Conflict of interest: The authors have no conflicts of interest to declare. Funding sources: None.

Abstract:
COVID-19 is an infectious disease caused by SARS-CoV-2 that is characterized by respiratory symptoms, fever, and chills.¹ While these systemic symptoms are widely known and well understood, there have also been reports of dermatological manifestations in patients with COVID-19. These manifestations include chilblain-like lesions, maculopapular lesions, urticarial lesions, necrosis, and other varicella-like exanthems.² The pathogenesis of these lesions are not well understood, but the procoagulant and pro-inflammatory state induced by COVID-19 infections may be contributing to varied cutaneous manifestations.³ Drug interactions and concurrent hypersensitivity reactions have also been postulated.⁴ This review aims to compile and analyze various retrospective studies and case reports to summarize the clinical presentation of dermatological lesions associated with COVID-19 infections and suggest further areas of research.

Keywords: COVID-19, cutaneous manifestations, hypersensitivity, dermatology

Introduction

Coronavirus disease 2019 (COVID-19) has had a huge impact on global health, with well over 700 million cases reported worldwide (World Health Organization, February 2024). It is believed to originate from bats and the transmission modality is through contact and respiratory droplets.⁵ Once the virus enters the body, the capsid protein binds to angiotensin-converting enzyme 2 (ACE2) receptors on host cells and enters the cell through a process called endocytosis.⁵ After cellular entry, the virus releases its content and utilizes host machinery to replicate and produce new viral particles to be released.⁶ This process triggers a cytokine storm, involving interleukin (IL)-8, IL-10, IL-12, tumor necrosis factor-α, and interferon-β,⁶ as well as induces a pro-inflammatory and procoagulant state that has been linked to the development of skin lesions and eruptions.³ In a microscopic and immunohistologic study, Margo et al. demonstrated that purpuric skin lesions in COVID-19 patients exhibited deposition of complement proteins (C5b-9 and C4d) and inflammatory thrombogenic vasculopathic changes.³ In some cases, the presence of spike proteins was detected in the microcirculation of the skin.³ Additionally, skin manifestations may be secondary in nature, possibly due to side effects of medications or other concurrent infections.⁴ Another cause of skin symptoms is the pro-inflammatory state induced by COVID-19 promoting drug hypersensitivity that results in cutaneous eruptions.⁷ Through analyzing the literature, we provide a categorization for the different dermatological manifestations associated with COVID-19 infections: chilblain-like lesions, maculopapular lesions, vesicular eruptions, urticarial lesions, and necrosis/livedo. Histological features and clinical patterns of the lesions are also described.

Classifications

Chilblain-like Lesions

Chilblain lesions are characterized by inflammatory and swollen patches and blisters on the extremities, such as the hands and feet.⁸ Classically, they occur after cold exposure causing the arteries and veins to constrict.^8,9 Formation of vesicles or pustules can be accompanied by edema.¹⁰ These lesions are more commonly found in young children and are correlated with lower disease severity.^4,8,10 Chilblain-like eruptions seem to be the most common manifestations reported in patients with COVID-19 exposure or infection, often appearing after the presentation of other COVID-19 symptoms.⁹ In a nationwide prospective study in Spain analyzing 375 patient cases, 19% of the cases were associated with chilblainlike lesions in the acral areas.¹⁰ A retrospective study in France also indicated that acral chilblain-like lesions were the most common and histological examination of some of these lesions showed microthrombi.¹¹ Histological features of chilblain lesions include perivascular lymphocytic infiltrate, microhemorrhages, necrotic keratinocytes, and lymphocytic vasculitis.^8,12 In some pediatric patients, viral particles were detected in the epithelium of eccrine glands.¹²

Maculopapular Lesions

Maculopapular lesions are characterized by both discolored patchy rashes (macules) as well as raised lesions (papules) that span larger areas of the skin.^13,14 These can occur in any part of the body, but are predominantly found on the back, abdomen, chest, and extremities.¹⁰ Rashes can vary extensively in terms of distribution, appearance, scaling, and degree of itching.^14,15 Alba et al., in an analysis of 176 maculopapular cases, presented 6 further subcategorization of maculopapular lesions associated with COVID-19 infections: 1) morbilliform, 2) purpuric, 3) erythema multiforme-like eruptions, 4) pityriasis rosea-like, 5) perifollicular, and 6) erythema-elevatum diutinum.¹⁵ Morbilliform is the most common of the maculopapular lesions and is characterized by erythematous macules interspersed between areas of normal skin.¹⁵ In a histopathological examination of these lesions, researchers demonstrated the presence of perivascular dermatitis, dense lymphocyte infiltration, and, in some cases, thrombosis in vessels.^16,17 Interestingly, these features are consistent with the lymphocytic vasculitis seen in immune complex and cytokine activation, which occurs in COVID-19 infections.^4,16 It is also important to note that drugs can induce maculopapular rashes, so it may not be the best indicator for diagnostic purposes.^4,18 Casas et al. noted that patients with maculopapular and urticarial lesions were more commonly taking drugs at the same time.¹⁰ Some of these drugs include hydroxychloroquine, azithromycin, remdesivir, and corticosteroids.^4,17

Vesicular Lesions (Varicella-like Exanthem)

Vesicular lesions, also known as varicella-like exanthem, are characterized by small red vesicles that appear on the trunk and extremities.^10,13 They tend to appear after respiratory COVID-19 symptoms and last a mean total of 10 days.¹⁹ A nationwide study in Spain demonstrated that vesicular lesions are more commonly seen with middle aged patients and are associated with mild severity of disease.¹⁰ Among 277 COVID-19 patients in a study, 15% developed a vesicular rash.¹¹ Vesicular eruptions are often induced by viral infections, specifically varicella zoster virus and herpes simplex virus, but it is not known whether SARS-CoV-2 follows the same pattern due to limited studies.²⁰ Interestingly, a prospective study demonstrated two main patterns of distribution and appearance of vesicular lesions: 1) smaller monomorphic localized lesions that were 3-4 mm and 2) diffuse larger polymorphic lesions that can be up to 7-8 mm.¹⁹ Histologically, these lesions show swollen keratinocytes, some of which exhibited necrosis and acantholysis, surrounded by fibrosis and inflammation.¹⁹ Disrupted organization of the epidermis was also a key characteristic.² In the prospective study by Nieto et al., the majority of patients were not on medications, which suggests that these vesicular eruptions are less likely to be induced by drugs,¹⁹ This contrasts with urticarial or maculopapular eruptions, in which the pathogenesis may have a drug-related component.

Urticarial Lesions

Urticarial lesions (hives) are characterized by wheals.²¹ In retrospective studies from France and Spain, urticarial eruptions were seen in 9% and 19% of patients with COVID-19 infections, respectively.^10,11 Most of the eruptions occurred on the face, trunks, and limbs.^10,22 These lesions are often short-lasting, compared to other skin manifestations such as chilblains, maculopapular rashes, or necrotic lesions.¹⁰ Although, frequently appearing concurrently with other symptoms of COVID-19, hives can precede these other signs.^10,22 Like maculopapular rashes, urticarial lesions are often drug induced, which can make it difficult to determine whether the reaction is due to the viral infection or due to the drug effect.²¹ Treatment with antihistamines is effective for urticarial lesions.^21,22

Necrosis/Livedo

Necrotic and livedo lesions are much less common, but their presentation can signal a more severe disease course in COVID-19 patients.¹⁰ In a study of 375 patients, 7% exhibited necrotic lesions with a 10% mortality rate.¹⁰ The lesions are generally dark and can either be diffuse or localized.¹⁰ Livedo patterns are characterized by reticular reddish-blue, lace like lesions due to poor and constricted blood flow.¹³ Many studies categorize livedo and necrotic lesions in the same category along with other vasculitis manifestations due to similarities in the occlusive vascular pathology.¹⁰ Histopathology shows pauci-inflammatory thrombogenic vasculopathy, necrotic keratinocytes, and infiltration of lymphocytes.^13,23 Other severe necrotic manifestations include skin bullae and dry gangrene, which was reported in 7 patients in 2020.²⁴ These lesions are important to recognize due to their strong association with more aggressive and severe COVID-19 disease.¹⁰

Conclusion

There has been an increasing number of case reports illustrating the prevalence of dermatological manifestations in COVID-19 patients that are concurrent with respiratory and other systemic symptoms of COVID-19. These manifestations can be categorized into 5 broad types: chilblain-like lesions, maculopapular papular lesions, vesicular eruptions, urticarial lesions, and necrosis. Chilblain, maculopapular, and urticarial lesions are associated with milder disease, whereas necrotic lesions are seen in more severe disease courses. These lesions also have a strong association with age, in which chilblain lesions appear more commonly in younger patients and increased prevalence of necrosis/livedo in older patients.^4,8,10 Viral infections (such as herpes simplex and varicella-zoster) can lead to skin symptoms, but it is still unclear whether the lesions seen in COVID-19 patients are directly the result of viral infection, concurrent illnesses, drug interactions, or other secondary causes.²⁰ The pro-inflammatory and procoagulant state in COVID-19 infections may be implicated in the development of the skin eruptions, but this remains a topic for further investigation.

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¹Stony Brook University School of Medicine, Stony Brook, NY, USA
²Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, USA

Conflict of interest:
Steven Feldman has received research, speaking and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Baxter, Boeringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, Taro, Abbvie, Cosmederm, Anacor, Astellas, Janssen, Lilly, Merck, Merz, Novartis, Regeneron, Sanofi, Novan, Parion, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. He is founder and majority owner of www.DrScore.com and founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. Sarah Taylor and Todd Wechter have no conflicts to disclose.

Abstract
Primary focal hyperhidrosis is a relatively common disease that has a significant impact on afflicted patient’s quality of life. The pathogenesis of the disease is thought to stem from increased cholinergic activity on eccrine sweat glands. Topical aluminum chloride based antiperspirants are good first-line agents for all affected body sites. Anticholinergic agents are emerging as effective topical alternatives. Iontophoresis passes an electrical current through the skin and is an excellent treatment option for palmoplantar disease. Botulinum toxin type A injections remain a mainstay second-line treatment. Local procedural advances including microwave thermolysis, laser therapy and focused ultrasound are emerging as safe and effective alternatives for refractory disease. Oral anticholinergics are generally well tolerated and can also be used for intractable disease. Last-line interventions include local surgical options and sympathectomy, though some patients may prefer permanent treatment. Further investigation of novel treatments as well as ways to optimize existing therapeutic options are needed.

Key Words:
antiperspirants, aluminum chloride, botulinum toxin, anticholinergics, focused ultrasound, hyperhidrosis, iontophoresis, microwave thermolysis

Introduction

Primary focal hyperhidrosis, characterized as sweating beyond what is needed for adequate thermoregulation, can have a dramatic effect on quality of life and has an estimated prevalence of 4.8% in the United States.^1,2 Primary focal disease differs from secondary hyperhidrosis in that it is located in discrete areas of the body (e.g. palms, soles, axilla, face or scalp) and is not induced by medications or other medical conditions.^3,4 While a complete understanding of the cause or causes of primary focal hyperhidrosis remains unknown, its pathogenesis is thought to be linked to the thermoregulatory center of the hypothalamus and the autonomic nervous system.⁵ Post-ganglionic sympathetic cholinergic neurons release the neurotransmitter acetylcholine, which acts on eccrine sweat glands leading to sweat secretion.⁶ Increased sympathetic activity on eccrine glands can be induced by either emotional or thermal stimuli.⁷ Thus, potential treatment targets include the neurotransmitter, nerves, eccrine glands, and eccrine ducts (Figure 1).

There are many treatment options that exist for primary focal hyperhidrosis, which can be local or systemic and range from topical therapies to surgical management.⁸ Disease severity, disease location, treatment cost, side effect profile and patient preference are all important considerations when deciding on therapeutic options.⁸ Here, we review current and emerging treatment options for primary focal hyperhidrosis. We summarize our findings in Table 1 and then provide our treatment recommendations in Table 2.

Methods

A review of the literature was performed utilizing multiple databases, including PubMed, ClinicalTrials.gov and Google Scholar. Search criteria included general terms such as, “Hyperhidrosis therapy” and “Hyperhidrosis treatment”, as well as more specific terms relating to each respective therapy.

Local Non-Surgical Therapies

Topical Therapies

Topical antiperspirants are generally regarded as first-line options for primary focal hyperhidrosis and can be used as initial therapy for palmoplantar, axillary or craniofacial disease.^3,4,8 They are considered effective with a reasonable side effect and cost profile.⁹ Typically, aluminum chloride based antiperspirants are used, which precipitate with mucopolysaccharides, damage ductal epithelial cells and block the duct, ultimately preventing sweat secretion (Figure 1E).^3,10 In mild cases, over-the-counter aluminum chloride based medications may prove effective, although for more severe cases, prescription aluminum chloride hexahydrate at concentrations of 10% to 35% is recommended.^3,4,8,11 Aluminum chloride based antiperspirants require continued administration, as the injured epithelium of the eccrine duct will eventually redevelop; although prolonged administration can result in persistent damage to eccrine glands and produce a more durable response.^3,4,10

One study of 20 patients with plantar hyperhidrosis demonstrated that aluminum chloride hexahydrate at concentrations of both 12.5% and 30% produced an approximately 52% decrease in sweating after 6 weeks of treatment, as assessed by Minor’s iodine sweat test.¹² Another study of 20% aluminum sesquichlorohydrate foam for palmar and axillary disease demonstrated a mean 61% reduction in Minor score after 4 weeks of treatment.¹³

Local skin irritation is the major side effect of topical aluminum based antiperspirant therapy, although non-alcohol containing formulations, such as aluminum chloride hexahydrate in salicylic gel, may be more tolerable.¹⁴ Application of white petroleum jelly prior to aluminum chloride antiperspirant application can also help to prevent skin irritation.¹⁵

Topical anticholinergic therapy is another emerging treatment option for hyperhidrosis that likely works through hindering cholinergic activation of eccrine glands (Figure 1C).^3,16 In a prospective study of 40 patients with axillary hyperhidrosis, treatment with 2% glycopyrrolate spray decreased sweating similar to botulinum toxin type A injections.¹⁷ Another randomized, double-blind, split area study of patients with palmar, plantar or axillary disease found that 10% topical oxybutynin treatment resulted in a mean Dermatology Life Quality Index (DLQI) score reduction of 7.6 points when compared to pretreatment scores.¹⁸ Topical anticholinergic therapies such as umeclidinium and glycopyrronium are also being further studied in clinical trials.^16,19,20 In particular, glycopyrronium tosylate topical wipes (DRM04, Qbrexza^™), recently approved by the US FDA, have been shown to be well tolerated and efficacious for the treatment of axillary disease.²⁰ In two recent phase 3 clinical trials, patients treated with once daily DRM04 topical wipes experienced significant improvement in Axillary Sweating Daily Diary scores (ASDD) and in sweat production as measured by gravimetry.²⁰

Iontophoresis

Iontophoresis involves passing an electrical current through the skin and is an acceptable first-line treatment for palmoplantar hyperhidrosis after a trial of topical antiperspirants for more severe disease.^8,21 Patients submerge their hands and/or feet in tap water and an electrical current is applied.²¹ Although its exact mechanism of action remains unknown, therapy does not alter the structure of the glands.²² Iontophoresis is effective with the added benefit of at-home treatment options.²³

In a recent clinical trial examining patients treated with tap water iontophoresis for palmar disease, approximately 93% of patients had symptomatic improvement after 2 weeks of treatment, as measured by starch-iodine test, compared to 38.5% in the sham group.²⁴ Gravimetric analysis revealed that iontophoresis treated patients had a mean reduction in sweat rate of 91.8% and 69% at 2 and 6 weeks post-treatment, respectively.²⁴ Another study demonstrated that with tap water iontophoresis treatment 3 days per week for 4 weeks, patients experienced on average a 75% and 65% reduction of symptoms on their palms and soles, respectively, as measured by self-assessed disease severity scores.²⁵

Iontophoresis can also be used as a mechanism to deliver other medications such as aluminum chloride and anticholinergics.^26-28 For example, in a 2011 study of 22 patients with palmar hyperhidrosis, treatment with glycopyrronium bromide iontophoresis resulted in a 54% reduction of mean sweat production as measured by gravimetry.²⁸

Side effects of iontophoresis are generally mild and their severity may depend on the voltage and current used, and can include local skin irritation, pain and burns.^25,29

Botulinum Toxin

Botulinum toxin type A (BTX-A) is generally considered a second-line therapy for primary focal hyperhidrosis, although in severe or craniofacial disease it can be considered for first-line use.⁸ The treatment is effective, however, it is invasive and more expensive than topical options and typically requires repeated administration.³⁰ The injected toxin acts by cleaving the SNARE protein complex, which is required for the pre-synaptic release of acetylcholine, thus halting its effect on the eccrine gland (Figure 1B).³¹

One randomized, double-blind, multi-institution, prospective study of 207 patients with axillary disease found that 4 weeks after their first BTX-A injection patients experienced a mean decrease in sweat production of 84.6% as measured by gravimetry.³² Furthermore, approximately 96% of patients reported higher satisfaction with BTX-A injection compared to previous treatments they had received.³² Another 2008 study demonstrated that axillary injection with BTX-A is more effective when compared to topical 20% aluminum chloridebased antiperspirants in patients with moderate to severe disease (mean Hyperhidrosis Disease Severity Scale [HDSS] reduction of 2.4 vs.1.33 at 4 weeks of therapy, respectively, p<0.0001).³³ Long-term use of BTX-A is safe and effective, and repeated injections may increase the duration of symptomatic relief.³⁴ In a retrospective study of patients receiving a mean of 4 axillary BTX-A injection sessions, the last injection resulted in a 3 month longer median duration of efficacy compared to the first injection.³⁴

Side effects are typically minor and include pain and irritation at the injection site, subjective feeling of increased sweating and reversible muscle weakness.^32-35 Pain from the injection is sometimes a limitation of the therapy, although studies of less painful administration methods such as diluting BTX-A in lidocaine or transdermal jet nebulization have been promising.^36,37

Emerging Procedural Interventions

Microwave Thermolysis

Microwave thermolysis (miraDry®) is a relatively new secondline therapy for axillary hyperhidrosis that was FDA cleared in 2011.³⁸ The treatment uses microwave energy focused on the dermal-hypodermal junction to heat and permanently destroy both eccrine and apocrine glands (Figure 1D).³⁹

In one group’s report involving 50 patients, 80% experienced more than a 50% sweat reduction after two treatments.⁴⁰ In a multiinstitution clinical trial limited to patients with HDSS scores of 3 or 4, 89% of patients had HDSS scores of 1 or 2, compared to 54% in the sham group 1 month after microwave therapy.⁴¹ At 6 month follow-up, 67% of treated patients had HDSS scores of 1 or 2, however, there was not a statistically significant difference in sweat production between the treatment and sham groups, as measured by gravimetry.⁴¹ Another 2012 study, also limited to patients with HDSS scores of 3 or 4, demonstrated more durable results for the therapy.⁴² Approximately 90% of treated patients reported an HDSS score of 1 or 2, at both 1 month and 1 year after treatment.⁴² This result was corroborated by gravimetry, with more than 90% of patients experiencing a 50% or greater reduction in sweat production at both 1 month and 1 year followups. ⁴²

Microwave thermolysis is generally well tolerated by patients and the side effects of treatment include pain, local irritation, transient subcutaneous nodules, reversible neuropathy, and swelling.^40,41 One limitation of the therapy is its potentially prohibitive cost, as the treatment is often considered to be cosmetic by insurance companies.³⁸

Laser Therapy

Another treatment modality that destroys the sweat glands and yields longer lasting results for patients with axillary hyperhidrosis is laser therapy.³⁸ There are two types of lasers utilized in the treatment of axillary hyperhidrosis: neodymium:yttrium aluminum garnet (Nd:YAG) and 800 nm diode lasers.⁴³

Nd:YAG laser therapy is often used for hair removal, however, it also damages the surrounding eccrine glands through optomechanical and thermal mechanisms (Figure 1D).^44,45 Histological examination after axillary Nd:YAG treatment shows a decrease in the density of eccrine glands, highlighting its ability to destroy the glands.⁴⁴ In one 17 participant study, treatment with a 1064 nm Nd:YAG laser resulted in 70.6% of patients experiencing an excellent result as per patient’s global assessment and a decrease in mean area of sweating of 48 cm².⁴⁵ Side effects were minimal and included swelling, burns, transient neuropathy and transient axillary hair loss.⁴⁵

While 800 nm diode lasers have been used in the treatment of axillary hyperhidrosis, there is comparatively less supporting literature available.⁴⁶ In a 21 patient, randomized, half-side, comparison trial, five treatments with an 800 nm diode laser resulted in a median sweat rate reduction of 41 mg/minute (min) and 13 mg/min in the treated axilla and untreated axilla, respectively.⁴⁶ Interestingly, there was no difference in gravimetric results between the treated and untreated axilla (p=0.10), which the authors credited to placebo effect.⁴⁶ The 800 nm diode laser does not appear to decrease the density of axillary eccrine glands, as was seen after Nd:YAG laser therapy.^44,46 The only side effect observed in the study was an isolated case of transient axillary skin depigmentation.⁴⁶

Focused Ultrasound Therapy

Focused ultrasound is a relatively new treatment option for axillary hyperhidrosis.⁴⁷ The ultrasound energy is targeted beneath the superficial dermis where eccrine sweat glands exist and acts through a thermal mechanism to damage the sweat glands (Figure 1D).⁴⁷

A randomized, double-blinded, pilot study found that after two micro-focused ultrasound treatments, 83% of patients had a 50% or greater decrease in sweat secretion as measured by gravimetry.⁴⁷ Patients were also pleased with the treatment, as approximately 92% reported that they would recommend the therapy and 83% noted decreased embarrassment from their disease.⁴⁷ The most common side effect reported was local tenderness, with other common side effects including paresthesia and bruising.⁴

In another 2009 prospective study, patients treated with focused ultrasound therapy experienced a 62% mean improvement in sweating when comparing pre-treatment and post-treatment patient assessment scores.⁴⁸ Side effects noted during this study were generally mild and included blistering, seroma formation and hyperpigmentation.⁴⁸

Surgical Management

Local Surgical Options

Local surgical management is generally considered one of the last-line options for axillary hyperhidrosis.⁸ The principle behind local surgical techniques is to remove the sweat glands, thus theoretically permanently eliminating the source of the disease.⁴⁹ Local surgical options typically include destruction and removal of the glands through curettage, suction, excision or a combination of these techniques (Figure 1D).^49-53

A recent 2017 study of 20 patients with axillary disease found an approximately 80% mean reduction in sweat rate 3 months after treatment with suction curettage.⁵⁰ Interestingly, there was no significant difference in mean sweat rate reduction between suction-curettage and BTX-A treated groups (mean sweat rate reduction of 68.22 mg/min vs. 71.17 mg/min, respectively, p=0.21).⁵⁰ This finding was corroborated in another study that demonstrated similar efficacy between the two treatment options, with a mean sweat rate reduction of 60.4% and 72.1%, for suction curettage and BTX-A injection treated groups, respectively (p=0.29).⁵¹

Suction curettage has persistent results.⁵² In a prospective study of 28 patients treated with axillary suction curettage, the mean resting sweat rate of treated patients was reduced by 58% from baseline at 1 year follow-up.⁵² The study also noted that suction curettage was more effective in patients with higher baseline sweat rates, which led the authors to question the use of the procedure in patients with pre-operative sweat rates of less than 25 mg/min.⁵²

Axillary skin excision is a less commonly used treatment method for hyperhidrosis, and there are multiple techniques available with varying amounts of tissue excision.^49,53 In a 2006 prospective study of patients with axillary hyperhidrosis, treatment with local skin excision resulted in a mean sweat reduction of 65% as assessed by post-operative patient reporting.⁴⁹ Another 56 patient retrospective study found that 88% of patients undergoing axillary skin resection were satisfied with the results 3 months after surgery.⁵³

Although surgical methods carry more significant adverse effects than less invasive treatment options, they remain an alternative for patients with refractory axillary disease.^49-53 Major side effects of local surgical options include pain, bruising, bleeding, swelling, scaring, and infection.^49-53

Sympathectomy

Sympathectomy is the most invasive surgical procedure for primary focal hyperhidrosis and is reserved as a last-line treatment option for refractory palmar, axillary and craniofacial disease.⁸ By surgically damaging the thoracic sympathetic outlets, the upstream source of eccrine gland stimulation is disrupted, leading to symptomatic relief (Figure 1A).⁵⁴ The surgery is often done endoscopically and there are multiple methods of sympathetic interruption, including cutting, clipping and electrocauterization.^54-57 Although effective, a major limitation of sympathectomy is compensatory sweating.^54,55,57

One study of 283 patients that had undergone bilateral T3- T4 endoscopic sympathectomy demonstrated a mean sweat rate reduction of 91.8% and 63.3%, in the palms and axilla, respectively.⁵⁵ These results were persistent through 3 years of follow-up.⁵⁵ Although most patients experienced compensatory sweating, approximately 76% considered it acceptable at 3 years follow-up.⁵⁵

In a study of 352 patients undergoing thoracoscopic sympathectomy, 91.1% reported dry skin after an average of 16 years of follow-up.⁵⁷ The surgery was more effective for palmar disease than axillary disease, and high rates of compensatory sweating were again noted.⁵⁷

Additional research has examined less invasive surgical methods of disrupting sympathetic outflow.^56,58-60 For example, singleport videoscopic surgery is a safe and effective method of minimally invasive sympathectomy.^56,60 Smaller incisions with a needlescopic approach have also been successfully attempted.^58,59

Surgical sympathectomy is an invasive procedure and carries typical surgical risks.⁵⁴ Major side effects include pneumothorax, Horner’s syndrome, neuropathy, subcutaneous emphysema and bradycardia.^54,55,57

Systemic Therapies

Systemic therapies are generally considered second- or thirdline options depending on disease severity and location.⁸ The main class of oral medication prescribed for hyperhidrosis is anticholinergics, although antihypertensives and psychiatric medications have also been utilized.⁶¹ Anticholinergic medications act through blocking sweat gland muscarinic receptor activation by acetylcholine (Figure 1C).⁶¹ Although many anticholinergic medications are effective, there is some reluctancy to use them as a result of their side effect profile.^61-65

In a 2012 prospective study investigating the efficacy and safety of low dose oral oxybutynin, approximately 35% and 39% of treated patients reported their quality of life as “much better” or “a little better,” respectively.⁶² This was compared to just 13.6% of patients in the placebo group reporting “a little better” quality of life, and none reporting “much better” quality of life.⁶² Dry mouth was the only adverse effect noted during the study and was considered moderate to severe in 26.1% and 34.8% of patients receiving 5 mg and 10 mg oxybutynin therapy, respectively.⁶²

Glycopyrrolate is another anticholinergic drug that has been studied in primary hyperhidrosis.⁶⁴ In one retrospective study including 31 pediatric patients with recalcitrant disease, oral glycopyrrolate therapy resulted in “major improvement” in 71% of treated patients.⁶⁴ The medication was generally well tolerated and the most common side effect was dry mouth.⁶⁴

Methantheline bromide is additional systemic anticholinergic option.^61,65 In a 2013 multicenter clinical trial involving 339 patients with axillary or palmar disease, axillary sweat secretion was reduced 41% after 1 month of oral methantheline bromide treatment; no significant difference in palmar sweat production was noted.⁶⁵ Treated patients also experienced decreases in both HDSS and DLQI scores.⁶⁵ Similar to other anticholinergic medication studies, dry mouth was the most frequently experienced side effect.⁶⁵

Research into methods of reducing the side effects of anticholinergic medications has also yielded some promising results.⁶³ For example, recent study of an oxybutynin/pilocarpine combination drug demonstrated both efficacy and a lower incidence of dry mouth.⁶³

Side effects of anticholinergic medications generally include dry mouth, dry eyes, changes in vision, and decreased intestinal motility.^61,64,65 Caution must be exercised when prescribing these drugs, especially in patients that may experience urinary retention or acute closed angle glaucoma.⁶¹ There is also literature suggesting that long-term anticholinergic use may be a risk factor for cognitive impairment.^66,67

Conclusion

Primary focal hyperhidrosis afflicts a significant number of patients in the United States and greatly impacts their quality of life. Treatment decisions should take into consideration disease location, severity and patient preference. Topical antiperspirants remain a reasonable primary treatment option for all forms of disease. BTX-A is an effective second-line therapy, particularly for axillary disease. Iontophoresis is a superior option for palmoplantar disease and further investigation into the utilization of iontophoresis to deliver sweat reducing medications may yield additional treatment prospects. More recent procedural interventions such as microwave thermolysis, focused ultrasound and laser therapies have also demonstrated considerable promise in the treatment of refractory disease. Oral systemic therapies, specifically anticholinergic medications, appear to be a safe and effective alternative option for all forms of primary hyperhidrosis. More invasive options such as suction curettage and surgical sympathectomy, while effective, should be reserved for more severe refractory cases. Continued research into novel treatment options and methods of improving the efficacy and reducing the side effects of existing treatment options is needed.

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¹University of Buffalo School of Medicine, Buffalo, NY, USA
²The Corvallis Clinic, Corvallis, OR, USA
³Center for Dermatology Research, Departments of Dermatology, Pathology and Public Health Sciences; Wake Forest University School of Medicine, Winston-Salem, NC, USA

ABSTRACT
Prescribing medications off-label is commonplace in dermatology. Recent policy changes on the regulatory abilities of the US FDA and legal precedents regarding this topic have led to intense debate on free speech about off-label drug use by physicians and drug manufacturers. Here, we summarize and discuss the risks and benefits of off-label promotion and how this relates to quality patient
care in dermatology.

Key Words:
labeling, pharmaceutical, promotion, advertising, FDA, regulations, dermatology

Introduction

Pharmaceuticals are often prescribed for uses beyond those listed on the drug’s US Food and Drug Administration (FDA) approved label. This off-label use includes treatments for disorders not formally reviewed by the FDA, dosages or delivery mechanisms not approved by the agency, or use of the agents in patient populations not tested in FDA approved clinical trials.¹ In order for a drug company to market a medicine for a particular use or disease, it must go through rigorous evaluation by the FDA. This entire process, which includes preclinical testing and three clinical phases, takes an average of 8 to 12 years.² This course is so rigorous that for every 5,000 to 10,000 compounds that enter preclinical testing, only one is approved for marketing.³ Off-label prescribing compensates for this scrupulous and time-consuming approval process by allowing physicians to use treatment options that are readily available. The off-label use of drugs has significantly contributed to the therapeutic armamentarium of many different diseases in medicine.

Off-label prescribing is particularly common in dermatology. This can in part be explained by the relative lack of clinical trials evaluating the multitude of therapeutic options for any given dermatologic condition. For many skin diseases, few – if any – medications are FDA-approved, and use of off-label medications is the standard of care in dermatology.^4,5 Off-label prescribing is used in a wide range of dermatologic conditions, from disorders that are common and have multiple treatment options, such as actinic keratosis and acne vulgaris, to the more rare conditions that have very few if any FDA-approved treatments, such as pyoderma gangrenosum, pemphigus vulgaris, and lichen planus. Off-label options can be used for common conditions when treatment with approved medications have been exhausted or have proved unsuccessful or even when the off-label treatment is deemed better than on-label options.

Increasing prevalence of off-label prescribing has come with a fair share of conflicts between the FDA, insurance companies, physicians and pharmaceutical companies, as the FDA has sought to regulate the pharmaceutical industry’s promotion of unapproved therapies. During the past decade, pharmaceutical companies have faced government investigations regarding the marketing and promotion of their products. Companies have been fined billions of dollars for promoting their product for indications other than those listed on the FDA-approved label. Although regulations on the pharmaceutical industry were designed to protect the public, they may have unexpected negative consequences. Branding a drug’s particular use as “off-label” not only limits the dissemination of information about the drug, but also decreases patient access to the agent. While patients, physicians not employed by pharmaceutical companies, insurers and government researchers are free to discuss whatever they want about off-label uses, the pharmaceutical company is prohibited from entering the discussion. These limitations on the dissemination of information have become a major topic of controversy in recent years. Because the off-label use of drugs and devices will remain a major part of the practice of medicine in the future, there needs to be a balance between the regulatory authority of the FDA, the circulation of information coming from the pharmaceutical companies, and the ability of physicians to provide the best possible care for their patients. In this paper we discuss a brief history on the drug approval process and the development of FDA regulations over off-label drug promotion, recent legal cases surrounding off-label drug speech, and the risks and benefits of off-label drug promotion in dermatology (Table 1).

A Brief History of Drug Regulation

The process of bringing to market a new drug or new use of a drug is rigorous, involving preclinical testing with animals, three phases of human clinical trials, and two stages of approval from the FDA. This process is a multi-year, multi-stage course and generally costs millions of dollars. If a drug survives all three phases of clinical trials, a New Drug Application (NDA) containing all the preclinical and clinical information obtained during testing is submitted to the FDA. The FDA then performs an independent review, after which a NDA may be approved or rejected. After FDA approval for a given disease, a medication is often subject to phase 4 post-marketing studies, which are designed to evaluate long-term efficacy and safety in a larger patient population and a longer time period. It is reported that this entire process from lab to patient may take as long as 10 to 15 years, with clinical trials accounting for 7 of those years, and may cost an average of $1.2 billion per drug.⁶ Even when drug manufacturers desire to obtain FDA approval for an off-label use that is similar to indications listed on the label, they must submit a “supplemental new drug” application. The drug then has to undergo extensive clinical trials to determine the efficacy of this off-label use. While the FDA claims they are speeding up the supplemental new drug approval process, the data show there are still long delays.⁷

The first federal laws to regulate the sale and content of food and drugs came in 1906 with the Pure Food and Drug Act. Since then, the passage of over 200 laws has created a stringent regulatory system with the goal of protecting consumers.⁸ The federal Food, Drug and Cosmetic Act (FDCA) of 1938 was one of the major milestone laws that gave the FDA authority to regulate promotional materials of the pharmaceutical companies. The FDCA indirectly prohibits the promotion of off-label use in two ways: 1) By prohibiting drug manufacturers from introducing a new drug into interstate commerce unless both the drug and the label have gained FDA approval, and 2) By prohibiting the drug manufacturer from introducing a “misbranded” drug. A drug is considered misbranded if the label contains information about unapproved uses or misleading information. Visual aids and handouts used by sales representatives are considered part of the drugs label even if they are not packaged with the product.¹ The FDA has long held to these rules when reviewing promotional materials of pharmaceutical companies. The off-label promotion of drugs was further restricted by the indirect effects of the 1962 Amendments, which gave the FDA stricter control over how companies performed clinical trials.⁸ These amendments were a major contribution in shaping the rigorous structure that is currently in place for FDA approval.

The FDA’s strict regulations on the promotion of unapproved drugs have become slightly more permissive over time. While the FDA previously had an absolute authority to prohibit the dissemination of off-label information, newer guidelines under the FDA Modernization Act of 1997 (FDAMA) allow drug manufacturers to distribute reprints of peer-reviewed articles that describe unapproved use of their products.⁹ However, even this change of policy came with its fair share of regulations. The FDA imposed a list of conditions to be met before companies could circulate the articles. Some of these requirements include: the information must be published in a peer-reviewed scientific or medical journal, the company must submit a supplemental new drug application and they must provide the FDA with advance copies of the articles they intend to redistribute.¹ Despite the series of laws and amendments, there remains a considerable amount of uncertainty about what exactly manufacturers are able to promote.

Recent Legal Precedents

There are now more than one hundred ongoing civil and criminal investigations involving the US Department of Justice and the US Department of Health and Human Services. These investigations, in which pharmaceutical companies were accused of off-label promotion, held companies liable under both the FDCA and the False Claims Act (FCA).¹⁰ The FCA makes it unlawful to file a false claim with the government. This theory has been applied to off-label promotion, regardless of whether the information about off-label use is truthful or not. These legal actions have had a major hit on pharmaceutical companies, with settlements ranging from tens of millions to hundreds of millions of dollars and occasionally even jail time for company executives.¹

A recent legal case could have broad ramifications for the pharmaceutical industry and the role of off-label promotion in medicine. In this landmark case of United States v. Caronia, No. 09–5006–CR, 2012 WL 5992141 (2d Cir. December 23, 2012), the US Court of Appeals for the Second Circuit overturned the conviction of a pharmaceutical sales representative who was accused of promoting a drug for its off-label uses. The Court’s holding, in full, reads: “[W]e decline to adopt the government’s construction of the [Food, Drug, and Cosmetic Act’s (FDCA’s)] misbranding provisions to prohibit manufacturer promotion alone as it would unconstitutionally restrict free speech. We construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs.” Ibid., 15. The case has led to an increased focus on the issues that exist with the FDA’s regulation on off-label use of drugs, and the negative impact this has had on healthcare. There is a distinction between truthful communication about off-label drug uses, many of which are proven efficacious and safe by the medical community, and claims that are not validated or are simply factitious. References to the First Amendment have hampered the FDA’s ability to regulate offlabel promotion and will likely have an impact on the future of off-label drug discussions.

While some may believe that dermatologists are free from the FDA litigations over off-label promotion, this is not necessarily true for physicians who participate in clinical trials or promote products on behalf of manufacturers. In January 2010, the FDA sent a warning to a Florida dermatologist for mentioning in interviews with magazines that an anti-wrinkle drug she was conducting a clinical trial on had demonstrated to work better than a competitor’s product.¹¹ Upsetting the FDA by promoting an off-label indication in dermatology may have far worse consequences than a warning letter. In 2004, oral tazarotene for the treatment of psoriasis was denied FDA approval. While the advisory board claimed there was not enough data to support that the benefits outweigh the risks, the committee repeatedly asked Allergan about how they had promoted the off-label of oral tazarotene for acne via posters at an American Academy of Dermatology conference.¹² Approval for oral tazarotene, a product that had the potential to benefit patients with psoriasis, was eventually denied, perhaps in part because of concerns over off-label promotion. Although physicians are supposedly free to discuss any off-label indications with colleagues and patients, this freedom is limited when the physician is acting as an agent of a pharmaceutical company. With the FDA’s authoritative power in approving medication uses, a company could potentially win a First Amendment battle over off-label promotion but lose a war if the FDA chose to delay or not to approve future products.

Risks with Off-Label Promotion

Before regulations on the content and promotion of pharmaceutical agents, drug makers were able to produce and sell products that would seem criminal in today’s day and age. For instance, “Peter’s Specific, The Great Blood Purifier System Regulator” was recommended as a treatment for dermatologic disease and as an alternative tonic, invigorator and blood purifier.¹³ While drug manufacturers are no longer able to make scientifically unfounded claims, many physicians prescribe offlabel for uses that lack significant scientific support.¹⁴ By “word of mouth” marketing, highly influential academic physicians may, for better or worse, indirectly help pharmaceutical companies promote products’ off-label uses.¹⁵ This promotion often comes in the form of industry-sponsored abstracts, posters and publications. If a poster demonstrates promising preliminary results but the follow-up studies show no benefit, the negative findings may not get widespread notice. This leaves the medical community with the potential for an incomplete, overly favorable, impression of the product. The spread of invalid data is not only the fault of pharmaceutical companies, but also of physicians who may try and promote new off-label uses out of desperation when all conventional therapies have failed. While many efficacious treatment strategies are discovered by trial and error, this also lends to the potential widespread use of products that are not beneficial. In 2008, topical bimatoprost (Latisse®) was approved for the treatment of eyelash hypotrichosis. Since then, some have advocated the use of bimatoprost to stimulate hair growth in other areas such as the scalp or eyebrows, despite the lack of any published scientific evidence on this use.¹⁶ Furthermore, allowing drug manufacturers to redistribute information about off-label uses may disincentivize companies to conduct clinical trials to gain FDA approval.¹⁷ Without the rigorous scientific scrutiny that comes with FDA approval, the safety and efficacy of off-label uses may not be well elucidated. Limiting manufacturers from promoting off-label use is the primary method used by the FDA to “protect the public from promotional claims that are unsubstantiated at best, and false at worst.”¹⁸ The FDA regulations are designed to protect not only patients, but also physicians as they prevent them from receiving biased information that may inappropriately influence their prescription choices. However, limiting the dissemination of information may be harmful to public health as it decreases the data readily available to physicians when making treatment decisions.

Benefits of Off-Label Promotion in Dermatology

“FDA restrictions on off-label promotion has made it more difficult for physicians to learn about new uses of drugs and devices.”¹⁹ The medical community, federal courts and even the FDA all agree that drug manufacturers are often the best source of information on the data regarding the risks and benefits of offlabel drug uses. Any speech on off-label use is subject to the same penalties, regardless of whether or not the information is true. With the wide range of dermatologic disorders and the limited number of well-designed clinical trials assessing the multitude of therapeutic options, off-label prescribing is now commonplace in dermatology. Clinical trials often reveal significant evidence supporting the benefit of off-label uses long before these agents gain FDA approval. This lag time to FDA approval is evident in a wide variety of dermatologic disorders, most recently in the treatment of complicated infantile hemangiomas. On March 17th, 2014, Pierre Fabre Dermatologie obtained marketing authorization from the FDA for the pediatric drug Hemangeol™ (propranolol hydrochloride), making it the first and only FDA approved treatment for proliferating infantile hemangioma requiring systemic therapy.¹³ However, since 2008, when the efficacy of propranolol for hemangiomas was first proposed,propranolol has proven efficacious in accelerating the involution infantile hemangiomas through a wide variety of case series and clinical trials.²⁰ Also common in dermatology is the wide spread use of products to treat conditions well beyond those reflected on their FDA approved label. Tacrolimus (Protopic™), while only FDA approved for the treatment of atopic dermatitis, has been used off-label to treat many other skin disorders including lichen planus, allergic contact dermatitis, seborrhoeic dermatitis, vitiligo, pyoderma gangrenosum, and balanitis xerotica obliterans.^21,22 While some of these uses are based on small case series, there is statistically significant evidence from multiple randomized, double-blind studies that supports the use of 0.1 % tacrolimus ointment in some forms of psoriasis.^23,24 Despite this proven efficacy in a multitude of conditions, the manufactures are confined to only discussing the product’s one FDA approved use. These restrictions may contribute to the underuse of products that have tremendous potential to help other patients.

Moving Forward

The increasing popularity of off-label prescribing combined with recent law proceedings that have undermined the FDA’s ability to regulate off-label marketing activities, has led to some concerns about how to most effectively keep physicians informed while still protecting patients. The FDA’s concerns over protecting physicians from inappropriate influence by pharmaceutical companies are often seen as unnecessary and even insulting to the practitioners. With the recent legal cases highlighting protection under the First Amendment, there may be an increase in the free speech by pharmaceutical companies. The necessity of clinical trial transparency and a greater emphasis on improving research quality will become even more important in this setting. The requirements of advanced registration for clinical trials and the stipulation that summary results of clinical trials must be published have made it more difficult to hide negative studies, ensuring that physicians and patients will have access to the most honest and up to date information.²⁵

Many have proposed that to decrease off-label drug use and promotion the FDA must modify their approval system into a streamlined process for approving new uses of drugs. However, such changes to the regulatory system are not likely to occur anytime soon. Off-label promotion will continue to be a necessity as the FDA’s current drug approval process is unlikely to keep pace with the rapid expansion of therapeutic options in dermatology. The evolving nature of the FDA’s regulatory guidelines on the dissemination of information regarding off-label uses, combined with efforts to improve research quality and transparency, will hopefully expand the realm of knowledge available to physicians, allowing for the best possible management of their patients’ dermatologic conditions. Allowing for open discussion about off-label uses should be seen not as a form of pharmaceutical promotion but as a form of education.

References

1. Mello MM, Studdert DM, Brennan TA. Shifting terrain in the regulation of off-label promotion of pharmaceuticals. N Engl J Med. 2009 Apr 9; 360(15):1557-66.
2. Heilman RD. Drug development history, “overview,” and what are GCPs? Qual Assur. 1995 Mar;4(1):75-9.
3. Klees JE, Joines R. Occupational health issues in the pharmaceutical research and development process. Occup Med. 1997 Jan;12(1):5-27.
4. Sugarman JH, Fleischer AB, Jr., Feldman SR. Off-label prescribing in the treatment of dermatologic disease. J Am Acad Dermatol. 2002 Aug; 47(2):217-23.
5. Li VW, Jaffe MP, Li WW, et al. Off-label dermatologic therapies. Usage, risks, and mechanisms. Arch Dermatol. 1998 Nov;134(11):1449-54.
6. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003 Mar;22(2): 151-85.
7. Tabarrok A. Assessing the FDA via the anomaly of off-label drug prescribing. The Independent Review. 2000 Jul 1;5(1).
8. Nasr A, Lauterio TJ, Davis MW. Unapproved drugs in the United States and the Food and Drug Administration. Adv Ther. 2011 Oct;28(10):842-56.
9. O’Reilly J, Dalal A. Off-label or out of bounds? Prescriber and marketer liability for unapproved uses of FDA-approved drugs. Ann Health Law. 2003;12(2):295-324, table.
10. Osborn JE. Can I tell you the truth? A comparative perspective on regulating off-label scientific and medical information. Yale J Health Policy Law Ethics. 2010;10(2):299-356.
11. Singer N. F.D.A. aims at doctors’ drug pitches. New York Times. 2010 Jan 31. Available at: http://www.nytimes.com/2010/02/01/business/01wrinkle.html?pagewanted=all&_r=0. Accessed March 8, 2015.
12. Department of Health and Human Services FaDACfDEaR. Tazarotene capsules in the treatment of psoriasis. 2004.
13. Barkan ID. Industry invites regulation: the passage of the Pure Food and Drug Act of 1906. Am J Public Health. 1985 Jan;75(1):18-26.
14. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among officebased physicians. Arch Intern Med. 2006 May 8;166(9):1021-6.
15. Fugh-Berman A, Melnick D. Off-label promotion, on-target sales. PLoS Med. 2008 Oct 28;5(10):e210.
16. Schweiger ES, Pinchover L, Bernstein RM. Topical bimatoprost for the treatment of eyebrow hypotrichosis. J Drugs Dermatol. 2012 Jan; 11(1):106-8.
17. Ventola CL. Off-label drug information: regulation, distribution, evaluation, and related controversies. P T. 2009 Aug;34(8):428-40.
18. Copland H HP. Off-label, not off-limits: the FDA needs to create a safe harbor for off-label drug use. Issue brief no.15 January 2013. Manhattan Institute for Policy Research.
19. Conko G. Hidden truth: the perils and protection of off-label drug and medical device promotion. Health Matrix Clevel. 2011;21(1):149-87.
20. Leaute-Labreze C, Dumas de la RE, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun 12;358(24):2649-51.
21. Kaliakatsou F, Hodgson TA, Lewsey JD, et al. Management of recalcitrant ulcerative oral lichen planus with topical tacrolimus. J Am Acad Dermatol. 2002 Jan;46(1):35-41.
22. Ebert AK, Vogt T, Rosch WH. Topical therapy of balanitis xerotica obliterans in childhood. Long-term clinical results and an overview. Urologe A. 2007 Dec;46(12):1682-6.
23. Remitz A, Reitamo S, Erkko P, et al. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol. 1999 Jul;141(1):103-7.
24. Carroll CL, Fleischer AB, Jr. Tacrolimus ointment: the treatment of atopic dermatitis and other inflammatory cutaneous disease. Expert Opin Pharmacother. 2004 Oct;5(10):2127-37.
25. Outterson K. Clinical trial transparency–antidote to weaker off-labelpromotion rules? N Engl J Med. 2014 Jul 3;371(1):1-3.

Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

ABSTRACT
Biologic agents were introduced during the past decade as a new class of treatments for chronic psoriasis. These agents provide therapeutic alternatives to traditional topical and systemic therapies. Alefacept, the first such biologic agent, was approved by the
US FDA in January 2003 for the treatment of chronic plaque psoriasis. This review will discuss data from clinical trials that have provided new insights into the efficacy, safety, and cost effectiveness of alefacept as a treatment for psoriasis.

Key Words:
alefacept, Amevive®, biologics, plaque psoriasis

Psoriasis is a chronic autoimmune, inflammatory disease that
affects an estimated 2% of Americans and Europeans.¹ Onethird
of psoriatic patients have moderate to severe disease
and are candidates for phototherapy or systemic treatment.²
Biologic agents developed in the past decade provide
additional therapeutic alternatives for these patients. Alefacept
(Amevive®) was the first US FDA sanctioned biologic agent
for the treatment of psoriasis, approval was granted in
January 2003.³ Alefacept is a human fusion protein of the
CD2-binding region of leukocyte function-associated
antigen-3 and the CH2 and CH3 domains of immunoglobulin
G1 and acts to inhibit T cell activation and induce apoptosis
of memory T cells.³ Since the introduction of alefacept, 5
other biologic agents have been approved for the treatment
of moderate to severe psoriasis, including efalizumab
(Raptiva®), a humanized form of a murine antibody against
CD11a (withdrawn in 2009 due to the increase risk of
adverse events); the anti-tumor necrosis factor (anti-TNF)
agents etanercept (Enbrel®), infliximab (Remicade®), and
adalimumab (Humira®); and the IL-12/IL-23 inhibitor
ustekinumab (Stelara™). Herein, we review what has been
learned during the past decade regarding the efficacy, safety,
and cost effectiveness of alefacept as a treatment for psoriasis.

Clinical Trials with Alefacept Monotherapy

Alefacept was effective as a monotherapy for chronic
plaque psoriasis (CPP) in several clinical studies. Ellis et al.
conducted a phase II, multicenter, randomized controlled
trial of 229 patients who received 1 of 3 doses of intravenous
(IV) alefacept (0.025mg, 0.075mg, or 0.150mg per kilogram
of body weight) or placebo control weekly for 12 weeks, with
follow-up for 12 weeks after treatment.⁴ Two weeks after
therapy, the Psoriasis Area Severity Index (PASI) score was
improved by 38% to 53% in the groups receiving alefacept,
compared with 21% in the placebo group. Improvement
correlated with a reduction in the number of memory effector T lymphocytes with alefacept treatment. Clinical
improvement was sustained during the 12-week follow-up
period, with 28 patients achieving scores of clear or almost
clear of psoriasis, compared with 3 patients in the placebo
group.⁴ Long-term follow-up of patients achieving a clear or
almost clear response demonstrated sustained improvement
for a median of 10 months and for up to 18 months before
retreatment was required.⁵ Subsequent phase III trials
demonstrated improved clinical efficacy and tolerability
in patients receiving two 12-week courses of IV alefacept
therapy.^6,7 Intramuscular (IM) alefacept administered as a
once weekly injection of 10mg or 15mg for 12 weeks was
proven to be similarly safe and effective in improving CPP,
and is a convenient alternative to IV therapy.^8,9

Cafardi et al. examined alternative dosing regimens for
alefacept to determine whether administration of the drug at
double the recommended dose or at an increased loading dose
improved overall response in patients with CPP.¹⁰ Measures
of efficacy included the percentage of patients achieving a
75% reduction in the PASI (PASI 75), the Physician Global
Assessment (PGA) scale of disease severity, body surface
area (BSA) involvement, and photographic evaluation of a
target lesion. Cafardi et al. found that higher doses of alefacept
failed to improve clinical response, but were associated with
an increased incidence of adverse events (AEs), including
mild infection, headache, pruritus, and erythroderma.¹⁰

In an analysis of phase III clinical trials of alefacept, Menter
et al. determined the efficacy of multiple courses of alefacept
in patients who failed to achieve a ≥50% reduction in PASI
after a first course of treatment.11 Clinical response was
assessed by PGA and PASI at baseline and every 2-4 weeks
during follow-up. Of patients who failed to demonstrate
a meaningful response to the first course of alefacept, a
majority showed an improved clinical response with a second
course of therapy. Successive treatment courses resulted in incremental clinical improvement, with an increase in the
percentage of patients achieving PASI 75 from 29% after
1 course to 54% after 5 courses.¹¹ The results of this study
are limited by the open-label, uncontrolled design in the
third through fifth courses and the number of patients, which
decreased over treatment courses. However, the findings
suggest that multiple courses of alefacept are well tolerated
and result in continued clinical improvement in psoriatic
symptoms, at least in patients whose initial response was
such that they chose to undertake additional treatment.
Recent data by Goffe et al. from 13 clinical trials in patients
with CPP receiving up to 9 courses of alefacept therapy over
5 years provide further evidence that long-term therapy with
alefacept is safe and well tolerated.¹²

To date, no randomized controlled trials have directly
compared the efficacy of alefacept with other biologics
approved for treating psoriasis. To attempt to answer this
question, Brimhall et al. performed a quantitative metaanalysis
of randomized controlled trials of 4 biologic agents:
alefacept, efalizumab, etanercept, and infliximab.¹³ Across
all trials, efficacy was measured by achievement of PASI 75
after 10-14 weeks of treatment, and the relative risk and
number needed to treat was pooled and compared. The
study showed that all agents were efficacious for improving
psoriasis, though alefacept was the least effective of the
agents studied. Pooled relative risk of achieving PASI 75
was 4, 7, 12, and 19 for alefacept, efalizumab, etanercept,
and infliximab, respectively, compared with placebo.¹³
The corresponding numbers needed to treat were 8, 4, 3,
and 2. The risk of experiencing 1 or more AEs was lowest
for alefacept (9%), compared with efalizumab (15%) and
infliximab (18%).¹³ The most common AEs were headache,
pruritus, chills, pharyngitis, and upper respiratory infections
(URIs). According to the study, none of the agents carried an
increased risk for serious AEs.

Additional studies have helped to establish alefacept as a
safe and well tolerated treatment for psoriasis. Perlmutter et
al. conducted a records review of 201 patients treated with
IM or IV alefacept once weekly for 12- or 16-week dosing
regimens.¹⁴ Fatigue and arthralgias were the most common
AEs, reported in 23% and 17% of patients, respectively.
URIs were reported in < 4% of patients.¹⁴ Despite concerns
that alefacept acts as an immunosuppressant, there were no
reports of tuberculosis, or disseminated viral or opportunistic
infections. Malignancies were reported in 5 of 201 patients
and consisted primarily of basal cell and squamous cell
carcinomas in individuals with a prior history of exposure to
methotrexate (MTX) and ultraviolet photo
Goffe et al. analyzed the incidences of AEs, includingtherapies.¹⁴

infections and malignancies, in patients receiving long-term
alefacept therapy.¹² The group reviewed data from 13 clinical
trials in patients who received up to 9 courses of alefacept
therapy over 5 years. The most common AEs reported by
patients were headache, nasopharyngitis, influenza, URIs,
and pruritus.¹² No opportunistic infections or infection related deaths were reported. The incidence of infection
was unrelated to CD4+ T lymphocyte count. The rates of
discontinuation due to AEs, serious AEs, and infections or
malignancies were low and did not increase with repeated
treatment courses.

Alefacept as Part of Multi-therapeutic Approaches

The previous studies demonstrated the safety and efficacy
of alefacept as a monotherapy for CPP. However, in the
clinical setting a multi-therapeutic regimen is often used
to optimize treatment efficacy and minimize toxicity.
Perlmutter et al. reviewed the records of 201 patients who
received IM or IV alefacept once weekly for the standard 12-
week or extended 16-week regimens.¹⁴ Patients receiving IM
therapy were treated with either the standard 15mg dose or a
double loading dose of 30mg. Investigators analyzed several
parameters, including BSA involvement; degree of severity;
concomitant topical, photo, or systemic therapy; treatment
duration; and response to therapy, defined as improvement
relative to baseline, which was based on a graded assessment
by the treating physician.¹⁴

A majority of patients demonstrated clinical improvement
following a single course of alefacept treatment, with 17% of
patients achieving an excellent response and 35% achieving
either good or better responses.¹⁴ Half of the patients who
achieved an excellent response received an alternative
therapeutic regimen, including extended treatment duration
or increased loading dose. Over 70% of patients received
alefacept with a concomitant therapy, including MTX,
cyclosporine, systemic retinoids, or ultraviolet A (UVA)/
psoralen plus UVA. Forty-one percent of patients who
received alefacept monotherapy achieved a good response or
better after 1 course of treatment. Good or better responses
were achieved by 42% of patients receiving concomitant
phototherapy, 36% receiving systemic retinoids, 27%
receiving MTX, and 19% receiving cyclosporine.¹⁴ After
only 1 course of alefacept added to an existing therapy, many
patients were able to successfully discontinue prior systemic
therapies without evidence of disease flare. In addition,
patients experienced prolonged disease free periods even
after treatment completion. Of the 62 patients for whom
remission time could be determined, 43 (69%) experienced
remissions of ≥6 months, 15 (24%) had remissions of ≥1
year, and 3 (5%) experienced remissions lasting ≥2 years.¹⁴
The average remission time was 7 months and the maximum
remission time was 25 months. This study demonstrated the
efficacy of long-term alefacept therapy for psoriasis.

A recent study by Krueger et al. examined the safety and
efficacy of multiple courses of alefacept in combination
with traditional psoriasis therapy for the treatment of CPP.³
Patients received up to 3 courses of 15mg IM alefacept once
weekly for 12 weeks, either alone or with 1 concomitant
therapy, and then were observed for clinical response over
an additional 12 weeks. Concomitant therapies included
topical agents, MTX, cyclosporine, systemic retinoids, and
ultraviolet B (UVB). Disease severity was assessed using the PGA scale. More than 75% of patients improved by 1 PGA
category, while greater than 44% improved by 2 or more PGA
categories across all treatments.³ Greater than 30% achieved a
PGA rating of mild or better with the addition of alefacept to
the treatment regimen, compared with 3% at baseline, while
16% achieved a rating of clear or almost clear. Although the
study was not powered to assess efficacy between treatments,
the authors noted that patients receiving alefacept plus UVB
treatment showed greater improvement than patients in any of
the other concomitant treatment groups. Similar to previous
studies, AEs included mild URIs and non-melanoma skin
cancers; however, the incidences were low and comparable
across all courses and treatment combinations.³ The results
suggest that alefacept is well tolerated and efficacious alone
and in combination with other psoriasis therapies.

Cost Comparison of Alefacept & Traditional Therapies

An important factor when selecting from among available
psoriatic therapies is cost. Mikhael et al. performed a cost
comparison analysis of various psoriasis treatments over a
10-year period in Ontario, Canada.¹⁵ They used a hypothetical
patient with moderate plaque-type psoriasis exhibiting a PASI
10 score, 20% BSA involvement, and no joint involvement,
and calculated the cost to treat this patient with different
therapeutic regimens. The results of their analysis depended
on the weight of the patient. In a 60kg patient, alefacept,
administered in two 12-week courses, was the most costly
therapy, followed by infliximab 5mg/kg.¹⁵ In a 90kg patient,
infliximab 5mg/kg was the most costly, followed by alefacept
as the second most costly treatment option. The least costly
treatment was UVB phototherapy.

A recent study by Beyer et al. analyzed the total cost of
systemic psoriasis therapies using a cost comparison model
based on costs listed in the Consumer Price Index-Urban.16
The total annual cost for alefacept therapy, administered
in two 12-week courses, was $27,577 US, significantly
more costly than MTX therapy, which was $1197 US. The
authors concluded that despite higher monitoring costs for
traditional options, the cost of biologics exceeds those of
other therapies.¹⁶

Conclusion

Over the past decade, numerous studies have shown the
safety, efficacy, and cost effectiveness of alefacept as a
therapy for moderate to severe psoriasis. These studies
demonstrate that although alefacept is not the most
efficacious or cost effective treatment, it seems to be, at
least in our opinion, one of the safest treatments, if not the
single safest biologic treatment, available. We did not find
any reports of opportunistic infections with alefacept, as
have been reported with TNF inhibitors. However, far fewer
patients have received alefacept compared with those who
have received TNF antagonists, thereby limiting the extent to
which we know the overall safety profile of alefacept.

Alefacept is slower to act than and is not as effective as TNF
inhibitors for most psoriasis patients. However, the efficacy of alefacept for a particular patient is, as of now, unpredictable.
In practice, there is no single right treatment for all, as some
patients place more weight on efficacy, others on safety, and
others on the convenience of the dosing regimen. For patients
who want the safest biologic therapy (and certainly for those
who have failed other options), alefacept may be a good
choice of treatment, and it may also have a role in multitherapeutic
approaches to treating psoriasis.

References

1. Stern RS, Nijsten T, Feldman SR, et al. Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Investig Dermatol Symp Proc 9(2):136-9 (2004 Mar).
2. Fleischer AB, Jr., Feldman SR, Rapp SR, et al. Disease severity measures in a population of psoriasis patients: the symptoms of psoriasis correlate with self-administered psoriasis area severity index scores. J Invest Dermatol 107(1):26-9 (1996 Jul).
3. Krueger GG, Gottlieb AB, Sterry W, et al. A multicenter, open-label study of repeat courses of intramuscular alefacept in combination with other psoriasis therapies in patients with chronic plaque psoriasis. J Dermatolog Treat 19(3):146-55 (2008).
4. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 345(4):248-55 (2001 Jul 26).
5. Krueger GG, Ellis CN. Alefacept therapy produces remission for patients with chronic plaque psoriasis. Br J Dermatol 148(4):784-8 (2003 Apr).
6. Krueger GG, Papp KA, Stough DB, et al. A randomized, doubleblind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 47(6):821-33 (2002 Dec).
7. Krueger GG. Clinical response to alefacept: results of a phase 3 study of intravenous administration of alefacept in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol 17(Suppl 2):17-24 (2003 Jul).
8. Lebwohl M, Christophers E, Langley R, et al. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 139(6):719-27 (2003 Jun).
9. Ortonne JP. Clinical response to alefacept: results of a phase 3 study of intramuscular administration of alefacept in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol 17(Suppl 2):12-6 (2003 Jul).
10. Cafardi JA, Cantrell W, Wang W, et al. The safety and efficacy of highdose alefacept compared with a loading dose of alefacept in patients with chronic plaque psoriasis. Skinmed 7(2):67-72 (2008 Mar).
11. Menter A, Cather JC, Baker D, et al. The efficacy of multiple courses of alefacept in patients with moderate to severe chronic plaque psoriasis. J Am Acad Dermatol 54(1):61-3 (2006 Jan).
12. Goffe B, Papp K, Gratton D, et al. An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy. Clin Ther 27(12):1912-21 (2005 Dec).
13. Brimhall AK, King LN, Licciardone JC, et al. Safety and efficacy of alefacept, efalizumab, etanercept and infliximab in treating moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials. Br J Dermatol 159(2):274-85 (2008 Aug).
14. Perlmutter A, Cather J, Franks B, et al. Alefacept revisited: Our 3-year clinical experience in 200 patients with chronic plaque psoriasis. J Am Acad Dermatol 58(1):116-24 (2008 Jan).
15. Mikhael D, Babcock K, DesGroseilliers JP. Cost comparison of psoriasis treatments. J Cutan Med Surg 13(6):303-7 (2009 Nov).
16. Beyer V, Wolverton SE. Recent trends in systemic psoriasis treatment costs. Arch Dermatol 146(1):46-54 (2010 Jan).

1. Department of Dermatology, University of Virginia, Charlottesville, VA, USA
2. Department of Dermatology, University of California, San Francisco, CA, USA
3. Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

ABSTRACT

To date, the US FDA has approved three tumor necrosis factor (TNF)-a inhibitors for use in dermatology. Etanercept (Enbrel^®, Amgen-Wyeth), a fully human fusion protein of TNF receptor II bound to the Fc component of human IgG1, is approved for use in psoriasis (2004) and psoriatic arthritis (2002). Infliximab (Remicade^®, Centocor) is a chimeric monoclonal antibody that is approved for use in psoriasis (2006) and psoriatic arthritis (2005), and adalimumab (Humira^®, Abbott Laboratories), a fully human monoclonal antibody, is approved for use in psoriatic arthritis (2005). While data regarding the efficacy and safety of these therapies is abundant, it proves nearly impossible to objectively compare and contrast agents as there are no head-to-head trials. Clinical experience and post-marketing reporting has allowed dermatologists to identify the relative strengths and limitations of each agent. The well-founded enthusiasm for these agents, because of their excellent initial efficacy and safety profile, is reasonably tempered by concerns about declining efficacy over time, the risk of infection, lymphoma and demyelinating disorders, and cost. The distinct and targeted mechanism of action of the TNF inhibitors allows dermatologists to customize therapy to match the individual needs and characteristics of patients who are candidates for systemic or phototherapy.

Key Words:
TNF inhibitors, tumor necrosis factor, etanercept, infliximab, adalimumab

Efficacy

The efficacy of the tumor necrosis factor (TNF) inhibitors for the treatment of chronic plaque psoriasis and psoriatic arthritis has been well established in clinical trials and through real world experience. The improvements in the psoriasis area and severity index (PASI) and American College of Rheumatology (ACR) scores are comparable, and in many cases superior, to traditional antipsoriatic drugs and disease-modifying antirheumatic drugs (DMARDs), respectively. Clinical trials also demonstrate improvement in physical and health-related quality of life (HRQoL) measures in psoriasis patients who were treated with biologics when compared with placebo.¹

Long-term studies objectively demonstrating continued efficacy for plaque-type psoriasis are limited, given the relatively recent FDA approval of the individual agents for this use. Tyring and colleagues recently reported extended efficacy of etanercept (50mg twice weekly) out to 96 weeks of continuous therapy.2 Clinical experience suggests that a percentage of patients on long-term therapy with TNF inhibitors may begin to show a decline in original efficacy. Long-term trial data is necessary to further explore this clinical observation.

Safety

Assessing efficacy of the TNF inhibitors from trial data is accomplished with relative ease, while safety assessments are much more difficult. Interdrug comparison is difficult because of the lack of head-to-head trials, the differences in trial design and patient characteristics, and the lack of consistency in mandatory postmarketing reporting of adverse events. Anti-TNF agents act with greater target specificity than traditional systemic agents and to date, more than 1 million patients have been exposed across indications, allowing a reasonable degree of confidence in the safety of these drugs. Given the molecular role that TNF plays in the immune system, the primary safety concerns regarding the use of these drugs include risk of infection and malignancy.

Adverse Events

The most common adverse events in the short-term are injection site (etanercept and adalimumab) and infusion reactions (infliximab). The most concerning short-term risk is serious infection, which includes sepsis, infection from opportunistic organisms, and reactivation of latent tuberculosis. All anti-TNF agents carry a warning about reactivation of tuberculosis (black box for infliximab and adalimumab; bold letter for etanercept).^3-6 The risk of infection is higher in patients with predisposing underlying conditions, such as diabetes mellitus, congestive heart failure, a history of active or chronic infections, or concurrent use of immunosuppressive drugs.

Other Safety Concerns

Other class-wide safety concerns include the risk of malignancy, demyelinating disease, and exacerbation or development of congestive heart failure.^7,8 The risk of lymphoma among patients treated with anti-TNF agents remains controversial. The incidence of lymphoma was higher in anti-TNF treated patients compared with controls during the controlled portion of trials of all approved agents. In patients with psoriasis, no clear findings identify whether lymphoma risk is associated with disease severity, treatment, other unidentified factors, or a combination of factors.9 To date, there is no consensus on the estimated risk of lymphoma with anti-TNF therapy. Although nonmelanoma skin cancer and lymphoma rates are greater in patients treated with anti-TNF agents, conclusions are difficult to draw in light of the pre-existing association of lymphomas with severe rheumatoid arthritis, psoriasis, and systemic inflammation. Furthermore, prior systemic therapies and environmental risk factors, such as sun exposure and smoking, confound the data. National registries to date show no increase in solid cancers vs. the general population.

Demyelinating Diseases

TNF has been implicated in multiple sclerosis (MS) pathogenesis, has been identified in active MS lesions, and is known to be toxic to oligodendrocytes in vitro. A double-blind, placebo-controlled phase II study of an anti-TNF molecule (lenercept, a recombinant TNF receptor p55 immunoglobulin fusion protein) conducted in MS patients documented significantly increased and earlier occurrences of MS exacerbations and more severe neurologic deficits in the lenercept treatment groups compared to placebo.¹⁰ Although a causal relationship between TNF inhibitors and demyelinating disease remains unclear, optic neuritis, transverse myelitis, MS, seizures, and Parkinson’s disease have been reported in patients taking TNF inhibitors. The drugs should be withheld from any patient who has a history of, or first degree relative with a demyelinating disease; Patients should be monitored vigilantly for suspicious signs or symptoms.

Congestive Heart Failure

TNF inhibitors were previously evaluated as a therapy for congestive heart failure (CHF), but trials were halted due to lack of efficacy. Although data from one of the etanercept CHF trials suggested higher mortality in treated patients vs. placebo, analyses did not identify any specific risk factors. Postmarketing reports of CHF have included:

1. new onset cases
2. cases with no identifiable risk factors, such as previous myocardial infarction, coronary artery disease, or hypertension
3. cases in patients under the age of 50.¹¹

Most patients improved or symptoms resolved once therapy was stopped, though rare fatal incidences have been recorded.

Autoimmunity

The issue of autoimmunity requires further study. Autoantibody formation (ANA, anti-dsDNA, and anticardiolipin) appears to be more common with infliximab than with etanercept; only limited reports exist for adalimumab. Development of human antihuman antibodies and human antichimera antibodies also seem to be slightly more common with infliximab than with other agents. Infliximab data suggests that development of these antibodies is loosely associated with reduced efficacy and a higher incidence of infusion reactions.12 The impact of long-term treatment with anti-TNF agents on the development of autoimmune diseases is unknown.

Pregnancy and Breastfeeding

All anti-TNF agents are pregnancy category B (no human studies conducted, but no adverse effects noted in animal studies). Because human data is not available, therapy should be avoided, if possible, in pregnant or breastfeeding women.

Primary Issues of Concern

Two primary issues of concern facing the clinicians who are prescribing these agents include long-term safety and the appropriate choice of screening/ monitoring tests. Long-term safety profiles remain to be established. Patient selection is key; not all patients are good candidates for treatment with anti-TNF agents. Patients must be predetermined to be reliable, compliant with follow-up visits, and able to self assess and report the onset of new signs or symptoms that may herald the onset of an adverse event. Although guidelines regarding objective screening and monitoring are yet to be established, a reasonable approach includes a detailed history and physical examination, TB testing (US FDA-mandated for adalimumab and infliximab), and additional baseline lab tests that are deemed appropriate as a result of the history and examination. Close and routine follow-up is warranted to assess both the continued efficacy and safety of these drugs in individual patients.

Cost

Compared with traditional treatments for psoriasis, such as phototherapy and methotrexate, treatment with the anti-TNF drugs represents a tremendous financial burden. A year of methotrexate at 15mg/week costs an average of $375 USD (not including lab fees), while a year of biologic therapy can vary between $10,000 USD and $25,000 USD (or more) based on the dosage and treatment regimen prescribed.¹³ Moreover, insurance carriers often require failure of, or contraindications to, one or more standard therapies prior to approval of coverage for a biologic agent, thus presenting a major obstacle to patients in need. Cost is not only a concern to patients, but to their dermatologists and the entire healthcare system in general. The cost of treatment is a primary reason many dermatologists do not consider biologic agents as first-line therapy for moderate-to-severe or socially disabling psoriasis, and reinforces the first-line use of more traditional, efficacious, and cost effective treatments such as ultraviolet light.14 In the case of psoriatic arthritis, however, the low cost of time-proven agents, such as methotrexate, may no longer be considered worth the risk of potential toxicity.

Conclusion

The discovery, use, and great clinical success of anti-TNF molecules for the treatment of moderate-to-severe psoriasis and psoriatic arthritis have engendered well-founded enthusiasm, but the cost of therapy and unknown long-term safety and efficacy profile gives us pause. The addition of these agents to the available therapeutic modalities for treating psoriasis, which can be physically, psychologically, and socially devastating, is excitedly welcomed. However, as with any new drug class, the high price of therapy and the unknown long-term effects represent major obstacles to selection of these drugs as first-line agents in all patients with moderate-to-severe or debilitating psoriasis/ arthritis. The excellent initial efficacy seems to hold up fairly well over 12-36 months, but a trend toward declining efficacy thereafter is being observed in some cases. Combination therapy with methotrexate is observed to maintain the efficacy of infliximab, but the additional cost and risk of combination may not be appropriate for all patients.

The major focus of concern now and in the future remains safety. Objective screening and monitoring guidelines are needed, as current clinical practice varies from no screening to indiscriminate panel testing. Given safety data, including postmarketing reports, a reasonable approach to patient selection and monitoring includes specific tests for all patients and additional tests based on individual patient need. A thorough history and physical examination with careful assessment for neurologic abnormalities and a baseline tuberculin skin test (PPD), complete blood count, and metabolic profile are a minimum. Additional laboratory testing and subsequent monitoring should be selected individually given the patient, region of practice, and drug to be utilized. Frequent in-office follow-up to assess efficacy and safety is warranted.

References

1. Katugampola RP, Lewis VJ, Finlay AY. The Dermatology Life Quality Index: assessing the efficacy of biological therapies for psoriasis. Br J Dermatol 156(5):945-50 (2007 May).
2. Tyring S, Gordon KB, Poulin Y, et al. Long-term safety and efficacy of 50mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 143(6):719-26 (2007 Jun).
3. Immunex Corporation. Enbrel^® (etanercept) package insert; 2005. Thousand Oaks, CA, USA.
4. Centocor Inc. Remicade^® (infliximab) package insert; 2005. Malvern, PA, USA.
5. Abbott Laboratories. Humira^® (adalimumab) package insert; 2006. Chicago, IL, USA.
6. Keane J. TNF-blocking agents and tuberculosis: new drugs illuminate an old topic. Rheumatology (Oxford). 44(6):714-20 (2005 Jun).
7. Scheinfeld N. A comprehensive review and evaluation of the side-effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab. J Dermatolog Treat 15(5):280–94 (2004 Sep).
8. Hochberg MC, Lebwohl MG, Plevy SE, Hobbs KF, Yocum DE. The benefit/risk profile of TNF-blocking agents: findings of a consensus panel. Semin Arthritis Rheum 34(6):819-36 (2005 Jun).
9. Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol 139(11):1425-9 (2003 Nov).
10. Arnason BGW, et al. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53(3):457-65 (1999 Aug 11).
11. Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 138(10):807-11 (2003 May).
12. Kapetanovic MC, Geborek P, Saxne T, et al. Development of antibodies against infliximab during infliximab treatment in rheumatoid arthritis: relation to infusion reactions and treatment response. Arthritis Rheum 52(suppl):S543 [abstract 1440] (2005).
13. Prices based on those found at http://www.drugstore.com, last accessed August 22, 2007.
14. Miller DW, Feldman SR. Cost-effectiveness of moderate-to-severe psoriasis treatment. Expert Opin Pharmacother 7(2):157-67 (2006 Feb).