaneously administered injectable incretin agents. They mimic the action of endogenous GLP-1 hormones, which are normally secreted in response to meals by the cells of the small intestine.¹⁰ GLP-1 stimulates glucose-dependent insulin secretion, suppresses postprandial glucagon release from pancreatic alpha cells, signals satiety, and slows gastric emptying.¹⁰ In other words, GLP-1 appears to be a physiologic regulator of appetite and food intake. GLP-1 is rapidly metabolized and inactivated by dipeptidyl peptidase-4 (DPP-4) enzymes.¹⁰ The amplification of insulin secretion elicited by hormones secreted from the gastrointestinal (GI) tract is called the “incretin effect.”¹⁰ Obesity, insulin resistance, and type 2 diabetes greatly reduce the incretin effect.¹⁰

Insulin intensification should be guided by glucose monitoring using the 7-point technique or staggered glucose checks.

GLP-1RAs mimic the incretin effect and are not degraded by endogenous DPP-4 enzymes.¹⁰ They provide a pharmacologic level of GLP-1 activity, including beneficial glucose effects (via insulin secretion and glucagon suppression), but they also increase GI adverse effects, such as nausea and vomiting.^11-15 Further, they can suppress appetite and contribute to weight loss.^11-15

GLP-1RAs can be considered as an add-on therapy for patients whose HbA1c exceeds 7% and whose fasting blood glucose ranges from 80 to 130 mg/dL, or for patients with a basal insulin dose >0.5 unit/kg/d. The 5 currently available GLP-1RAs (exenatide, exenatide extended-release, liraglutide, albiglutide, and dulaglutide) are compared in TABLE 2.^11-15

Dosing varies with each agent and includes twice daily before meals for exenatide, once daily (independent of meals) for liraglutide, and once weekly for exenatide extended-release, albiglutide, and dulaglutide. These agents should not be used for patients with a history of pancreatitis or a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2. Because exenatide is cleared through the kidneys, its use is contraindicated in patients with a creatinine clearance <30 mL/min or end-stage renal disease. Caution is advised for its use in patients with a creatinine clearance of 30 to 50 mL/min.¹¹

Basal plus one strategy

To best utilize prandial insulin, it is important to know what the patient’s glucose readings are before and after meals as assessed by the 7-point or staggered blood glucose monitoring techniques described earlier. Once you have clarified which meal(s) are raising the patient’s glucose levels, selecting appropriate treatment becomes easier. To reduce the glucose-monitoring burden for the patient, it may be acceptable to allow the patient to omit the fasting glucose measurement (if stable).

The first major decision is whether to treat one meal per day (basal plus one) or all meals (basal-bolus). Adding a rapid-acting insulin prior to one meal a day (usually the largest meal) is a reasonable starting point.¹⁶

The meal that produces the highest postprandial glucose readings can be considered the meal of greatest glycemic impact. The “delta” value—the difference between pre-meal glucose and 2-hour postprandial glucose readings—also helps to determine the largest meal of the day.¹⁷ The average physiologic delta is ≤50 mg/dL.¹⁷ If the delta for a meal is >75 mg/dL, consider initiating prandial insulin prior to that meal and titrating the dose to achieve a target glucose level of <130 mg/dL before the next meal.

A GLP-1RA can be considered for patients with an HbA1c >7% and a fasting glucose ranging from 80 to 130 mg/dL.

Using 4 to 6 units of a rapid-acting insulin per meal is a good initial regimen for a basal plus one (as well as for a basal-bolus) approach.¹⁶ If the patient experiences significantly increased insulin demands as indicated by glucose patterns where the post-meal glucose is still consistently above 180 mg/dL, the initial regimen may be modified to 0.1 unit per kg per meal,^17-19 and then titrated up to a maximum of 50% of the total daily insulin dose (TDD) for basal plus one¹⁶ (or 10%-20% of TDD per meal for basal-bolus).

Consider the timing of administration. Rapid-acting insulin analogs exhibit peak pharmacodynamic activity 60 minutes after injection (TABLE 3).²⁰

Peak carbohydrate absorption following a meal occurs approximately 75 to 90 minutes after eating begins.^17,21 Thus, to synchronize the action of insulin with carbohydrate digestion, the analog should be injected 15 minutes before meals. This can be increased by titrating prandial insulin by 1 unit/d to a goal of either a 90-minute to 2-hour postprandial glucose of <140 to 180 mg/dL or the next preprandial glucose of <130 mg/dL.¹⁶ The goal is to obtain a near-normal physiologic delta of <50 mg/dL. The drop in delta noted with every unit of insulin added to the current dose can provide a rough approximation of how many additional insulin titrations will be needed to achieve a delta of <50 mg/dL.

Basal-bolus combination

A gradual increase from one injection before a single meal each day to as-needed multiple daily injections (MDIs) is the next step in hyperglycemia management. Starting slow and building up to insulin therapy prior to each meal offers structure, simplicity, and physician-patient confidence in diabetes management. The slow progression from basal plus one to basal-bolus combination allows the patient ease into a complex, labor-intensive regimen of MDIs. Additionally, the stepwise reduction of postprandial hyperglycemia with this slow approach often reduces the incidence of hypoglycemia (more on this in a moment).⁸

Advanced insulin users can calculate an “insulin-to-carbohydrate ratio” (ICR) to estimate the amount of insulin they need to accommodate the amount of carbohydrates they ingest per meal. An ICR of 1:10 implies that the patient administers 1 unit of insulin for every 10 grams of carbohydrates ingested. For example, if a patient with an ICR of 1:10 concludes that his meal contains a total of 60 grams of carbohydrates, then he would administer 6 units of insulin prior to this meal to address the anticipated post-meal hyperglycemia.

In order to use the ICR regimen, a patient would need to be able to accurately determine the nutritional content of his meals (starch, protein, carbohydrates, and fat) and calculate the appropriate insulin dosage. For successful diabetes management, it is essential to evaluate the patient’s skills in these areas before starting an ICR regimen, and to routinely assess hypoglycemic episodes at follow-up visits.

An ICR approach is usually reserved for patients who require tighter glucose control than that obtained from fixed prandial insulin doses, such as patients with type 1 diabetes, those with variable meal schedules and content, those with a malabsorption syndrome that requires consuming meals with a specific amount of carbohydrates, athletes on a structured diet with specific carbohydrate content, and patients who want flexibility with carbohydrate intake with meals.

The risk of hypoglycemia is a major barrier to initiating basal-bolus insulin therapy. Hypoglycemia is classified as a blood glucose level of <70 mg/dL, and severe hypoglycemia as <50 mg/dL, regardless of whether the patient develops symptoms.²² Symptoms of hypoglycemia include dizziness, difficulty speaking, anxiety, confusion, and lethargy. Hypoglycemia can result in loss of consciousness or even death.²²

A patient who has frequent hypoglycemic episodes may lose the protective physiologic response and may not recognize that he is experiencing a hypoglycemic episode (“hypoglycemia unawareness”). This is why it is crucial to ask patients if they have had symptoms of hypoglycemia, and to correlate the timing of these symptoms with blood glucose logs. For example, it is possible for a patient to experience hypoglycemic symptoms for blood glucose readings in the 100 to 200 mg/dL range if his or her average blood glucose has been in the 250 to 300 mg/dL range. Such patient may not realize he is experiencing hypoglycemia until he develops severe symptoms, such as loss of consciousness.

Adding a rapid-acting insulin prior to one meal a day is a reasonable starting point for intensifying insulin therapy.

Hypoglycemia unawareness must be addressed immediately by reducing insulin dosing to prevent all hypoglycemic episodes for 2 to 3 weeks. This has been shown to “reset” the normal physiologic response to hypoglycemia, regardless of how long the patient has had diabetes.^23,24 Even if your patient is aware of the warning signs of a hypoglycemic episode, it is important to routinely ask about hypoglycemia at all diabetes visits because patients may reduce insulin doses, skip doses, or eat defensively to prevent hypoglycemia.

Other than the risk of hypoglycemia, insulin typically has fewer adverse effects than oral medications used to treat diabetes. Most common concerns include weight gain, hypoglycemia, injection site reactions and, rarely, allergy to insulin or its vehicle.¹⁶

CORRESPONDENCE
Jay Shubrook, DO, FAAF P, FACOF P, BC-ADM, Touro University College of Osteopathic Medicine, 1310 Club Drive, Vallejo, CA 94592; jay.shubrook@tu.edu