Cutaneous side effects of antietumor necrosis factor biologic therapy: A clinical review

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1 REVIEW Cutaneous side effects of antietumor necrosis factor biologic therapy: A clinical review Aikaterini-Evaggelia Moustou, MD, a Athina Matekovits, MD, a Clio Dessinioti, MD, a Christina Antoniou, MD, a Petros P. Sfikakis, MD, b and Alexander J. Stratigos, MD a Athens, Greece Background: Anti-tumor necrosis factor (anti-tnf) biologic agents have been associated with a number of adverse events. Objective: To review the cutaneous reactions that have been reported in patients receiving anti-tnf therapy. Methods: We performed a systematic MEDLINE search of relevant publications, including case reports and case series. Results: Reported cutaneous events included infusion and injection site reactions, psoriasiform eruptions, lupus-like disorders, vasculitis, granulomatous reactions, cutaneous infections, and cutaneous neoplasms. Infusion reactions and injection site reactions were definitely associated with anti-tnf administration, whereas all other events had a varying strength of association and severity, not necessarily requiring drug discontinuation. Limitations: Most information was derived from spontaneous case reports, where ascertainment biases and frequency of reporting may impair detection methodology and causal relationships. Conclusions: As anti-tnf biologic agents are progressively being used in clinical practice, cutaneous adverse events will be encountered more frequently. Until more data are accumulated with respect to their pathogenesis and potential association with anti-tnf therapy, dermatologists should become more familiar with the clinical presentation and management of such events. ( J Am Acad Dermatol 2009;61: ) INTRODUCTION Tumor necrosis factor (TNF) is the name attributed to a distinct group of naturally occurring cytokines, possessing important anti-tumor and immune-regulating properties. Two distinct members of the TNF family are TNF-alfa and TNF-beta. TNFalfa, initially referred to as cachectin, 1 is a ubiquitous molecule, produced by a wide variety of cells in different tissues, whereas TNF-beta (also known as lymphotoxin-alfa) is produced mainly by activated lymphocytes. 2 From the 1st Department of Dermatology, Andreas Sygros Hospital, a and the 1st Department of Propaedeutic and Internal Medicine, Laiko General Hospital, b University of Athens Medical School. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Alexander J. Stratigos, MD, Andreas Sygros Hospital, 5 Dragoumi Street, Athens 10671, Greece. alstrat@hol.gr. Published online July 23, /$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi: /j.jaad Abbreviations used: AD: atopic dermatitis ANA: antinuclear antibody CD: Crohn s disease CTCL: cutaneous T-cell lymphoma DMARD: disease-modifying antirheumatic drug dsdna: double-stranded DNA HR: hazard ratio IGD: interstitial granulomatous dermatitis LCV: leukocytoclastic vasculitis LE: lupus erythematosus NMSC: non-melanoma skin cancer PUVA: psoralen and ultraviolet A light RA: rheumatoid arthritis SLE: systemic lupus erythematosus TNF: tumor necrosis factor UVB: ultraviolet B light TNF-alfa is a significant regulator of apoptosis and an important proinflammatory cytokine with pleiotropic actions. 3 Dysregulation of TNF-alfa production has been associated with the pathogenesis of various inflammatory disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease, ankylosing spondylitis, psoriatic arthritis, and psoriasis. In an effort to down-regulate the effects of TNF-alfa excess 486

2 VOLUME 61, NUMBER 3 Moustou et al 487 production in these diseases, a new category of biologic agents, designated as anti-tnf agents, has been recently developed and used in clinical practice. Currently, more than 1,500,000 patients have been treated with the 3 licensed agents etanercept, infliximab, and adalimumab (recently a fourth anti- TNF agent, CIMZIA, was approved for the treatment of RA). Etanercept is a dimeric fusion protein composed of two soluble TNF receptor type 1 molecules linked to the Fc portion of an IgG1, 4 which neutralizes the soluble forms of both TNF-alfa and TNFbeta, imitating the inhibitory effects of naturally occurring soluble TNF receptors. Infliximab is a chimeric monoclonal antibody, composed of the variable region of a murine anti-human TNF-alfa antibody fused to the constant region of a human IgG1, 5 whereas adalimumab is a totally human recombinant IgG1 monoclonal antibody. 6 Both agents bind the soluble as well as the transmembrane form of TNF-alfa, without neutralizing TNF-beta. Moreover, the two monoclonal anti-tnf antibodies have been shown to induce lysis of the cells expressing transmembrane TNF-alfa in vitro. 7 Randomized placebo-controlled trials of anti-tnf agents have demonstrated their efficacy and safety in the treatment of rheumatic diseases, Crohn s disease (CD), and psoriasis. Nevertheless, certain untoward reactions have been documented, namely, opportunistic infections, reactivation of latent tuberculosis, lupus-like syndrome, demyelinating disease, and heart failure There are scarce data on cutaneous adverse events occurring during biologic anti-tnf therapy. Indeed, most information comes from isolated case reports or case series, while randomized controlled or retrospective studies often fail to address in detail all cutaneous adverse events that develop during anti-tnf treatment. The objective of this study was to perform a literature-based review of the cutaneous reactions that have been reported with infliximab, etanercept, or adalimumab treatment for a variety of chronic inflammatory disorders. We also sought to provide an assessment of the frequency and strength of association of each such reaction with the use of anti-tnf agents and discuss their clinical presentation, pathogenic mechanisms and management. METHODS We performed a MEDLINE search of all cutaneous events reported in association with anti-tnf treatment. Randomized controlled studies, open-label studies, retrospective studies, meta-analyses, case series, and case reports published through July 2008, and reporting cutaneous reactions during anti-tnf treatment have been the main sources of our investigation. The search terms used were as follows: infliximab, etanercept, adalimumab, CD, psoriasis, psoriatic arthritis, Adamantiades-Behçet s disease, juvenile idiopathic arthritis, ulcerative colitis, cutaneous adverse effects, lupus, infections, granulomatous reactions, eczema, lymphoma, melanoma, squamous cell carcinoma, and basal cell carcinoma. In addition, we attempted a critical appraisal of the strength of association between the reported adverse events and the use of an anti-tnf agent. Several criteria were used in order to classify the cutaneous reactions during anti-tnf treatment in 4 groups, namely, definitely associated, strongly associated, moderately associated, and poorly associated. These criteria included (1) the type of study reporting the adverse event, that is, meta-analyses, randomized controlled trials, prospective or retrospective studies of large-groups of treated patients, case series or case reports; (2) the number of anti-tnf agents that have been reported in association with the specific event (one vs two vs all 3 agents); (3) the number of inflammatory disorders treated with anti- TNF agents in which such events have occurred; and (4) whether discontinuing the medication led to resolution of the side-effect (de-challenge) and, conversely, whether re-challenge with the same agent led to reappearance of the event. RESULTS A total of 91 studies were found reporting a cutaneous eruption or condition developing during anti-tnf treatment. Each type of reaction is discussed thoroughly below, based on reported evidence. A summary of all cutaneous eruptions is provided in Table I. Cutaneous adverse events of anti-tnf agents can be classified according to their clinical presentation and/or histologic features. Apart from infusion reactions related to the intravenous administration of infliximab, and injection site reactions specifically encountered with the subcutaneous injection of etanercept and adalimumab, all other adverse events mentioned below have been observed with at least one of the 3 anti-tnf agents currently in clinical use. In Table I, we describe in detail the reported cutaneous events, their estimated frequencies and the strength of association, based on the criteria described in the Methods section. Definite associations were demonstrated for infusion/injection site reactions, whereas psoriasis and psoriasiform lesions, lupuslike syndromes, vasculitis, and cutaneous infections were found to be strongly associated with anti-tnf agents. A moderate association was apparent between anti-tnf treatment and eczematous reactions, lichenoid reactions, and granulomatous diseases,

3 Table I. Reported cutaneous adverse events of anti-tnf-alfa treatment Cutaneous adverse events Drug Disease Clinical outcome Type of study Infusion reactions Acute Infl All indications Delayed Infl All indications Injection site reactions Papulopustular eruptions Psoriasis, psoriasiform eruptions Eczema Etan, All indications All indications All indications Resolution w/ reduction of infusion rate, systemic administration of antihistamines and/or corticosteroids. Discontinuation of tx in \1%, if severe reactions occur Resolution and prevention of relapses w/ concomitant administration of systemic immunosuppressives (MTX, Aza). Prevention w/ regular infusions during maintenance tx Self-limited. Decrease in frequency w/ continuation of tx. Recall reactions may occur. Resolution w/ either topical tx, UVB or PUVA, or anti-tnf discontinuation Resolution w/ either topical tx, or discontinuation Estimated frequency Rechallenge Strength of association Multiple RCT \5% of infusions 1 Definite Multiple RCT \1% of infusions Definite RCT ;10% of patients 1 Definite Prospective \1% of patients 1 Strong controlled studies 38,46 Prospective study 45 Case series 43 Multiple case reports Prospective Unknown Moderate/strong controlled study 38 Prospective study Moustou et al SEPTEMBER 2009

4 Lichenoid drug reactions Autoimmune skin disorders LE (systemic, subacute, discoid types) Vasculitis LCV Granulomatous reactions Granuloma annulare Cutaneous infections Bacterial infections (skin and soft tissue) RA, AS Resolution w/ discontinuation and/or systemic corticosteroids Rheumatic diseases, CD All indications RA All indications Resolution w/ discontinuation and/or systemic corticosteroids, anti-malarial agents, or immunosuppressive agents Resolution w/ discontinuation and/or systemic corticosteroids, immunosuppressive agents Resolution w/ topical corticosteroids; anti- TNF discontinuation was necessary in only 2 patients out of 9 Resolution w/ appropriate tx Case reports 83,84 Unknown 1 Moderate (limited experience) Retrospective studies 68 \0.5% of patients 1 Strong Case series 73 Multiple case reports Prospective \0.5% of patients Strong controlled study 38 Case series 73 Retrospective study 75 Retrospective study 94 \5% of patients Poor/moderate Prospective \5% of patients Strong controlled study 38 Prospective study 45 Prospective controlled study 100,107 Retrospective study 99 RCT 108,109 Continued VOLUME 61, NUMBER 3 Moustou et al 489

5 Table I. Cont d Cutaneous adverse events Drug Disease Clinical outcome Type of study Non-tuberculosis mycobacterial skin infection Fungal infections Herpesvirus infections (HSV 1, 2 e VZV) Infl Rheumatic diseases, CD Rheumatic diseases Rheumatic diseases Cutaneous malignant neoplasms Lymphomas CTCL Infl, Etan Psoriasis, PsA, AS, CD Lymphomatoid papulosiselike eruption Systemic ALCL w/ cutaneous involvement Resolution after appropriate tx Resolution w/ appropriate tx Resolution w/ appropriate tx Improvement after tx discontinuation, death RA Spontaneous resolution; development of non-hodgkin ALCL 2 years later Estimated frequency Rechallenge Strength of association Retrospective study 99 Extremely rare Moderate/strong Case reports 111,112 Prospective \8% Strong controlled study 38 Prospective study 45 Prospective 1%-2% of patients Strong controlled study 38 Prospective study 45 Prospective controlled study 107 RCT 108 Case reports ,130 Prospective study 38 1 event/289 RA patients Infl CD Death Case report 126 Poor Sézary syndrome Infl AS Partial remission w/ infliximab discontinuation and MTX tx NMSC RA, psoriasis Excision Case report 129 Prospective controlled study 38 Retrospective controlled study 138 RCT 22,139 Case reports Poor Poor Poor Poor 490 Moustou et al SEPTEMBER 2009

6 VOLUME 61, NUMBER 3 Moustou et al 491 RCT: 1 case 35 Poor Case reports 143 Tx w/ isolated limb chemotherapy in one patient, lymph node dissection in second patient Melanoma Etan, Psoriasis, RA Keratoacanthoma Infl RA Discontinuation Case report 132 Poor Poor Benign cutaneous neoplasms Infl, Etan CD, psoriasis Case reports 145 Eruptive nevomelanocytic nevi, imumab; ALCL, anaplastic large-cell lymphoma; AS, ankylosing spondylitis; Aza, azathioprine; CD, Crohn s disease; CTCL, cutaneous T-cell lymphoma; Etan, etanercept; HSV, herpes simplex virus; Infl, infliximab; MTX, methotrexate; NMSC, non-melanoma skin cancer; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RCT, randomized controlled trial; TNF, tumor necrosis factor; tx, therapy/treatment; VZV, varicella-zoster virus; w/, with. whereas cutaneous lymphomas, non-melanoma skin cancers, and melanoma, mainly described in case reports, were poorly linked to anti-tnf treatment. Infusion reactions Monoclonal antibodies injected for therapeutic reasons in humans generate anti-globulin responses directed against these non-self proteins. 12 These responses appear to be directly linked to the development of infusion reactions and to the reduced clinical efficacy in treated patients Infusion reactions have been consistently documented with the intravenous administration of infliximab. 11,16-20 Measurable serum concentrations of anti-infliximab antibodies are detected in most patients who present with infusion related reactions. 15,21 Adverse events occurring during the infusion or in the first 24 hours following the infusion are defined as acute reactions, whereas those manifesting 24 hours to 14 days postinfusion are considered to be delayed-type reactions. Acute reactions occur in approximately 3% to 6% of treated patients with infliximab. 11,18,21,22 These reactions are classified as mild, moderate, or severe depending on the assessment of the patient s vital signs and symptoms, which typically consist of hypotension or hypertension, chest pain, palpitations, dyspnea, fever, skin eruptions, headache, nausea, and vomiting. 19,20 Cutaneous symptoms may vary from a burning sensation with minimal erythema, to a flushing and/or urticarial rash. Lobel, Korelitz, and Warman 23 have reported a red-man syndrome elike reaction to infliximab, similar to the one observed with the rapid infusion of vancomycin. Fewer than 1% of these reactions are severe enough to interrupt treatment and to require immediate intervention. In most cases, reduction of infusion rate leads to the resolution of the symptoms. 17 The pathogenic mechanism underlying the vast majority of these reactions is considered to be of a nonimmune-mediated type, rather than a true anaphylactic response. 14,18 Therefore, in cases of mild or moderate infusion reactions, the drug has been subsequently re-administered under certain routine prophylactic measures, such as premedication with antihistamines and/or corticosteroids and adjustment of the infusion rate. 18,20 Overall, acute infliximabinduced infusion reactions have become significantly less common during the past 5 years, most probably because of the increasing experience and awareness of treating physicians. 24 Delayed-type infusion reactions occur in approximately 1% to 2.8% of infliximab-treated patients, manifesting as serum sickness elike reactions and presenting with fatigue, myalgias, arthralgias,

7 492 Moustou et al SEPTEMBER 2009 headache, fever, facial edema, and urticarial eruption. 11,18,22 These reactions are deemed to be immune mediated, usually type III hypersensitivity reactions. Antibodies to infliximab are increasingly implicated in their pathogenesis, as most of the patients experiencing delayed-type infusion reactions have increased titers of anti-infliximab antibodies. 20,21 Furthermore, a decrease in clinical response has been observed in these patients, probably related to the neutralizing action of antibodies generated against infliximab. 15,21 A number of approaches have been implemented in an effort to establish an immune tolerance against infliximab, including the concomitant administration of immunosuppressive drugs (methotrexate or azathioprine) and maintenance therapy with regular infusions every 8 weeks, avoiding long intervals between sequential infliximab infusions. 15,20 It is worth mentioning that anti-etanercept antibodies have also been isolated in the sera of patients undergoing treatment with this agent, but they do not seem to be related to any adverse reaction, nor do they influence the clinical response. 25 imumab has also been proposed as an alternative therapeutic option in patients presenting with infusion reactions to infliximab, although long-term data are required to determine its immunogenicity. 29 Injection site reactions The subcutaneous administration of etanercept may cause an injection site reaction manifested by mild to moderate erythema, itching, tenderness, and/or swelling. This kind of local reaction occurs in 10% to 20% of patients during the first month of treatment and usually decreases in frequency with the continuation of therapy A small percentage of patients receiving etanercept develop relapses of local reactions ( recall reactions ) at the site of previous injections, when subsequent injections are given. 33 Histologic and immunophenotypic studies reveal a superficial perivascular lymphocytic infiltrate composed mostly of CD4-positive (CD41) lymphocytes in the case of injection-site reactions and CD81 lymphocytes in recall-site reactions. 30 Similar manifestations at the injection sites of adalimumab have been documented at a rate of 6% to 12% of treated patients. 34,35 Psoriasis and psoriasiform eruptions A vast number of case reports and case series describing the appearance of either psoriasiform eruptions or typical psoriasis of different clinical subtypes have been reported in patients treated with anti-tnf agents for various inflammatory conditions, such as rheumatoid arthritis, CD, ankylosing spondylitis, and Adamandiades-Behçet s disease Plaque-type psoriasis, guttate psoriasis, palmoplantar pustulosis, psoriasis of the nail and scalp have all been described in the context of anti-tnf treatment. Reports in the literature are of wide heterogeneity concerning the type of agent, underlying disease, treatment duration, type of eruption, and presence or absence of personal or family history of psoriasis. In a recent review, Wollina et al 43 identified 120 published cases in which patients developed psoriasis under anti-tnf therapy, including 37 with palmoplantar pustulosis and 73 with different types of psoriasis. Most of these patients had rheumatoid arthritis (n = 61) while the rest had ankylosing spondylitis, psoriasis, CD, SAPHO syndrome, psoriatic arthritis, and other diseases. A positive personal or family history was noted in 25 and 8 patients, respectively, leaving a significant portion of patients with no previous disease association or family history. In a recent prospective study of 9826 patients included in the British Society for Rheumatology Biologics Register, 25 cases of RA were diagnosed with new onset of psoriasis as a consequence of anti- TNF treatment for RA. 46 In the comparison group of 2880 patients treated with traditional disease-modifying anti-rheumatic drugs, none developed psoriasis during the same observation period, although ascertainment and misclassification biases as well as differences in detection methodology may have influenced the results. Fifty percent of patients who developed psoriasis had been treated with adalimumab, whereas 25% were treated with either infliximab or etanercept indicating an anti-tnf-related class-effect rather than a drug-specific type of hypersensitivity. 46 The lesions appear with the typical psoriatic morphology, consisting of scaly erythematous plaques on the trunk, extremities, or scalp. New onset of nail psoriasis has also been noted, presenting as nail pitting, onycholysis, nail discoloration, and/or subungual keratosis. The most characteristic pattern of psoriasis associated with anti-tnf-alfa treatment, however, is a localized pustular eruption occurring symmetrically on the palms and soles, resembling palmoplantar pustulosis. The eruption has been reported in approximately one third of all reported cases and consists of painful or itchy pustular lesions based on erythematous areas of the acral sites, with or without concomitant psoriatic plaques or pustular lesions in other cutaneous sites. On the basis of histology, the reported cases of psoriasis developing under anti-tnf treatment have the typical features of the disease, including epidermal hyperplasia, parakeratosis, elongation of the rete ridges, dilated capillaries in the dermis, perivascular infiltration

8 VOLUME 61, NUMBER 3 Moustou et al 493 and, in the case of pustular eruptions, an intraepidermal collection of neutrophiles. In certain cases, however, the histology of the lesions had distinct lichenoid features Verea et al 47 reported a patient suffering from CD in whom a psoriasiform eruption developed. Histologic examination revealed infiltration by lymphocytes and histiocytes of a lichenoid pattern accompanied by focal necrotic keratinocytes. 49 A lichenoid-type histology was also reported by Senechal et al, 48,49 who described a CD8-positive inflammatory infiltration in 3 patients with psoriasiform eruption after anti-tnf treatment. Certain features of the anti-tnf-induced psoriasiform manifestations are reminiscent of Reiter s syndrome. A patient with CD and ankylosing spondyloarthropathy treated with adalimumab and leflunomide developed a psoriasiform rash involving the groin, axillary folds, trunk, and periumbilical region, in combination with circinate balanitis, and plantar keratoderma. Histologic findings were consistent with a psoriasiform pattern, and the skin lesions regressed after doxycycline treatment and topical steroids. 50 Overall, the reported cases of psoriasis or psoriasiform eruptions have differed with respect to their severity and treatment response. In most cases, topical treatment was sufficient to control the eruption. 36,38-40,42,44 In other cases, psoralens and ultraviolet A treatment or UVB phototherapy were initiated, 42,44 while, in more severe or persistent cases, discontinuation of anti-tnf therapy or switching to an alternative anti-tnf regimen was necessary. 36,38,41,43,44 The improvement of the eruption after discontinuation of the anti-tnf agent in some cases and relapse upon re-treatment with the same agent (positive rechallenge) further supports the causal association of anti-tnf agents with the development of psoriasiform eruptions. 36 Eczema-dermatitis Eczematous skin lesions have been reported with the use of anti-tnf therapy for rheumatic diseases. In the prospective study of Flendrie et al, which included 289 patients with RA on TNF-alfa blocking therapy, 20 cases of eczema were documented, 5 of which were confirmed by histopathology. These cases included dyshidrotic eczema, contact dermatitis, nummular eczema, atopic dermatitis, papular lesions, and a nonspecific eruption. 38 Lee et al 45 conducted a prospective study in 135 patients with rheumatic diseases treated with anti-tnf agents and observed 35 patients with cutaneous adverse events. Seven of these developed an eczematoid eruption and one of them presented with atopic dermatitis (AD). Additional cases of AD-like reactions have been reported in several patients receiving anti-tnf agents. 51,52 Two other patients with psoriasis who were receiving infliximab treatment developed severe AD after the sixth infusion and the seventh infusion, respectively. 53 In most cases, eczema-like reactions occurring in the context of anti-tnf therapy were of moderate intensity and responded well to topical treatment with topical steroids, alone or in combination with calcineurin inhibitors, with no need to discontinue anti-tnf treatment. Severe cases, however, necessitating hospitalization or discontinuation of therapy have been described. 38 A patient with psoriasis receiving infliximab therapy developed a severe atopic dermatitiselike eruption complicated by impetigo. Infliximab was discontinued, and the patient responded well to antibiotics and cyclosporine. 53 A young patient with juvenile idiopathic arthritis and a history of AD, who was receiving etanercept therapy, also developed a severe flare of dermatitis and had to discontinue treatment. 54 Drug-induced lupus erythematosus Patients receiving anti-tnf therapy often develop antinuclear antibodies (ANAs), antibodies against double-stranded DNA (anti-dsdna) and against single-stranded DNA, but rarely manifest clinical symptoms of lupus erythematosus (LE) The initial presence of positive ANA titers in some patients, before the commencement of anti-tnf therapy, has been associated with an increased frequency of subsequent anti-dsdna positivity, mainly of the IgM class and most commonly after infliximab treatment. 16,59,60 According to Atzeni et al, 61 administration of infliximab leads to the induction of ANA in 63.8% of patients with RA and 49.1% of those with CD, while anti-dsdna antibodies become measurable in 13% of RA patients and in 21.5% of CD patients, respectively. Etanercept therapy induces ANA and anti-dsdna in 11% and 15% of RA patients, respectively. 61 Clinical trials using adalimumab in RA patients have demonstrated a prevalence of 5.3% in ANA positivity and 12.9% in anti-dsdna positivity. 61 In the study by Gottlieb et al, 62 conducted in psoriatic patients receiving infliximab, ANA and anti-dsdna antibodies were induced in 25% and 4.3% of the cases, respectively. In a recent cohort study of 28 psoriatic patients with severe recalcitrant disease, an increase in ANA titers after 22 weeks of infliximab therapy was reported in 72% of the patients, compared with only 12% at baseline. Anti-dsDNA IgM increased in 68% of patients, whereas anti-dsdna IgG did not show a statistically significant elevation. 63 In symptomatic patients, anti-tnf-induced lupus manifests as systemic, subacute cutaneous or discoid

9 494 Moustou et al SEPTEMBER 2009 lupus erythematosus The clinical and laboratory findings of drug-induced lupus are similar to those of the idiopathic disease; however, central nervous system and kidney involvement are extremely rare. 65 In a recent French national survey conducted in more than 11,000 patients receiving either infliximab or etanercept for rheumatic diseases, the incidence of drug-induced lupus was found to be the same for both agents (approx 0.18%). Of the 25 cases reported as having lupus, only 12 patients fulfilled at least 4 of the SLE criteria proposed by the American College of Rheumatology, while the other 10, who presented solely with cutaneous involvement, were classified as having a limited skin lupus or toxicodermia. 68 All reported cases were seropositive for ANA and anti-dsdna antibodies. Cutaneous manifestations consisted of malar rash, increased photosensitivity, urticarial rash, purpura, alopecia, and perniosis. 68 In other case reports, patients receiving either infliximab or etanercept developed diffuse scaly erythematous reactions, histologically compatible with discoid lupus erythematosus In their literature-based-analysis ( ) of patients who developed autoimmune syndromes after the initiation anti-tnf treatment, Ramos-Casals et al 73 identified 92 cases of LE in a total of 233 published cases of autoimmune diseases. Most of these cases (77 of 92) were treated for RA, while the remainder received therapy for other autoimmune arthritides or Crohn s disease. Only 51% of cases fulfilled more than 4 criteria of the American College of Rheumatology classification for SLE and, after a more careful analysis, only 35% of the reviewed patients could be considered as having new onset of lupus, whereas the remaining patients had several preexisting features of lupus and may have represented an overlapping syndrome between RA and SLE. Cutaneous manifestations were described in 67% of cases. Drug-induced lupus usually recedes within a few weeks after the discontinuation of an anti-tnf agent, demonstrating the reversibility of this syndrome in the majority of cases. Adjuvant medication is needed only for some cases and usually consists of topical or systemic corticosteroids as well as anti-malarial and immunosuppressive agents. Vasculitis There are several reports of leukocytoclastic vasculitis (LCV) associated with the use of anti-tnf The Adverse Events Reporting System of the US Food and Drug Administration documented 35 patients with LCV, out of 116,000 and drugs. 16,71,72, ,000 individuals treated with etanercept and infliximab, respectively. 75 The majority of these cases were treated for RA. The diagnosis of LCV was histologically confirmed in 17 patients, showing typical histopathologic features of this entity. In 15 patients, the initial lesions appeared on the lower extremities and in 3 of them, receiving etanercept, the lesions appeared at the injection site. Clinically the lesions included bullae, petechiae, nodules, and urticarial wheals. Aside from the cutaneous manifestations, several patients had systemic manifestations, for example, arthralgias, fever, fatigue, myalgias, pedal edema, peripheral neuropathy, abdominal pain, pleuritic pain, pericardial effusion, and hematuria. 75 Cessation of anti-tnf therapy resulted in marked improvement in 22 patients, whereas in 4 patients the lesions persisted despite drug discontinuation. Interestingly, LCV recurred in 5 patients taking etanercept after readministration of the same anti-tnf agent and in one patient who switched from infliximab to etanercept. 75 Despite the possible coexistence of vasculitis in patients with autoimmune disorders, such as RA, 80 the close temporal association of LCV with the initiation of anti-tnf therapy, the appearance of vasculitic lesions at the injection sites of etanercept, and the resolution of vasculitis in most of the patients after treatment discontinuation (and reappearance upon re-treatment) support a direct relation between LCV and anti-tnf therapy. In their prospective study of 289 RA patients, Flendrie et al 38 reported 5 cases of LCV developing during treatment with anti-tnf agents. The diagnosis was confirmed by a skin biopsy in 4 cases. Only one of these cases (a necrotizing LCV with ulceration) was considered to be probably related to the administration of infliximab, while the remaining cases were considered as possibly or unlikely related, as they did not have a positive relation with the time of initiation of anti-tnf therapy and their resolution was independent of the cessation of the TNF-blocking agent. In their case series, Ramos-Casals et al 73 identified 113 cases of vasculitis in patients who had received anti-tnf between 1990 and The majority of the patients (84%) were treated for RA. The main histologic finding was leukocytoclastic vasculitis (63% of cases). One fourth of the patients with cutaneous vasculitis also experienced extracutaneous manifestations, especially peripheral neuropathy and renal vasculitis. Autoantibodies were detected in a remarkable number of cases (ANAs in 27 cases, antineutrophilic cytoplasmatic antibodies in 10, cryoglobulins in 5, anti-dna in 4, anti-phospholipid antibodies in 3, and anti-ro/la antibodies in 1 patient). Drug discontinuation was the first step taken in the management of most

10 VOLUME 61, NUMBER 3 Moustou et al 495 patients (89%), with some requiring additional therapy, such as systemic corticosteroids (25%) and immunosuppressive agents (15%). Other cutaneous manifestations with vascular pathology have been described in the context of anti-tnf treatment, such as necrotizing vasculitis, LCV, Henoch- Schönlein purpura, vasculitis accompanied by cryoglobulinemia, purpura of Doukas-Kapetanakis, urticarial vasculitis, and perniosis. 71,72,76,81,82 Lichenoid reactions Anti-TNF agents have been implicated in several cases of erythema multiforme and lichenoid drug eruptions, clinically manifested by papular erythematous lesions and histologically consistent with an interface dermatitis pattern. 76,83,84 The reported cases were treated for RA and ankylosing spondylitis. Histopathologic features revealed a diffuse lymphocytic infiltrate in the superficial dermis with a liquefactive degeneration of the basal cell layer and foci of epidermal necrosis, a pattern implying an immunemediated cytotoxic mechanism. The triggering factors initiating this kind of reaction are not clearly understood, but the fact that all 3 anti-tnf drugs have been involved in the development of lichenoid reactions suggests an immunologic effect due to TNF inhibition rather than a direct antigenic stimulation by these agents. Granulomatous reactions Noninfectious cutaneous granulomatous reactions, including cutaneous sarcoidosis, interstitial granulomatous dermatitis, and disseminated granuloma annulare, have been documented in a total of 20 patients during anti-tnf therapy. Paradoxically, TNF-blocking therapy has been used as an off-label treatment of refractory sarcoidosis with contradictory results. 85 Infliximab and adalimumab have been found to be efficacious in the majority of cases; however, 11 of 16 patients with progressive pulmonary sarcoidosis treated with etanercept had worsening of the disease There are two other reports describing the development of cutaneous and pulmonary sarcoidosis as a consequence of etanercept treatment for ankylosing spondylitis and RA, respectively. Skin lesions consisted of red-brown nodules, positive on diascopy, and skin biopsy revealed noncaseating granulomas extending through the dermis. Discontinuation of etanercept in one case and systemic corticosteroid administration in the second case led to complete resolution. 89,90 Interstitial granulomatous dermatitis (IGD, also known as atypical granuloma annulare, and palisaded neutrophilic and granulomatous dermatitis) has been associated with the use of infliximab, etanercept, and adalimumab in patients with RA or psoriatic arthritis. Skin lesions had a rapid onset and presented as asymptomatic annular macules or indurated papules or plaques, some with a clear center and a slightly elevated border. The trunk, shoulders, and upper extremities were affected. Skin biopsy revealed diffuse interstitial granulomatous infiltrates of lymphocytes, histiocytes, and eosinophils palisading around degenerated collagen. Withdrawal of the anti-tnf agent led to complete resolution of the skin lesions. 91,92 It is likely that IGD represents a reactive phenomenon with a spectrum of histopathologic features and possible associations with numerous disorders, including autoimmune diseases (RA), lymphoproliferative disorders, and drug reactions. 92 The close temporal relation, however, between IGD development and anti-tnf administration, as well as the resolution of the dermatosis upon drug discontinuation, support an inducing or triggering role of anti-tnf therapy in the development of IGD. On the other hand, infliximab has been successfully used in one patient with IGD, although spontaneous regression of IGD could not be excluded in this case. 93 In addition, 9 cases of disseminated granulomas annulare (2 with infliximab, 6 with adalimumab, 1 with etanercept) have been documented during anti-tnf therapy in 197 RA patients. The lesions were successfully treated with topical corticosteroids, and treatment discontinuation was necessary in only two patients. 94 Cutaneous infections It is uncertain to what extent treatment with anti- TNF agents for RA is associated with increased risk of serious infections, given the fact that the incidence rate of infections in the RA population is nearly twice as high as in matched non-ra controls. 95 Studies in patients with RA have been inconsistent, with some showing an elevated risk of infection with anti-tnf agents and others failing to demonstrate any association. 55, As highlighted in recent meta-analyses of randomized controlled trials of anti-tnf agents in RA and psoriasis, comparative data on cutaneous infections are lacking in most publications In a retrospective study of 709 patients treated with a TNF-blocker for RA, spondyloarthropathy, or other inflammatory disorder, skin infections comprised 21% of all diagnosed infections, which were caused by bacteria in 53%, viruses in 30.5%, and fungi in 6.5% of cases. In cases with serious infections, the most frequent sites of involvement were skin and skin-associated tissues (40.4%). The two reported cases of mycobacterial infections

11 496 Moustou et al SEPTEMBER 2009 occurred with infliximab therapy, one of which was a cutaneous non-tuberculosis mycobacterial infection. Regarding infection site patterns of the 3 TNF-blockers, skin localization was more frequent for infliximab (11.6% of infliximab treatment courses) and adalimumab (6.6% of adalimumab treatment courses). 99 In a study of 150 patients with rheumatic diseases receiving anti-tnf-alfa therapy, 35 patients experienced cutaneous side effects, among whom 13 patients were diagnosed with an infectious skin disease, mainly of fungal and bacterial etiology. Those patients included 3 cases of pityriasis versicolor, 3 cases of tinea corporis, 1 case of herpes simplex reactivation, 5 cases of microbial eczema, and 1 case of an acute cutaneous staphylococcal infection. These infections were mild and easily controlled by appropriate treatment. 45 Moreover, a patient treated with infliximab for RA developed a fatal necrotizing fasciitis by b-hemolytic group A streptococcus isolated from blood cultures andskinswabs. 105 An invasive Trichophyton rubrum infection occurred in a patient treated with infliximab and oral prednisone, which highlights the need of a thorough cutaneous examination of the patient for signs of dermatophytosis before TNF-alfa inhibitors are initiated. 106 A prospective observational study of 7664 anti-tnf-treated patients versus 1354 patients with RA treated with disease-modifying antirheumatic drugs (DMARDs) showed a 4-fold increased risk of serious skin and soft tissue infections in the anti-tnf-treated group. There was no difference in infection risk among the 3mainanti-TNFdrugs. 100 It is interesting that anti- TNF therapy was not associated with an increased risk of overall serious infections compared with DMARD treatment. The authors suggested that TNF may act differentially at different anatomic sites. Similarly, in a prospective controlled nonrandomized study of the frequency of infections in approximately 900 patients with RA who received TNF inhibitors (infliximab or etanercept) versus 601 patients who received DMARDs, a significantly increased risk of skin and subcutaneous tissue infections in patients receiving TNF inhibitors was observed. The total rate of bacterial skin infections was significantly higher in the TNF group, including erysipelas, furuncles, abscesses, and paronychia. In addition, there were 3 fungal skin infections, 10 mild to moderate herpes simplex skin infections, and 10 herpes zoster skin infections in the anti-tnf-treated group. 107 In addition, cases of serious cellulitis have been reported in randomized controlled trials of infliximab and etanercept and a case of varicella zoster virus infection was reported with infliximab Atypical mycobacterial infections of the skin have also been reported, including two cases of cutaneous Mycobacterium marinum infection that developed during infliximab treatment for ankylosing spondylitis and Crohn s disease, respectively. Interestingly, the first case was receiving isoniazid for latent tuberculosis, which is ineffective in preventing M marinum infection. The patient was successfully treated with rifampicin and ethambutol for 8 months, while continuing on infliximab therapy. 111,112 There are few data concerning cutaneous infections in psoriatic patients treated with anti-tnf therapy. Similar rates of infections have been reported in patients with psoriasis treated with infliximab versus placebo. 113 Clinical studies of infliximab and etanercept in psoriatic patients reported mild cutaneous infections, including lower leg and breast cellulitis, furuncles, and cutaneous abscesses. 114,115 In addition, a cutaneous Cryptococcus albidus infection has been reported in a 14-year-old boy after 8 months of etanercept therapy for psoriasis. The infection presented as an inflamed, tender lesion on his scalp with drainage of purulent material, and no systemic symptoms. A fungal culture was negative, but a deep culture revealed an infection by the yeast C albidus, which resolved after etanercept discontinuation and oral fluconazole administration. 116 Case reports of human papillomavirus recurrence and molluscum contagosium appearance have also been described with infliximab treatment in psoriatic patients. 117 Cutaneous lymphomas An increased incidence of lymphomas in patients with autoimmune disorders, such as RA, subjected to anti-tnf agents has been shown in some studies, while other studies have failed to provide supportive evidence of such an association Patients with psoriasis or RA both carry an increased risk of lymphomas, in comparison with the general population, and the increased frequency of lymphomas that has been reported in patients with RA treated with anti-tnf agents may reflect the severity of the disease which could be associated with greater TNF-alfa activity Chronic inflammation, leading to an altered state of immune regulation, and previous immunosuppressive therapies (e.g., azathioprine, cyclophosphamide, methotrexate) are known to increase the risk of lymphoproliferative disorders, especially non-hodgkin s lymphoma. 120 Therefore, it is very difficult to assess the actual contribution of anti-tnf therapy to the potential causality of lymphomas in these patients. There are few reports on the possible association of TNF-blocking agents with primary cutaneous

12 VOLUME 61, NUMBER 3 Moustou et al 497 lymphomas. Since no cutaneous B-cell lymphomas have been described, all reported cases consisted of cutaneous T-cell lymphomas. Mahe et al 125 described a case of CD301 T-cell lymphoma presenting after treatment of erythrodermic psoriasis with a combination of cyclosporine and 3 infusions of infliximab. Adams et al 126 reported one case of CTCL that developed in a patient who had been treated for 18 months with etanercept for psoriatic arthritis, as well as a case of systemic anaplastic largecell lymphoma with cutaneous involvement that developed after 3 doses of infliximab and concomitant treatment with 6-mercaptopurine for a presumptive diagnosis of early Crohn disease. Both cases were characterized by rapid onset, extensive cutaneous and systemic involvement, and a fulminant clinical course which led to death within months of diagnosis. In addition, there was one case of atypical CD81 CTCL presenting after treatment with infliximab, 127 and a patient with a lymphomatoid papulosiselike eruption that developed after 2 months of adalimumab therapy and disappeared within 6 weeks after adalimumab withdrawal (interestingly, the patient subsequently developed a large-cell anaplastic non-hodgkin lymphoma). 38 Other reports include one case of mycosis fungoides in a patient during the second year of infliximab therapy for ankylosing spondylitis, 128 one case of Sézary syndrome occurring 17 months after the onset of infliximab therapy for ankylosing spondylitis, 129 and one case of mycosis fungoideseassociated follicular mucinosis following a 7-month treatment with adalimumab for ankylosing spondylitis. There was improvement with discontinuation of adalimumab, and treatment with retinoids and PUVA therapy. 130 Non-melanoma skin cancers Non-melanoma skin cancers (basal cell and squamous cell carcinomas) and precancerous skin lesions such as actinic keratoses and Bowen s disease have been noted in RA patients receiving anti-tnf therapy. 38 In addition, rapid development of multiple keratoacanthomas and squamous cell carcinomas have been described in patients with RA and psoriasis following the initiation of either etanercept or infliximab Nevertheless, the relationship between the administration of anti-tnf agents and cutaneous carcinogenesis remains an issue of debate. In an open-label study of Klareskog et al, 134 comprising 549 patients with RA receiving etanercept, no increased risk of skin cancer was documented within an extended 5-year follow-up period. Other studies based on retrospective analysis of clinical trials of etanercept and post marketing surveillance databases have supported these findings, showing a comparable incidence of SCC in etanercept-treated patients and in the general population. 135 Moreover, experimental studies in animal models showed that the inhibition of TNF does not promote skin carcinogenesis, but, instead, may impede tumorigenesis and have a protective action. 124,136,137 In a large US cohort of 15,789 patients with RA, compared with 3639 patients with osteoarthritis, a small but significant increased hazard (hazard ratio [HR],1.19) of developing NMSC was noted in RA patients compared with those with osteoarthritis, suggesting that the underlying disease itself and the degree of associated inflammation may predispose to skin cancer. 138 When examining possible associations between immunosuppressive agents and NMSC in their RA cohort, the authors observed an increased risk of NMSC with prednisone use (HR, 1.28) and a similar trend with TNF inhibitors (HR, 1.24), particularly when combined with methotrexate (HR, 1.97). It remains, however, unclear whether this increased risk of NMSC is a function of immunosuppression or relates to the increased inflammatory activity of the underlying disease. It is obvious that, in this context, a clear causal association between anti-tnf therapy and the development of NMSC cannot be established. Furthermore, most previous findings have been reported on patients with RA, and caution should be taken when extrapolating these results to the population with psoriasis. It is well known that patients with psoriasis have a higher risk of skin cancer, largely because of previous carcinogenic treatments and their cumulative toxicities. In a randomized placebo-controlled trial of infliximab in psoriasis, 10 NMSCs (1 squamous cell carcinoma and 9 basal cell carcinomas) were reported, all in the infliximab groups. 22 A previous exposure to phototherapy was reported in all affected patients. In another randomized trial using etanercept in plaque-type psoriasis, 14 NMSCs were observed in 10 patients, half of whom had been previously exposed to UVB or PUVA. However, the incidence of NMSC was not statistically significant compared to the expected incidence in the psoriatic population. 139 Until further analysis of long-term data from clinical trials and post-marketing surveillance is available, skin cancer screening at regular intervals has been suggested for patients with psoriasis receiving anti-tnf therapy, particularly those with severe actinic damage, a history of multiple ([2) skin cancers, especially SCCs, and a record of high cumulative doses of PUVA therapy, given the previous example of enhanced PUVA-induced skin carcinogenesis by cyclosporine. 140

13 498 Moustou et al SEPTEMBER 2009 Melanoma The development or recurrence of melanoma is a potential concern in patients undergoing immunosuppressive therapy, particularly in the post-transplantation setting. 141,142 Fulchiero et al 143 reported two cases of late recurrence of eruptive locoregional recurrences occurring 6 and 9 years after surgical excision of a stage IB and IA melanoma, respectively. Each case occurred within 90 days after initiation of etanercept and adalimumab, respectively, suggesting that the inhibition of active immune surveillance by TNF inhibitors may augment malignant cell proliferation in previously treated melanomas. Despite the margin of safety related to a distant history of melanoma, disease reactivation or recurrence with anti-tnf therapy remains a possibility in patients with a previous diagnosis of melanoma. In addition, Gordon et al 35 reported the development of melanoma (Breslow thickness, 0.51 mm) 25 weeks after the initiation of adalimumab treatment in a psoriatic patient with a history of PUVA exposure. Interestingly, a recent report by Bovenschen et al 144 described the occurrence of eruptive nevomelanocytic nevi on the palms and soles of two patients with Crohn s disease, treated with a combination of azathioprine and infliximab. In a third case, a patient with plaque-type psoriasis developed eruptive nevi during two episodes of treatment with alefacept and etanercept, respectively. Although more commonly seen in posttransplant patients under immunosuppressive regimens, 145 the development of eruptive nevi arising in the context of biologic therapy for psoriasis is possible. DISCUSSION The advent of new anti-tnf agents has revolutionized our therapeutic approach to chronic inflammatory diseases. As these agents become widely used in clinical practice, cutaneous adverse events are being increasingly recorded, including infusion and injection site reactions, psoriasis and psoriasiform eruptions, autoimmune skin disorders, vasculitis, granulomatous reactions, and cutaneous infections. Several limitations make it difficult to assess the direct contribution of anti-tnf therapy to the potential causality of reported skin conditions. Although there are many randomized controlled studies in the literature focusing on the efficacy and safety of infliximab, etanercept, and adalimumab, only a few provide details concerning the observed cutaneous adverse events. Moreover, most data relate to patients with rheumatologic conditions that may have different characteristics from patients with psoriasis, such as baseline risk of immune reactions, lymphomas or infections, reaction to treatment, or previous immunosuppressive treatments. Retrospective studies include patients that are not always homogeneous with regard to the underlying disease, the dosage regimen used, or the treatment duration. In addition, data on cutaneous lymphomas, epithelial skin cancers, and melanoma mainly derive from isolated case reports which could detect events related to the disease or to previous carcinogenic or immunosuppressive treatments rather than the anti-tnf agent per se. Therefore, there is a strong need for continuous vigilance, long-term surveillance, and systematic reporting of any suspected association of cutaneous events with TNF-blocking therapies in order to document a causal relationship. In addition to reviewing the reported cutaneous adverse events, we attempted a critical consideration of the strength of association between a given event and the use of an anti-tnf agent. Several criteria were used, based on the type of study reporting the specific event, the number of anti-tnf agents involved, the type of inflammatory diseases in which the reaction had occurred, and the outcome upon withdrawal of or re-challenge with anti-tnf therapy. With the exception of infusion and injection site reactions that were definitely associated with the use of infliximab and adalimumab and etanercept respectively, the strongest associations ( $ 3 criteria) were suggested for psoriasis and psoriasiform-like lesions, lupus-like syndromes, cutaneous vasculitis, and cutaneous infections. A moderate association ( $ 2 criteria) was apparent between anti-tnf treatment and eczematous reactions, lichenoid disorders, and granulomatous reactions, although additional data are necessary to confirm this relationship. Furthermore, the scarce data on cutaneous lymphomas, epithelial skin cancers, and melanoma, do not support a clinically meaningful link between anti- TNF treatment and skin cancer. Our classification of events based on the strength of association does not conform to the stringent criteria and statistical workup of a meta-analytical study. However, it does provide a useful evidence-based approach that will aid the practicing dermatologist in defining the probabilities of association of a given cutaneous reaction with anti-tnf therapy. It is also important to emphasize that our investigation was based on current literature and that the reported associations may change in the future, as more evidence and experience are accumulated with the use of anti-tnf agents in clinical practice. Given the regulatory role of TNF in various immunologic functions, several authors have proposed potential pathophysiologic mechanisms in an effort to interpret the development of cutaneous adverse reactions. For most reactions, however, the