The past several decades have seen the advent and rapidly expanding use of biological agents in the treatment of chronic disease states. As increasingly large pools of patients have been enrolled in treatment protocols using these agents, physicians have become acquainted with both desired and adverse events associated with their use. Dermatologists frequently encounter patients affected by cutaneous drug reactions associated with the use of biological agents, thereby becoming familiar with the full range of side effects reported in the literature. This review discusses these adverse cutaneous effects, their underlying mechanisms, and efforts to predict and minimize their occurrence.
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More than 2 decades have passed since the Food and Drug Administration approval of muromonab-CD3 (Orthoclone OKT3) ushered in the era of monoclonal antibody therapy for the treatment of human disease.
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Despite having relatively favorable safety profiles overall, these drugs are not without potential side effects, some of which are occasionally severe enough to prompt discontinuation of the drug.
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The market for tumor necrosis factor α (TNFα) inhibitors is currently occupied by 4 monoclonal antibodies (adalimumab, infliximab, certolizumab pegol, and golimumab) directed against the TNFα protein, and 1 TNF-receptor fusion protein (etanercept).
Introduction
The past several decades have seen the advent and rapidly expanding use of biological agents in the treatment of chronic disease states ranging from organ transplant rejection to rheumatoid arthritis and lymphoproliferative disorders. As increasingly large pools of patients have been enrolled in treatment protocols using these agents, physicians have become acquainted with both desired and adverse events associated with their use. Dermatologists frequently encounter patients affected by cutaneous drug reactions associated with the use of biological agents, and should therefore be familiar with the full range of side effects that have been reported in the literature. This review discusses these adverse cutaneous effects, their underlying mechanisms, and efforts to predict and minimize their occurrence.
Adverse reactions to monoclonal antibodies
More than 2 decades have passed since Food and Drug Administration (FDA) approval of muromonab-CD3 (Orthoclone OKT3) ushered in the era of monoclonal antibody therapy for the treatment of human disease. With the introduction of infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira) to inhibit activity of tumor necrosis factor α (TNFα), physicians augmented their armamentarium in the battle against autoimmune diseases such as rheumatoid arthritis (RA), Crohn disease, and psoriasis. Monoclonal antibodies directed against vascular endothelial cell growth factor (VEGF) (bevacizumab), ErbB2 (trastuzumab), and CD20 (rituximab) have joined the anti-TNFα agents as the most extensively prescribed drugs in this class, which together account for some of the top-selling biotechnology drugs. To date more than 20 monoclonal antibody therapies have been approved for use by the FDA.
Despite having relatively favorable safety profiles overall, these drugs are not without potential side effects, some of which are occasionally severe enough to prompt discontinuation of the drug. Although adverse reactions affecting the skin are usually tolerated sufficiently to allow continued use, they can be distressing to the patients, who will often seek the attention of their physician(s). As a consequence it is important that rheumatologists and dermatologists who might encounter these adverse reactions in their clinical practice be familiar with the incidence and, when known, the pathogenesis of these reaction processes. In many cases, the adverse reactions fall under the rubric of a “class effect” and can therefore be expected from any of the agents using the same mechanism of action, whereas in other cases there appear to be reaction patterns that are specific to individual agents that are rare or unreported with remaining members of the class. This article reviews the reaction patterns observed across the broad range of biologics in use currently, while discussing possible underlying mechanisms and efforts to minimize their occurrence.
TNFα Inhibitors
The market for TNFα inhibitors is currently occupied by 4 monoclonal antibodies (adalimumab, infliximab, certolizumab pegol, golimumab) directed against the TNFα protein, and 1 TNF-receptor fusion protein (etanercept). These medications are used to treat a broad range of autoimmune conditions including psoriasis, RA, Crohn disease, ankylosing spondylitis, and various off-label conditions.
Injection-site and infusion reactions
The most common dermatologic complaint associated with the use of monoclonal antibodies is the injection-site reaction defined by edema, erythema, pruritus, and/or pain. The incidence of injection-site reactions ranges from 3% to 49%, and appears to be a function of both the specific anti-TNFα agent used and the underlying disease process. These studies indicate that RA patients, especially those treated with etanercept, are at significantly increased risk of developing injection-site reactions in comparison to patients with psoriasis or Crohn disease. While patients typically experience a decrease in frequency and severity of injection site reactions over the course of treatment, worsening reactions with continued administration are reported. Histologically, infiltrates of CD8 + T cells characterize the primary and recurrent reactions, consistent with a type IV delayed hypersensitivity reaction.
Infusion reactions include pruritus, urticaria, chills/fevers, anaphylaxis, and vital-sign alterations that occur, by definition, within 2 to 24 hours following infusion of the drug. Rates of infusion reactions with TNFα inhibitors range from 3% to 24%, depending on the trial and the disease under treatment. Pretreatment with corticosteroids in an effort to reduce infusion reactions appears to have little value, and may even have the paradoxic effect of increasing rates of infusions reactions. Instead, regular administration without prolonged interdose intervals seems to be the most effective means of preventing antibody formation leading to infusion reactions.
Infections
Numerous case reports have surfaced that suggest an association between infections and the use of TNFα inhibitors. Both systemic and cutaneous infections have been observed, suggesting that immunosuppression related to anti-TNFα therapies renders patients more susceptible to infectious pathogens. However, RA patients, one of the major patient demographics receiving TNFα inhibitors, exhibit higher infection rates compared with the general population, which may account for some of the observed infectious complications. That said, comparison between RA patients using anti-TNFα antibodies and those prescribed other disease-modifying antirheumatic drugs (DMARDs) revealed an adjusted relative risk of 4.28 (95% confidence interval, 1.06–17.17). Lee and colleagues reported 13 patients (of 150 in total) who developed cutaneous infections while on infliximab, adalimumab, or etanercept, which included pityriasis versicolor, tinea corporis, impetiginized eczema, herpes simplex, and Staphylococcus aureus .
Fungal, bacterial, and viral infections have all been reported at higher rates in patients using anti-TNFα agents, but none severe enough to require hospitalization. A study of 500 patients using infliximab described 48 patients with infectious events including cases of abscesses, upper respiratory tract infections, pneumonia, cellulitis, shingles, chicken pox, genital herpes, and candidal onychomycosis. As regards viral infections, a prospective cohort study comparing monoclonal anti-TNFα antibodies, etanercept, and DMARDs indicated a statistically significant increased risk for herpes zoster specific to the monoclonal agents, although the investigators considered that the risk fell below the level of clinical significance. Psoriasis patients treated with etanercept also experienced an increased incidence of viral warts. An important side effect directly linked with TNFα blockade therapy is the development of reactivated pulmonary tuberculosis, hence a relative contraindication to the use of the drug is a positive purified protein derivative test.
Inflammatory reactions of the skin
A broad range of inflammatory reactions of the skin has been reported in patients with TNFα blockade. Infliximab-induced acne is reported ( Fig. 1 ) New-onset dermatitis herpetiformis, alopecia areata, pityriasis rosea, and dermatitis sicca (anhidrosis) have been reported with use of various TNFα inhibitors, typically within the first year of initiating treatment. Leukocytoclastic vasculitis, lichenoid drug reactions, perniosis-like eruptions, superficial granuloma annulare, and acute folliculitis following infliximab therapy were reported in patients treated for Crohn disease or RA. Eczema, including dyshidrotic, nummular, contact, papular, and unspecified types, has also been associated with the use of infliximab and etanercept ( Fig. 2 ). Lichenoid reactions have been noted with the entire range of TNF-blocking agents ( Fig. 3 ).
Several case reports suggest a relationship between the development of palisading neutrophilic and granulomatous dermatitis and TNFα-inhibitor therapy ( Fig. 4 ). It has been proposed that TNFα inhibition initiates a leukocytoclastic vasculitis, possibly through interference with self-tolerance mechanisms or immune complex formation, which is followed by a granulomatous inflammatory process. Some investigators have postulated a granulomatous koebnerization in those cases associated with underling RA. Among the granulomatous infiltrates associated with TNFα therapy are rheumatoid nodules, interstitial granulomatous dermatitis, granuloma annulare, and sarcoid-like granulomas.
There have been 5 reported cases of erythema multiforme–like reactions to TNFα inhibitors, after which the offending medication was stopped and the patients’ lesions resolved with topical and oral steroids. The authors have encountered an adalimumab-triggered lymphocytic interface dermatitis mimicking erythema multiforme histologically in a patient with a drug-induced lupus-like symptom complex associated with a positive lupus band test ( Fig. 5 ); this histology mimics acute lupus erythematosus. One case of an eosinophilic cellulitis–like reaction following etanercept and one associated with adalimumab have also been reported.
Cutaneous neoplasms
Immunosuppressed patients experience an increased incidence of cutaneous neoplasms including melanoma, nonmelanoma skin cancer (NMSC), and cutaneous lymphoproliferative disorders. It has been postulated that the immunomodulatory effects of TNFα inhibition might effect an increase in rates of skin cancers among patients requiring long-term therapy. TNFα was initially identified as a potent proapoptotic signal for tumor cells. Animal studies in rats have indicated that anti-TNFα antibodies interfere with antitumor immune surveillance in response to implanted tumor cells that are otherwise robustly attacked in untreated animals. Similar results were obtained with the use of TNF knockout mice.
These findings suggest that antitumor surveillance mechanisms in humans might also be impaired by the chronic administration of anti-TNFα agents. The challenge in addressing the question of iatrogenic neoplasms resulting from anti-TNFα therapy remains the documented predisposition for malignancies associated with the underlying diseases. Sporadic case reports have laid claim to an association between TNFα inhibitors and the development of NMSCs and cutaneous lymphoproliferative disorders. Animal studies, however, have not borne out the association between de novo neoplasms and loss of TNFα, suggesting that the associations observed clinically may arise from susceptibilities independent of anti-TNFα therapy, and that the induced loss of immune surveillance creates a permissive environment that coincides with the inherently proneoplastic nature of the diseases being treated.
Infliximab has been associated with acute development of keratoacanthoma and squamous cell carcinoma (SCC), and rapid onset of SCCs has been noted following use of etanercept. The question of whether this implies promotion of underlying precancerous lesions or de novo carcinogenesis was brought into focus by a report describing basal cell carcinoma (BCC) and SCC in psoriasis patients with extensive prior exposure to light therapy who later began anti-TNFα therapy. A large national cohort study of RA patients showed an elevated risk for development of NMSC that was most closely associated with use of prednisone or TNFα inhibitors alone or with concomitant methotrexate. As is often the case, however, reports have surfaced that argue against such associations. A meta-analysis of randomized controlled trials using TNFα inhibitors in psoriasis patients (N = 6810) did not confirm an increased risk of malignancy. Lebwohl and colleagues also reported no evidence for increased risk of cutaneous SCC in patients receiving etanercept for up to 5 years. Aside from BCC and SCC, a single case of Merkel cell carcinoma has been reported in the context of adalimumab, methotrexate, and prednisone administration for RA.
In addition to the reports of NMSCs, there have been occasional reported cases of associated melanoma. In 2 patients with a remote history of surgically excised melanoma there was a late recurrence (6 and 9 years after excision) of eruptive locoregional metastases following the initiation of etanercept and adalimumab, respectively. Late recurrence of melanoma, however, is part of the natural history of melanoma, and whether this phenomenon can be attributed to TNFα inhibition in such cases is questionable. Although melanomas have been reported in patients with RA and Crohn disease receiving TNFα inhibitors, strong evidence for a causal association is lacking.
Other forms of melanocytic proliferation influenced by anti-TNFα therapy include cutaneous nevi associated with infliximab therapy in the setting of Crohn disease and eruptive melanocytic nevi associated with use of infliximab and etanercept in Crohn disease and psoriasis, respectively. Balato and colleagues extended the hypothesis that the proinflammatory cytokine milieu of psoriasis might establish relative inhibition of melanogenesis and melanocyte growth in light of the reduced incidence of pigmented lesions in these patients. If true, it is possible that initiation of TNFα inhibitors releases this inhibitory state and restores a native level of melanogenesis and melanocyte proliferation that is, by comparison, hyperactive.
Lymphoproliferative disorders are also among the list of cutaneous neoplasms reported in patients using TNFα inhibitors. Among these are reports of cutaneous γδ T-cell lymphoma in an RA patient using etanercept, mycosis fungoides (MF) in 2 patients using etanercept and infliximab, CD30 + T-cell lymphoma following cyclosporin and infliximab, MF-associated follicular mucinosis after 7 months of adalimumab, CD8 + cutaneous T-cell lymphoma with infliximab, Sezary syndrome associated with infliximab and etanercept, and cutaneous anaplastic large cell lymphoma following infliximab. Because of their inherent rarity and the small number of case reports available, the association between TNFα inhibitors and cutaneous T-cell lymphoma is tenuous. No large-scale trials have addressed this question.
Although additional investigation is required to establish a concrete link between cutaneous malignancies and the use of TNFα inhibitors, many of the alternative treatments for the intended patient population (eg, psoriasis patients) have well-established risks of malignancy with long-term use (eg, photochemotherapy, methotrexate, mycophenolate mofetil).
Other cutaneous reactions
Not infrequently, patients develop autoantibodies during their course of TNFα blockade. Following 6 months of treatment with etanercept or infliximab, 11% and 34% of patients, respectively, developed antinuclear antibodies. Anti–double-stranded DNA antibodies were found in 15% of patients taking etanercept and in 9% of patients using infliximab. Perhaps it is not surprising, then, that there are reports of patients developing systemic lupus erythematosus while on etanercept, sometimes with cutaneous involvement. There have been similar reports of new-onset cutaneous lupus with the use of infliximab and adalimumab. Meta-analysis of several hundred reported cases of autoimmune diseases associated with TNFα inhibitors revealed that cutaneous vasculitis, lupus-like syndromes, systemic lupus erythematosus, and interstitial lung disease were the most common. Dermatomyositis has also been reported in association with TNFα inhibition.
The anti-TNFα agents appear to have a negative impact on the control of psoriasis in some patients. Case reports of worsening or new-onset psoriasis are not infrequent in the TNF-inhibitor literature. A retrospective analysis of 12 years’ experience at the Mayo Clinic showed 56 patients with either new-onset psoriasis or exacerbation of underlying psoriasis who were treated with infliximab, adalimumab, or etanercept for Crohn disease or RA. New-onset psoriatic palmoplantar pustulosis has also been noted in 2 patients treated with infliximab for RA. Certolizumab for Crohn disease has been associated with development of psoriatic lesions. Cytokine imbalance with increased levels of interferon-α (IFN-α) has been proposed as a possible pathogenetic mechanism.
Interleukin-2 Inhibitors
To date there are 3 biological agents designed to target interleukin (IL)-2 signaling. Basiliximab (Simulect) is a chimeric mouse-human monoclonal antibody directed against the IL-2 receptor α subunit (CD25), used to prolong renal allograft survival. Daclizumab (Zenapax) is a humanized monoclonal antibody that targets the same α subunit of IL-2 receptor. Denileukin diftitox (Ontak) is an engineered protein, used in some cases of T-cell and B-cell lymphoma and advanced melanoma, which combines IL-2 with diphtheria toxin, thereby killing cells bearing IL-2 receptors that bind and internalize the toxin. Reports of cutaneous reactions to administration of these agents are sparse in the literature, perhaps reflecting a relatively benign profile as regards skin biology, but it is conceivable that basiliximab played a role in the pathogenesis of nephrogenic fibrosing dermopathy in 2 liver transplant patients.
A small dose-escalation study using denileukin diftitox reported a 14% incidence of generalized maculopapular/vesicular rashes and a single case of mild vascular leak syndrome. Capillary leak syndrome presenting with facial erythema and edema has been previously reported with denileukin diftitox, and presents in a manner similar to that seen with IL-2 immunotherapy for cancer. Pretreatment with corticosteroids appears to be effective in reducing the frequency of this complication. There has also been a report of a fatal rash consistent with toxic epidermal necrolysis occurring in a patient with follicular large-cell lymphoma receiving denileukin diftitox.
CD20 Inhibitors
Currently there are 3 FDA-approved monoclonal antibodies directed against the B-cell antigen CD20: rituximab (Rituxan), ibritumomab tiuxetan (Zevalan), and tositumomab (Bexxar). Of this class, rituximab has been most often reported to have significant adverse cutaneous reactions, although the remaining 2 agents have been available for a shorter period and have a less extensive history to mine for potential reactions.
Infusion reactions
Urticaria appears to be a common side effect in patients receiving rituximab, with incidence ranging from 3% to 14% in clinical trials. Severe infusion reactions have also been noted.
Infections
While systemic infectious complications have been reported in association with the use of rituximab, specific mention of cutaneous infections has been largely absent. Of the handful of cutaneous infections reported in patients treated for non-Hodgkin lymphoma, herpes simplex and herpes zoster constituted the majority.
Cutaneous malignancies
Associated malignancies with rituximab included reports of 6 BCCs, 2 SCCs, and 2 melanomas in a group of 1039 patients undergoing treatment for RA. Merkel cell carcinoma has also been reported in a patient using rituximab.
Other adverse cutaneous reactions
Although it appears to be a rare occurrence, there is a report of a patient experiencing Stevens-Johnson syndrome characterized by grade 1 mucositis after treatment with rituximab, which persisted for over a year until the patient’s death. Although there have yet to be any reports in humans of toxic epidermal necrolysis (TEN) with rituximab alone, reactions consistent with this classification have been observed in rhesus macaques following administration. There have been postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, TEN, bullous dermatitis, and exfoliative dermatitis in patients receiving the combined regimen of radiolabeled ibritumomab with rituximab (ie, the Zevalin therapeutic regimen).
CD30 Antagonists
Brentuximab is a chimeric monoclonal antagonist of the CD30 molecule and is used in CD30 + lymphoproliferative lesions. A patient with CD30 + anaplastic large-cell lymphoma developed an eczematous eruption while on brentuximab ( Fig. 6 ).
VEGF Inhibitors
Bevacizumab (Avastin) and ranibizumab (Lucentis) comprise the family of monoclonal antibodies currently approved to target VEGF in the treatment of various cancers, macular degeneration, and diabetic retinopathy. The bulk of reported reactions have been for the parent drug bevacizumab while the affinity-matured Fab fragment, ranibizumab, has comparatively few reports of adverse cutaneous effects to date. Among the dermatologic complaints in patients using bevacizumab, general rash is the most commonly reported. More specific classification of skin reactions includes reports of papulopustular eruptions, perforating dermatosis, and cutaneous lupus erythematosus. There has also been a report of impaired wound healing and skin-flap necrosis in a patient taking paclitaxel and bevacizumab after undergoing mastectomy for locally advanced breast cancer. An episode of acute generalized exanthematous pustulosis was reported in association with ranibizumab following intravitreal administration.
Epidermal Growth Factor Receptor Inhibitors
Monoclonal antibodies currently FDA approved for clinical use in targeting the epidermal growth factor receptor (EGFR) include cetuximab (Erbitux) and panitumumab (Vectibix). Both are indicated for metastatic colorectal cancer, and cetuximab is additionally approved for treatment of recurrent or metastatic SCC of the head and neck. The majority of the cutaneous reactions reported have been associated with cetuximab. The most common of these are eruptions of acneiform and rosaceiform lesions that serve as surrogate markers of tumor response. One report demonstrated the presence of coagulase-positive Staphylococcus infection in association with a papulopustular drug eruption. There have also been reports of eyelash trichomegaly, xeroderma pigmentosum, Grover disease, ecthymatous skin eruption, cicatricial ectropion, paronychia, and severe radiation dermatitis/TEN-like reactions. Panitumumab has also been associated with similar acneiform, papulopustular eruptions, but few reactions apart from this have been reported. Dose-escalation studies with cetuximab suggested that severity of skin reactions did not follow a dose-sensitive distribution. While both antibodies target the same effector molecule, there have been reports of differences in the patterns of toxicity seen for each agent when administered sequentially, suggesting possible non–class effect cutaneous toxicities.
Efalizumab (Raptiva)
Efalizumab targets the CD11a antigen involved in cellular adhesion and costimulatory signaling between leukocytes. Compared with several of the monoclonal agents discussed previously, efalizumab has low reported rates of infusion reactions. Its administration has been associated with increased incidence (in the range of ∼3%) of herpes infections. CD11a is one of the variable α-chain components of the leukocyte function–associated antigen (LFA)-1, which plays an important role in antibody-dependent cellular cytotoxicity directed against herpes-infected cells. Cell-culture studies have shown that monoclonal antibodies directed against CD11a, but not CD11b or CD11c, inhibit the early phase of the IFN-α response normally generated by exposure to herpes virus, suggesting a potential mechanism behind the increased incidence of herpetic lesions in patients using efalizumab. Along similar lines, there has been a report of disseminated eruptive giant molluscum contagiosum in a psoriasis patient using efalizumab. A small increase (∼1%) in the rate of impetigo and cellulitis has also been observed.
Efalizumab has been reported to increase the rate of acne compared with placebo (4% vs 1%) in a large double-blind study comprising 1928 patients. In addition to the adverse effects reported in larger studies, there have been specific reports of efalizumab-induced subacute cutaneous lupus erythematosus, DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome, dermatitis/lichen simplex chronicus, exacerbation of pityriasis rubra pilaris, eruptive seborrheic keratoses, eruptive dermatofibromas, and guttate psoriasis.
Efalizumab is approved for the treatment of psoriasis, so it has been a point of special interest among clinicians and researchers that subsets of patients using the agent develop de novo psoriatic lesions or experience worsening of preexisting psoriasis (ie, rebound psoriasis). Numerous placebo-controlled trials with large patient populations have reported psoriasis-related adverse events in 2.2% to 13.6% of patients, which frequently exceeds the rates reported for placebo (ranging from 0.8% to 11.2%). A unique type of inflammatory reaction has also been reported with the use of efalizumab in psoriasis patients resulting in the formation of eruptive papules composed of CD11b + , CD11c + , and inducible nitric oxide synthase–positive myeloid leukocytes with minimal CD3 + cells. It was proposed that these lesions arise from the expression of alternative β2 integrins that alter trafficking of circulating leukocytes to the skin.
Alefacept (Amevive)
Alefacept is an immunoglobulin G (IgG)1–LFA-3 fusion protein used in the treatment of chronic plaque psoriasis. It compares favorably with the anti-TNFα agents with regard to infusion reactions, with rates reported up to 8% higher than with placebo. Marketing studies of 1869 patients associated alefacept with NMSCs, including BCCs (n = 20) and SCCs (n = 26), in addition to a small number of melanomas (n =3). A smaller study with 201 patients reported 3 patients with BCC and 1 with SCC. Schmidt and colleagues reported the development of transformed MF after treatment with alefacept. Similar to several of the anti-TNFα agents, there have been reports of associated eruptive benign melanocytic nevi.
Trastuzumab (Herceptin)
Trastuzumab is a humanized monoclonal antibody that targets the HER2/neu receptor, the product of a gene (ERBB2) commonly overexpressed in a subset of aggressive breast cancers. As with many of the monoclonal therapies, infusion reactions are not uncommon. Although it is often used in concert with radiation therapy in the treatment of breast cancer, it does not appear that trastuzumab contributes significantly to rates of dermatitis beyond levels associated with radiation therapy alone. Several reports have surfaced regarding photosensitivity in combination with the taxane class of chemotherapeutics, although photosensitivity has been observed with taxanes in isolation. Tufted folliculitis of the scalp with scaling and pruritus was also reported in a patient following the transition from doxorubicin and cyclophosphamide to trastuzumab.
Alemtuzumab (Campath)
Mature T and B lymphocytes express CD52, a glycosylphosphatidylinositol-anchored antigen that serves as the target of the monoclonal antibody, alemtuzumab, in the treatment of lymphoproliferative disorders. Various reports have implicated alemtuzumab in disseminated molluscum contagiosum, generalized herpes simplex, varicella zoster, sarcoidosis, and acute CD30 + transformation of cutaneous T-cell lymphoma in a manner reminiscent of Richter syndrome.
Natalizumab (Tysabri)
Natalizumab is a humanized antibody directed against α4-integrin, an important cellular adhesion molecule target in the treatment of multiple sclerosis and Crohn disease. While there have been reports of generalized drug eruptions and severe cutaneous candidal infection in patients using natalizumab, perhaps the most striking adverse cutaneous effect involves the controversy surrounding accelerated evolution of nevi into melanoma. Studies performed more than a decade ago implicated α4-integrin expression at the primary tumor site as an important inhibitor for dyshesive growth. At the same time, however, once metastatic cells are present in the blood, α4-integrin expression appeared to aid in transendothelial migration at specific tissues. Future studies will likely clarify the potential risks posed by natalizumab therapy with regard to development and progression of melanoma. The authors have encountered a patient with multiple sclerosis who developed urticarial plaques while taking natalizumab, with a dermal hypersensitivity morphology on biopsy ( Fig. 7 ).
Adverse reactions to monoclonal antibodies
More than 2 decades have passed since Food and Drug Administration (FDA) approval of muromonab-CD3 (Orthoclone OKT3) ushered in the era of monoclonal antibody therapy for the treatment of human disease. With the introduction of infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira) to inhibit activity of tumor necrosis factor α (TNFα), physicians augmented their armamentarium in the battle against autoimmune diseases such as rheumatoid arthritis (RA), Crohn disease, and psoriasis. Monoclonal antibodies directed against vascular endothelial cell growth factor (VEGF) (bevacizumab), ErbB2 (trastuzumab), and CD20 (rituximab) have joined the anti-TNFα agents as the most extensively prescribed drugs in this class, which together account for some of the top-selling biotechnology drugs. To date more than 20 monoclonal antibody therapies have been approved for use by the FDA.
Despite having relatively favorable safety profiles overall, these drugs are not without potential side effects, some of which are occasionally severe enough to prompt discontinuation of the drug. Although adverse reactions affecting the skin are usually tolerated sufficiently to allow continued use, they can be distressing to the patients, who will often seek the attention of their physician(s). As a consequence it is important that rheumatologists and dermatologists who might encounter these adverse reactions in their clinical practice be familiar with the incidence and, when known, the pathogenesis of these reaction processes. In many cases, the adverse reactions fall under the rubric of a “class effect” and can therefore be expected from any of the agents using the same mechanism of action, whereas in other cases there appear to be reaction patterns that are specific to individual agents that are rare or unreported with remaining members of the class. This article reviews the reaction patterns observed across the broad range of biologics in use currently, while discussing possible underlying mechanisms and efforts to minimize their occurrence.
TNFα Inhibitors
The market for TNFα inhibitors is currently occupied by 4 monoclonal antibodies (adalimumab, infliximab, certolizumab pegol, golimumab) directed against the TNFα protein, and 1 TNF-receptor fusion protein (etanercept). These medications are used to treat a broad range of autoimmune conditions including psoriasis, RA, Crohn disease, ankylosing spondylitis, and various off-label conditions.
Injection-site and infusion reactions
The most common dermatologic complaint associated with the use of monoclonal antibodies is the injection-site reaction defined by edema, erythema, pruritus, and/or pain. The incidence of injection-site reactions ranges from 3% to 49%, and appears to be a function of both the specific anti-TNFα agent used and the underlying disease process. These studies indicate that RA patients, especially those treated with etanercept, are at significantly increased risk of developing injection-site reactions in comparison to patients with psoriasis or Crohn disease. While patients typically experience a decrease in frequency and severity of injection site reactions over the course of treatment, worsening reactions with continued administration are reported. Histologically, infiltrates of CD8 + T cells characterize the primary and recurrent reactions, consistent with a type IV delayed hypersensitivity reaction.
Infusion reactions include pruritus, urticaria, chills/fevers, anaphylaxis, and vital-sign alterations that occur, by definition, within 2 to 24 hours following infusion of the drug. Rates of infusion reactions with TNFα inhibitors range from 3% to 24%, depending on the trial and the disease under treatment. Pretreatment with corticosteroids in an effort to reduce infusion reactions appears to have little value, and may even have the paradoxic effect of increasing rates of infusions reactions. Instead, regular administration without prolonged interdose intervals seems to be the most effective means of preventing antibody formation leading to infusion reactions.
Infections
Numerous case reports have surfaced that suggest an association between infections and the use of TNFα inhibitors. Both systemic and cutaneous infections have been observed, suggesting that immunosuppression related to anti-TNFα therapies renders patients more susceptible to infectious pathogens. However, RA patients, one of the major patient demographics receiving TNFα inhibitors, exhibit higher infection rates compared with the general population, which may account for some of the observed infectious complications. That said, comparison between RA patients using anti-TNFα antibodies and those prescribed other disease-modifying antirheumatic drugs (DMARDs) revealed an adjusted relative risk of 4.28 (95% confidence interval, 1.06–17.17). Lee and colleagues reported 13 patients (of 150 in total) who developed cutaneous infections while on infliximab, adalimumab, or etanercept, which included pityriasis versicolor, tinea corporis, impetiginized eczema, herpes simplex, and Staphylococcus aureus .
Fungal, bacterial, and viral infections have all been reported at higher rates in patients using anti-TNFα agents, but none severe enough to require hospitalization. A study of 500 patients using infliximab described 48 patients with infectious events including cases of abscesses, upper respiratory tract infections, pneumonia, cellulitis, shingles, chicken pox, genital herpes, and candidal onychomycosis. As regards viral infections, a prospective cohort study comparing monoclonal anti-TNFα antibodies, etanercept, and DMARDs indicated a statistically significant increased risk for herpes zoster specific to the monoclonal agents, although the investigators considered that the risk fell below the level of clinical significance. Psoriasis patients treated with etanercept also experienced an increased incidence of viral warts. An important side effect directly linked with TNFα blockade therapy is the development of reactivated pulmonary tuberculosis, hence a relative contraindication to the use of the drug is a positive purified protein derivative test.
Inflammatory reactions of the skin
A broad range of inflammatory reactions of the skin has been reported in patients with TNFα blockade. Infliximab-induced acne is reported ( Fig. 1 ) New-onset dermatitis herpetiformis, alopecia areata, pityriasis rosea, and dermatitis sicca (anhidrosis) have been reported with use of various TNFα inhibitors, typically within the first year of initiating treatment. Leukocytoclastic vasculitis, lichenoid drug reactions, perniosis-like eruptions, superficial granuloma annulare, and acute folliculitis following infliximab therapy were reported in patients treated for Crohn disease or RA. Eczema, including dyshidrotic, nummular, contact, papular, and unspecified types, has also been associated with the use of infliximab and etanercept ( Fig. 2 ). Lichenoid reactions have been noted with the entire range of TNF-blocking agents ( Fig. 3 ).
Several case reports suggest a relationship between the development of palisading neutrophilic and granulomatous dermatitis and TNFα-inhibitor therapy ( Fig. 4 ). It has been proposed that TNFα inhibition initiates a leukocytoclastic vasculitis, possibly through interference with self-tolerance mechanisms or immune complex formation, which is followed by a granulomatous inflammatory process. Some investigators have postulated a granulomatous koebnerization in those cases associated with underling RA. Among the granulomatous infiltrates associated with TNFα therapy are rheumatoid nodules, interstitial granulomatous dermatitis, granuloma annulare, and sarcoid-like granulomas.
There have been 5 reported cases of erythema multiforme–like reactions to TNFα inhibitors, after which the offending medication was stopped and the patients’ lesions resolved with topical and oral steroids. The authors have encountered an adalimumab-triggered lymphocytic interface dermatitis mimicking erythema multiforme histologically in a patient with a drug-induced lupus-like symptom complex associated with a positive lupus band test ( Fig. 5 ); this histology mimics acute lupus erythematosus. One case of an eosinophilic cellulitis–like reaction following etanercept and one associated with adalimumab have also been reported.
Cutaneous neoplasms
Immunosuppressed patients experience an increased incidence of cutaneous neoplasms including melanoma, nonmelanoma skin cancer (NMSC), and cutaneous lymphoproliferative disorders. It has been postulated that the immunomodulatory effects of TNFα inhibition might effect an increase in rates of skin cancers among patients requiring long-term therapy. TNFα was initially identified as a potent proapoptotic signal for tumor cells. Animal studies in rats have indicated that anti-TNFα antibodies interfere with antitumor immune surveillance in response to implanted tumor cells that are otherwise robustly attacked in untreated animals. Similar results were obtained with the use of TNF knockout mice.
These findings suggest that antitumor surveillance mechanisms in humans might also be impaired by the chronic administration of anti-TNFα agents. The challenge in addressing the question of iatrogenic neoplasms resulting from anti-TNFα therapy remains the documented predisposition for malignancies associated with the underlying diseases. Sporadic case reports have laid claim to an association between TNFα inhibitors and the development of NMSCs and cutaneous lymphoproliferative disorders. Animal studies, however, have not borne out the association between de novo neoplasms and loss of TNFα, suggesting that the associations observed clinically may arise from susceptibilities independent of anti-TNFα therapy, and that the induced loss of immune surveillance creates a permissive environment that coincides with the inherently proneoplastic nature of the diseases being treated.
Infliximab has been associated with acute development of keratoacanthoma and squamous cell carcinoma (SCC), and rapid onset of SCCs has been noted following use of etanercept. The question of whether this implies promotion of underlying precancerous lesions or de novo carcinogenesis was brought into focus by a report describing basal cell carcinoma (BCC) and SCC in psoriasis patients with extensive prior exposure to light therapy who later began anti-TNFα therapy. A large national cohort study of RA patients showed an elevated risk for development of NMSC that was most closely associated with use of prednisone or TNFα inhibitors alone or with concomitant methotrexate. As is often the case, however, reports have surfaced that argue against such associations. A meta-analysis of randomized controlled trials using TNFα inhibitors in psoriasis patients (N = 6810) did not confirm an increased risk of malignancy. Lebwohl and colleagues also reported no evidence for increased risk of cutaneous SCC in patients receiving etanercept for up to 5 years. Aside from BCC and SCC, a single case of Merkel cell carcinoma has been reported in the context of adalimumab, methotrexate, and prednisone administration for RA.
In addition to the reports of NMSCs, there have been occasional reported cases of associated melanoma. In 2 patients with a remote history of surgically excised melanoma there was a late recurrence (6 and 9 years after excision) of eruptive locoregional metastases following the initiation of etanercept and adalimumab, respectively. Late recurrence of melanoma, however, is part of the natural history of melanoma, and whether this phenomenon can be attributed to TNFα inhibition in such cases is questionable. Although melanomas have been reported in patients with RA and Crohn disease receiving TNFα inhibitors, strong evidence for a causal association is lacking.
Other forms of melanocytic proliferation influenced by anti-TNFα therapy include cutaneous nevi associated with infliximab therapy in the setting of Crohn disease and eruptive melanocytic nevi associated with use of infliximab and etanercept in Crohn disease and psoriasis, respectively. Balato and colleagues extended the hypothesis that the proinflammatory cytokine milieu of psoriasis might establish relative inhibition of melanogenesis and melanocyte growth in light of the reduced incidence of pigmented lesions in these patients. If true, it is possible that initiation of TNFα inhibitors releases this inhibitory state and restores a native level of melanogenesis and melanocyte proliferation that is, by comparison, hyperactive.
Lymphoproliferative disorders are also among the list of cutaneous neoplasms reported in patients using TNFα inhibitors. Among these are reports of cutaneous γδ T-cell lymphoma in an RA patient using etanercept, mycosis fungoides (MF) in 2 patients using etanercept and infliximab, CD30 + T-cell lymphoma following cyclosporin and infliximab, MF-associated follicular mucinosis after 7 months of adalimumab, CD8 + cutaneous T-cell lymphoma with infliximab, Sezary syndrome associated with infliximab and etanercept, and cutaneous anaplastic large cell lymphoma following infliximab. Because of their inherent rarity and the small number of case reports available, the association between TNFα inhibitors and cutaneous T-cell lymphoma is tenuous. No large-scale trials have addressed this question.
Although additional investigation is required to establish a concrete link between cutaneous malignancies and the use of TNFα inhibitors, many of the alternative treatments for the intended patient population (eg, psoriasis patients) have well-established risks of malignancy with long-term use (eg, photochemotherapy, methotrexate, mycophenolate mofetil).
Other cutaneous reactions
Not infrequently, patients develop autoantibodies during their course of TNFα blockade. Following 6 months of treatment with etanercept or infliximab, 11% and 34% of patients, respectively, developed antinuclear antibodies. Anti–double-stranded DNA antibodies were found in 15% of patients taking etanercept and in 9% of patients using infliximab. Perhaps it is not surprising, then, that there are reports of patients developing systemic lupus erythematosus while on etanercept, sometimes with cutaneous involvement. There have been similar reports of new-onset cutaneous lupus with the use of infliximab and adalimumab. Meta-analysis of several hundred reported cases of autoimmune diseases associated with TNFα inhibitors revealed that cutaneous vasculitis, lupus-like syndromes, systemic lupus erythematosus, and interstitial lung disease were the most common. Dermatomyositis has also been reported in association with TNFα inhibition.
The anti-TNFα agents appear to have a negative impact on the control of psoriasis in some patients. Case reports of worsening or new-onset psoriasis are not infrequent in the TNF-inhibitor literature. A retrospective analysis of 12 years’ experience at the Mayo Clinic showed 56 patients with either new-onset psoriasis or exacerbation of underlying psoriasis who were treated with infliximab, adalimumab, or etanercept for Crohn disease or RA. New-onset psoriatic palmoplantar pustulosis has also been noted in 2 patients treated with infliximab for RA. Certolizumab for Crohn disease has been associated with development of psoriatic lesions. Cytokine imbalance with increased levels of interferon-α (IFN-α) has been proposed as a possible pathogenetic mechanism.
Interleukin-2 Inhibitors
To date there are 3 biological agents designed to target interleukin (IL)-2 signaling. Basiliximab (Simulect) is a chimeric mouse-human monoclonal antibody directed against the IL-2 receptor α subunit (CD25), used to prolong renal allograft survival. Daclizumab (Zenapax) is a humanized monoclonal antibody that targets the same α subunit of IL-2 receptor. Denileukin diftitox (Ontak) is an engineered protein, used in some cases of T-cell and B-cell lymphoma and advanced melanoma, which combines IL-2 with diphtheria toxin, thereby killing cells bearing IL-2 receptors that bind and internalize the toxin. Reports of cutaneous reactions to administration of these agents are sparse in the literature, perhaps reflecting a relatively benign profile as regards skin biology, but it is conceivable that basiliximab played a role in the pathogenesis of nephrogenic fibrosing dermopathy in 2 liver transplant patients.
A small dose-escalation study using denileukin diftitox reported a 14% incidence of generalized maculopapular/vesicular rashes and a single case of mild vascular leak syndrome. Capillary leak syndrome presenting with facial erythema and edema has been previously reported with denileukin diftitox, and presents in a manner similar to that seen with IL-2 immunotherapy for cancer. Pretreatment with corticosteroids appears to be effective in reducing the frequency of this complication. There has also been a report of a fatal rash consistent with toxic epidermal necrolysis occurring in a patient with follicular large-cell lymphoma receiving denileukin diftitox.
CD20 Inhibitors
Currently there are 3 FDA-approved monoclonal antibodies directed against the B-cell antigen CD20: rituximab (Rituxan), ibritumomab tiuxetan (Zevalan), and tositumomab (Bexxar). Of this class, rituximab has been most often reported to have significant adverse cutaneous reactions, although the remaining 2 agents have been available for a shorter period and have a less extensive history to mine for potential reactions.
Infusion reactions
Urticaria appears to be a common side effect in patients receiving rituximab, with incidence ranging from 3% to 14% in clinical trials. Severe infusion reactions have also been noted.
Infections
While systemic infectious complications have been reported in association with the use of rituximab, specific mention of cutaneous infections has been largely absent. Of the handful of cutaneous infections reported in patients treated for non-Hodgkin lymphoma, herpes simplex and herpes zoster constituted the majority.
Cutaneous malignancies
Associated malignancies with rituximab included reports of 6 BCCs, 2 SCCs, and 2 melanomas in a group of 1039 patients undergoing treatment for RA. Merkel cell carcinoma has also been reported in a patient using rituximab.
Other adverse cutaneous reactions
Although it appears to be a rare occurrence, there is a report of a patient experiencing Stevens-Johnson syndrome characterized by grade 1 mucositis after treatment with rituximab, which persisted for over a year until the patient’s death. Although there have yet to be any reports in humans of toxic epidermal necrolysis (TEN) with rituximab alone, reactions consistent with this classification have been observed in rhesus macaques following administration. There have been postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, TEN, bullous dermatitis, and exfoliative dermatitis in patients receiving the combined regimen of radiolabeled ibritumomab with rituximab (ie, the Zevalin therapeutic regimen).
CD30 Antagonists
Brentuximab is a chimeric monoclonal antagonist of the CD30 molecule and is used in CD30 + lymphoproliferative lesions. A patient with CD30 + anaplastic large-cell lymphoma developed an eczematous eruption while on brentuximab ( Fig. 6 ).
VEGF Inhibitors
Bevacizumab (Avastin) and ranibizumab (Lucentis) comprise the family of monoclonal antibodies currently approved to target VEGF in the treatment of various cancers, macular degeneration, and diabetic retinopathy. The bulk of reported reactions have been for the parent drug bevacizumab while the affinity-matured Fab fragment, ranibizumab, has comparatively few reports of adverse cutaneous effects to date. Among the dermatologic complaints in patients using bevacizumab, general rash is the most commonly reported. More specific classification of skin reactions includes reports of papulopustular eruptions, perforating dermatosis, and cutaneous lupus erythematosus. There has also been a report of impaired wound healing and skin-flap necrosis in a patient taking paclitaxel and bevacizumab after undergoing mastectomy for locally advanced breast cancer. An episode of acute generalized exanthematous pustulosis was reported in association with ranibizumab following intravitreal administration.
Epidermal Growth Factor Receptor Inhibitors
Monoclonal antibodies currently FDA approved for clinical use in targeting the epidermal growth factor receptor (EGFR) include cetuximab (Erbitux) and panitumumab (Vectibix). Both are indicated for metastatic colorectal cancer, and cetuximab is additionally approved for treatment of recurrent or metastatic SCC of the head and neck. The majority of the cutaneous reactions reported have been associated with cetuximab. The most common of these are eruptions of acneiform and rosaceiform lesions that serve as surrogate markers of tumor response. One report demonstrated the presence of coagulase-positive Staphylococcus infection in association with a papulopustular drug eruption. There have also been reports of eyelash trichomegaly, xeroderma pigmentosum, Grover disease, ecthymatous skin eruption, cicatricial ectropion, paronychia, and severe radiation dermatitis/TEN-like reactions. Panitumumab has also been associated with similar acneiform, papulopustular eruptions, but few reactions apart from this have been reported. Dose-escalation studies with cetuximab suggested that severity of skin reactions did not follow a dose-sensitive distribution. While both antibodies target the same effector molecule, there have been reports of differences in the patterns of toxicity seen for each agent when administered sequentially, suggesting possible non–class effect cutaneous toxicities.
Efalizumab (Raptiva)
Efalizumab targets the CD11a antigen involved in cellular adhesion and costimulatory signaling between leukocytes. Compared with several of the monoclonal agents discussed previously, efalizumab has low reported rates of infusion reactions. Its administration has been associated with increased incidence (in the range of ∼3%) of herpes infections. CD11a is one of the variable α-chain components of the leukocyte function–associated antigen (LFA)-1, which plays an important role in antibody-dependent cellular cytotoxicity directed against herpes-infected cells. Cell-culture studies have shown that monoclonal antibodies directed against CD11a, but not CD11b or CD11c, inhibit the early phase of the IFN-α response normally generated by exposure to herpes virus, suggesting a potential mechanism behind the increased incidence of herpetic lesions in patients using efalizumab. Along similar lines, there has been a report of disseminated eruptive giant molluscum contagiosum in a psoriasis patient using efalizumab. A small increase (∼1%) in the rate of impetigo and cellulitis has also been observed.
Efalizumab has been reported to increase the rate of acne compared with placebo (4% vs 1%) in a large double-blind study comprising 1928 patients. In addition to the adverse effects reported in larger studies, there have been specific reports of efalizumab-induced subacute cutaneous lupus erythematosus, DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome, dermatitis/lichen simplex chronicus, exacerbation of pityriasis rubra pilaris, eruptive seborrheic keratoses, eruptive dermatofibromas, and guttate psoriasis.
Efalizumab is approved for the treatment of psoriasis, so it has been a point of special interest among clinicians and researchers that subsets of patients using the agent develop de novo psoriatic lesions or experience worsening of preexisting psoriasis (ie, rebound psoriasis). Numerous placebo-controlled trials with large patient populations have reported psoriasis-related adverse events in 2.2% to 13.6% of patients, which frequently exceeds the rates reported for placebo (ranging from 0.8% to 11.2%). A unique type of inflammatory reaction has also been reported with the use of efalizumab in psoriasis patients resulting in the formation of eruptive papules composed of CD11b + , CD11c + , and inducible nitric oxide synthase–positive myeloid leukocytes with minimal CD3 + cells. It was proposed that these lesions arise from the expression of alternative β2 integrins that alter trafficking of circulating leukocytes to the skin.
Alefacept (Amevive)
Alefacept is an immunoglobulin G (IgG)1–LFA-3 fusion protein used in the treatment of chronic plaque psoriasis. It compares favorably with the anti-TNFα agents with regard to infusion reactions, with rates reported up to 8% higher than with placebo. Marketing studies of 1869 patients associated alefacept with NMSCs, including BCCs (n = 20) and SCCs (n = 26), in addition to a small number of melanomas (n =3). A smaller study with 201 patients reported 3 patients with BCC and 1 with SCC. Schmidt and colleagues reported the development of transformed MF after treatment with alefacept. Similar to several of the anti-TNFα agents, there have been reports of associated eruptive benign melanocytic nevi.
Trastuzumab (Herceptin)
Trastuzumab is a humanized monoclonal antibody that targets the HER2/neu receptor, the product of a gene (ERBB2) commonly overexpressed in a subset of aggressive breast cancers. As with many of the monoclonal therapies, infusion reactions are not uncommon. Although it is often used in concert with radiation therapy in the treatment of breast cancer, it does not appear that trastuzumab contributes significantly to rates of dermatitis beyond levels associated with radiation therapy alone. Several reports have surfaced regarding photosensitivity in combination with the taxane class of chemotherapeutics, although photosensitivity has been observed with taxanes in isolation. Tufted folliculitis of the scalp with scaling and pruritus was also reported in a patient following the transition from doxorubicin and cyclophosphamide to trastuzumab.
Alemtuzumab (Campath)
Mature T and B lymphocytes express CD52, a glycosylphosphatidylinositol-anchored antigen that serves as the target of the monoclonal antibody, alemtuzumab, in the treatment of lymphoproliferative disorders. Various reports have implicated alemtuzumab in disseminated molluscum contagiosum, generalized herpes simplex, varicella zoster, sarcoidosis, and acute CD30 + transformation of cutaneous T-cell lymphoma in a manner reminiscent of Richter syndrome.
Natalizumab (Tysabri)
Natalizumab is a humanized antibody directed against α4-integrin, an important cellular adhesion molecule target in the treatment of multiple sclerosis and Crohn disease. While there have been reports of generalized drug eruptions and severe cutaneous candidal infection in patients using natalizumab, perhaps the most striking adverse cutaneous effect involves the controversy surrounding accelerated evolution of nevi into melanoma. Studies performed more than a decade ago implicated α4-integrin expression at the primary tumor site as an important inhibitor for dyshesive growth. At the same time, however, once metastatic cells are present in the blood, α4-integrin expression appeared to aid in transendothelial migration at specific tissues. Future studies will likely clarify the potential risks posed by natalizumab therapy with regard to development and progression of melanoma. The authors have encountered a patient with multiple sclerosis who developed urticarial plaques while taking natalizumab, with a dermal hypersensitivity morphology on biopsy ( Fig. 7 ).
Adverse cutaneous reactions to intravenous immunoglobulin therapy
Because of its favorable safety profile, intravenous immunoglobulin (IVIG) therapy for a wide range of neurologic, dermatologic, and rheumatologic conditions has gained in popularity over recent years. As reviewed here, there has been an association between the use of IVIG and eruptions of eczematous lesions, most frequently affecting the palms and soles, which are usually self-limited and resolve after withdrawing IVIG treatment; some have required topical or systemic corticosteroids. In the vast majority of cases, treatments are well tolerated by patients, with minor adverse effects including headache, chills, myalgias, arthralgias, and nausea, but relatively few significant adverse effects. The frequency of localized and generalized cutaneous adverse effects associated with IVIG varies between 0.4% and 6%. As early as 1997 reports began to emerge that suggested an association between eczema and IVIG therapy. The current literature contains more than 60 cases of IVIG-associated eczematous reactions. Patients’ ages ranged from 7 years to the mid 70s, with the majority falling in the fifth through seventh decades of life. More than half of the patients presented with a picture of dyshidrotic eczema/pompholyx, which typically presented during the first infusion of IVIG, often within 5 to 10 days. Pompholyx is a relatively rare manifestation within the broader classification of eczema and can be seen following a variety of stimuli, including allergic and irritant contact reactions and dermatophytids. Among a series of 120 patients with pompholyx, IVIG was identified as the likely etiologic agent in only 1. Outside the context of IVIG use, pompholyx does not exhibit an unbalanced gender distribution while the majority of the patients experiencing this reaction in association with IVIG were males, perhaps signifying a male predominance for the underlying conditions being treated with IVIG, such as multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, and Guillain-Barré syndrome.
IVIG is composed of pooled IgG from the plasma of more than 1000 blood donors that is subsequently processed to remove infectious agents, with variable allowances for the level of immunoglobulin A content, sucrose, glucose, and preservatives. No single IVIG preparation is associated with the development of eczematous reactions, implying that formulation alone was not responsible, but there have been cases whereby switching between different manufacturers resulted in improvement. Whether this represents desensitization with subsequent infusions or a true variability in the reactivity of various IVIG products is unclear, as is the mechanism underlying IVIG-associated eczematous reactions as a whole.
There are 2 separate reports of IVIG reactions associated with hypocomplementemia of C4 with accompanying low levels of CH50 or CH100. In the case reported by Sarmiento and colleagues, a 39-year-old man receiving IVIG for progressive myopathy developed a widely distributed erythrodermic eczematous reaction and pompholyx with new-onset hypocomplementemia of C4 with low CH100, the levels of which normalized alongside resolution of the skin reaction. It was hypothesized that low complement levels might represent the formation of immune complexes containing fixed complement that triggered the observed skin reaction. Elevated IgG complement-fixing immune complexes have been observed in children with atopic eczema. Hypocomplementemia of C4 has led some investigators to suggest that complement-fixing immune complexes may play a role in the pathogenesis. It has been noted in cell-culture studies that IgG has the capacity to regulate the CD1 expression profile of dendritic cells. High IgG levels promote the expression of CD1d with low levels of CD1a, CD1b, and CD1c. IVIG treatment reverses this pattern of expression. Eczematous skin harbors elevated numbers of CD1a-positive Langerhans cells when compared with normal skin. Whether IVIG treatment influences the numbers of CD1a-expressing dendritic cells in the skin or the levels of CD1a expression in patients who develop the eczematous reaction has yet to be determined, although this remains an interesting question in light of the differential self-antigen versus foreign-antigen-presenting capabilities of the different isoforms.
Cutaneous drug reactions associated with chronic hydroxyurea therapy
Hydroxyurea or hydroxycarbamide is an antineoplastic agent that interferes with DNA synthesis by way of ribonucleotide reductase inhibition, and is used in the treatment of myeloproliferative disorders, including chronic myelogenous leukemia (CML), essential thrombocythemia, and polycythemia vera. It has been used as a treatment for recalcitrant psoriasis and as a means to reduce the frequency of painful attacks in patients with sickle-cell disease. Well-known systemic and metabolic side effects include leukopenia and thrombocytopenia, but there are also less well-known cutaneous sequelae of long-term hydroxyurea use.
Pseudodermatomyositis with Chronic Hydroxyurea Therapy
For many years it was recognized that patients undergoing long-term hydroxyurea therapy were subject to a host of skin reactions including xerosis, pigmentary change, ulcer formation, alopecia, palmar/plantar keratoderma, tissue atrophy, and chromonychia. Many of these reactions are common to the antineoplastic agents as a family. The first reports of hydroxyurea-induced erythematosquamous lesions involving the dorsa of metacarpophalangeal and interphalangeal joints came in 1975 with a description of 3 patients treated for CML who developed lesions 3 to 4 years after initiation of therapy. Following this initial report, Burns and colleagues reported a 31-year-old male patient with similar lesions that developed after 7 years of therapy. In 1984, Sigal and colleagues published a report describing 3 additional patients presenting with band-like erythema on the dorsum of the fingers and toes in a morphology that was highly reminiscent of dermatomyositis. There have since been widespread reports of what has since been referred to as pseudodermatomyositis lesions after chronic hydroxyurea therapy, typified by the erythematous, linear, scaly plaques often on the dorsal aspect of the interphalangeal and metacarpophalangeal joints. Lesions can also develop outside the classic joint distribution and may include scaly, poikilodermatous plaques or violaceous papules on the feet, elbows, palms, and face. Facial involvement can also result in edema ( Fig. 8 A, B). Atrophic change with the development of telangiectasias is common, similar to that seen in dermatomyositis proper. In many such cases there were concomitant ulcers, most commonly affecting the legs and feet.
Skin biopsies show perivascular mononuclear cell infiltrates with vacuolar degeneration of basal keratinocytes and accumulation of colloid bodies in the papillary dermis ( Fig. 8 C). Reaction patterns such as these are nonspecific and support a differential diagnosis that includes dermatomyositis, poikiloderma, lichenoid reactions, and graft-versus-host disease. There is no accompanying muscle involvement in hydroxyurea-associated dermatomyositis-like reactions. Prolonged presence of lesions has been suggested to lead to an atrophied, cigarette paper–like appearance that can be characterized by signs of accelerated physiologic photoaging of the skin, seen histologically as severe dermal elastosis. The mechanism that underlies the dermatomyositis-like lesions that develop with chronic hydroxyurea is still uncertain, but similar reactions have been observed for a variety of medications including several statins, penicillamine, bacillus Calmette-Guérin vaccination, the 5-fluorouracil derivative tegafur, cyclophosphamide, and etoposide. It is interesting that psoriasis patients who are treated with lower doses of hydroxyurea experience mucocutaneous reactions, pigmentation of nails and skin, and occasionally xerosis and alopecia, but do not appear to develop dermatomyositis-like reactions with the same frequency as do those patients with myeloproliferative disorders. This finding suggests that perhaps dose and underlying disease state influence the pathogenesis.
Nonmelanoma Skin Cancers and Hydroxyurea
As far back as the early 1980s it was recognized that hydroxyurea had the potential to enhance tumorigenesis in the skin of mice when administered before exposure to the carcinogen N -methyl- N -nitrosourea. There have been many observations of the propensity for patients using hydroxyurea to develop accelerated photoaging and actinic damage of the skin. Disdier and colleagues were the first to report an association between the rapid development of SCC and the use of hydroxyurea in a CML patient. Patients tend to develop NMSC in sun-exposed and non–sun-exposed areas after a 2- to 13-year latency period, while precursor epithelial dysplasia has also been observed to improve after discontinuation of hydroxyurea therapy. There has been a report of Merkel cell carcinoma arising in a patient using hydroxyurea. Most reported SCC cases arose in patients with Fitzpatrick skin types I and II, primarily in sun-exposed areas. For these lesions, ultraviolet (UV) irradiation and mutagenesis is likely to have played a role, but the temporal association and the well-documented latency period suggest that hydroxyurea participates in the process. By interfering with DNA synthesis, hydroxyurea inhibits DNA damage repair mechanisms that would normally be triggered by UV-induced DNA damage. Hydroxyurea is also converted into free radical nitroxide within cells, which can inflict oxidative damage on cellular proteins and lipids as well as disrupt normal biosynthetic and signaling pathways that control growth and proliferation. Random mutations in p53 as a primary initiating event is postulated in sporadic SCC, and normal UV-exposed skin harbors pockets of cells carrying p53 mutations that expand with further exposure. Chronic oxidative stress provided by hydroxyurea-derived nitroxides is also a source of tumor promotion that, in concert with UVB irradiation, tips the balance toward rapid development and progression of precancerous lesions. Skin biopsy specimens from hydroxyurea-induced pseudodermatomyositis patients have demonstrated aberrant p53 expression patterns, coinciding in at least one patient with the development of NMSCs that prompted cessation of therapy and eventual death due to myelodysplasia.
Ulcer Formation Following Hydroxyurea Administration
Some patients who presented with pseudodermatomyositis lesions following long-term (ie, more than 5 years) use of hydroxyurea developed painful, fibrous, recalcitrant ulcers of the leg, often accompanied by surrounding atrophy, characteristically localized to the malleolar or perimalleolar regions. Ulcers can also arise independently of the dermatomyositis-like reactions. In one large series, it was reported that the first occurrence was associated with multiple ulcers in 70% of the patients. Although ulcers on the leg typify the distribution pattern of this reaction, there have been cases reported with the feet and genitalia predominantly involved. Biopsied ulcers typically manifest epidermal atrophy and dermal fibrosis in the absence of an underlying vascular injury such as a leukocytoclastic vasculitis or diabetic microangiopathy ( Fig. 9 A–C). Thrombotic microangiopathy may be seen ( Fig. 10 ).
In one large series of patients with chronic myeloproliferative disease who developed leg ulcers, the mean duration of the ulcers was 10 months, despite attentive wound care. Cessation of hydroxyurea was necessary to achieve resolution of the ulcers, which typically resolved within 3 months of discontinuation. There is a variety of treatment protocols aimed at speeding the resolution of hydroxyurea-induced ulcers, which include prostaglandin E 1 /pentoxifylline combinations, granulocyte-macrophage colony-stimulating factor, Apligraf, topical fibroblast growth factor, or use of a protease-modulating matrix.
The antimetabolic properties of hydroxyurea are likely to blame for the pathogenesis of the associated ulcers. Slowing of keratinocyte turnover and growth impedes wound repair at the level of the basal keratinocyte layer, which is damaged secondary to either hydroxyurea dermopathy or concomitant microtrauma, as is common on the legs. Velez and colleagues has suggested that macroerythrocytosis (a common laboratory finding associated with the use of hydroxyurea that arises from inhibition of DNA synthesis) may contribute to the development of ulceration. Indeed, there is generally an increase of roughly 12% in size of red blood cells associated with a corresponding decrease in deformability, which could theoretically lead to reduced microvascular perfusion and parallel the ulceration seen with arterial insufficiency. Ulcer patients who were transitioned from hydroxyurea to pipobroman saw a subsequent decrease in the mean corpuscular volume from 121 μm 3 to 100 μm 3 over the course of a month with subsequent ulcer resolution. Wirth and colleagues explored a possible role of hydroxyurea-resistant thrombocytosis in ulcer formation in a 54-year-old woman with CML who showed improvement following anagrelide treatment to normalize platelet counts. The interpretation of this finding is clouded, however, by the paucity of data relating thrombocytosis and ulcer formation, along with the distinct possibility that the ulcers were due to the preceding, year-long course of hydroxyurea and the fact that healing coincided with discontinuation of hydroxyurea 5 months prior.
Adverse cutaneous reactions to other chemotherapy drugs
Other chemotherapeutic agents to exhibit cutaneous toxicities, especially with prolonged use, are reviewed elsewhere.
Sunitinib (Sutent)
Sunitinib is a multitargeted tyrosine kinase inhibitor that is used to treat renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors (GISTs). The mechanism of action is one of inhibition of various tyrosine kinases, including VEGF receptor, platelet-derived growth factor receptor, and CD117. Mucocutaneous reactions include stomatitis and an acneiform folliculitis with acrosyringeal accentuation ( Fig. 11 ); the authors have also observed a photodistributed eruption mimicking subacute cutaneous lupus erythematosus.
Retiform purpura in association with levamisole-adulterated cocaine
The past several years have seen numerous reports of a distinct vasculitis-like syndrome with retiform purpura ( Fig. 12 A), frequently involving the earlobes and face in association with the use of levamisole-adulterated cocaine. Levamisole is an anthelmintic with a well-documented capacity to induce vasculitic and thrombotic damage. Leukopenia, neutropenia, antiphospholipid antibodies, and antineutrophil cytoplasmic antibodies (ANCAs) have been reported in these patients alongside microvascular thrombosis and occasional small-vessel vasculitis ( Fig. 12 B, D).
More than 70% of cocaine shipments seized on entry into the United States have been found to contain levamisole, and 194 of 249 (78%) cocaine-positive urine toxicology studies at a 500-bed Denver hospital tested positive for levamisole using gas chromatography–mass spectrometry.
The earliest reports of vasculitis associated with use of cocaine described involvement of small vessels of the cerebral circulation. In vitro studies suggest that cocaine use facilitates the migration of monocytes across the blood-brain barrier and, as a result, may contribute to the development of vasculitis. Generalized cutaneous vasculitic lesions of the skin and Henoch-Schönlein purpura with necrotizing vasculitis have been reported following cocaine use, as has upper extremity large-vessel vasculitis diagnosed by angiography. There has been a single report of Stevens-Johnson syndrome related to the use of cocaine in a patient who had used cocaine on a daily basis for an extended period and reported the lesions only after procuring cocaine from a new source, suggesting that these lesions represented the effect of an adulterant not present in the previous supply. A similar presentation with scrotal gangrene requiring debridement was reported in a 22-year-old man 3 hours after smoking crack cocaine. An association between smoking of crack cocaine and Churg-Strauss vasculitis has been suggested in one case report, with eosinophilic angiitis seen on skin and muscle biopsies. Necrotizing granulomatous vasculitis associated with nasal destruction has also been reported in a chronic cocaine user, although most cases involving loss of nasal tissue do not show granulomatous infiltrates. Though considered controversial, there has been a suggestion that some patients with Buerger disease may actually represent the sequelae of recreational cocaine use because of the significant overlap of the clinicopathologic presentations.
The term cocaine-induced pseudovasculitis has been floated in the literature to reflect the observation that cocaine use in some patients produces symptoms mimicking Wegener granulomatosis (WG) without producing the histopathologic findings of a true vasculitis. Differentiation between a true vasculitis (such as WG) and the pseudovasculitis associated with cocaine use is important, because it spares the patient unnecessary treatment with high-dose corticosteroids and immunosuppressants. The use of ANCA positivity to differentiate vasculitis versus pseudovasculitis has been flagged as a potential pitfall, as there are situations whereby proteinase-3 (PR3)-ANCA (or cytoplasmic ANCA [C-ANCA]) is positive in individuals using cocaine. Whereas the PR3-ANCA may not reliably differentiate cocaine-induced lesions from WG, human neutrophil elastase ANCA (HNE-ANCA) has been proposed as a more discriminating assay, as it is positive following cocaine abuse.
Levamisole was introduced in 1966 as an anthelmintic agent before the recognition that it possessed antitumor properties useful in the adjunctive treatment of colon cancer, melanoma, and cancers of the head and neck. It was apparent early on that it could induce agranulocytosis, and could stimulate circulating immune complexes leading to vasculitis, typically a mixed leukocytoclastic vasculitis with microvascular thrombosis or microvascular thrombosis alone ( Fig. 12 C, D). Levamisole acts as a hapten, which can trigger the immune response. Children who were treated for nephrotic syndrome with levamisole occasionally went on to develop a vasculitic picture that was accompanied by circulating antinuclear, antiphospholipid, and anticytoplasmic autoantibodies that persisted long after the resolution of the skin lesions. Because of the high incidence of adverse effects, the drug was withdrawn from the market by the FDA in 2000, but remains in use primarily as a deworming agent in veterinary medicine. Beginning in 2005, levamisole surfaced as a cutting agent in cocaine samples within the United States, possibly because of its stimulant-enhancing properties and similar appearance to cocaine.
Beginning in 2010 a handful of reports emerged describing patients, frequently female, who presented with distinctive retiform purpuric lesions of varying severity often localized to the ears, cheeks, nose, and extremities (see Table 1 for a summary of reported cases) in the setting of current or recent cocaine use. The similarity of the lesions to the morphology and distribution reported previously for levamisole, taken together with Drug Enforcement Agency reports of the rise of levamisole contamination in street cocaine, led to the recognition that these reactions were likely due to the presence of this cutting agent. Biopsies from the majority of patients reported in Table 1 showed microvascular thrombosis, leukocytoclastic vasculitis, or a mixture of both. Neutropenia was a common finding in the majority of patients, although there were several patients with normal absolute neutrophil counts at presentation. Consistent with prior reports of autoantibody formation following levamisole exposure, 88% of the cases reviewed in Table 1 were perinuclear-ANCA or C-ANCA positive, often PR3-ANCA, myeloperoxidase-ANCA, and HNE-ANCA subtypes. Anticardiolipin antibody was positive in 13 patients (52%), and 20% of patients had positive antinuclear antibody (ANA) tests. Several patients were also found to have elevated erythrocyte sedimentation rate, C-reactive protein, D-dimer, and partial thromboplastin time. One patient exhibited low protein C and protein S levels. Patients often presented with a history of spontaneously resolving lesions that would recur whenever they used cocaine, whereas others had persistent lesions that responded to treatment with steroids or antibiotics (see Table 1 ). In one patient whose lesions failed to resolve spontaneously or with steroids, surgical debridement was necessary, followed by multiple reconstructive procedures. Although neutropenia was severe in some patients after their exposure to levamisole, most rebounded spontaneously to normal neutrophil counts after sustained abstinence from adulterated cocaine or following filgrastim (G-CSF) therapy.
| Authors Ref. | Age/Sex | Distribution | Neutropenia | Autoantibodies | Treatment and Outcome |
|---|---|---|---|---|---|
| Chung et al | 46, F | b/l ears, cheeks, upper and lower extremities | No | MPO- and PR3-ANCA+, anticardiolipin IgM+ | Steroids (improved) |
| 57, F | b/l ears and cheeks | Yes | MPO- and PR3-ANCA+, anticardiolipin IgM+ | IV antibiotics and filgrastim (improved) | |
| 46, F | b/l ears, neck, trunk, extremities | Yes | P-ANCA+, C-ANCA+, anticardiolipin IgM+ | Methylprednisone (improved) | |
| 22, F | b/l ears, cheeks, nose, buttocks, thighs | Yes | P-ANCA+, anticardiolipin IgM+ | Methylprednisone (improved) | |
| 37, M | b/l ears | No | P-ANCA+, elevated CRP, ESR, D-dimer; +ANA | Supportive | |
| 50, M | b/l ears, trunk, extremities | No | P-ANCA+, elevated CRP, ESR, D-dimer, PTT; +ANA | Antibiotics (rapidly improved) | |
| Farhat et al | 43, F | b/l lower extremities | N/A | P-ANCA+ | Pain control |
| 41, F | b/l thighs, buttocks, trunk, upper extremities, nose | N/A | P-ANCA+, anticardiolipin IgM+ | N/A | |
| Buchanan et al | N/A, M | b/l ears | Yes | N/A | Supportive |
| Walsh et al | 39, F | Legs and trunk | N/A | HNE-ANCA+, P-ANCA+, C-ANCA+, +ANA | N/A |
| 49, F | Legs and trunk | Yes | HNE-ANCA+, P-ANCA+, C-ANCA+, +ANA, elevated ESR | N/A | |
| Waller et al | 38, F | Ear, cheeks, right breast, b/l upper and lower extremities | Yes | PR3-ANCA+, lupus anticoagulant+ | N/A |
| 43, F | b/l lower extremity and ear, b/l arms and thighs | Yes | MPO-ANCA+, elevated PTT, anti-dsDNA+, lupus anticoagulant+, anticardiolipin IgM+ | N/A | |
| Lung et al | 44, F | b/l lower extremities, abdomen, face | Yes | N/A | N/A |
| Ullrich et al | 45, M | Extremities and ears | Yes | P-ANCA+, MPO- and PR3-ANCA+, anticardiolipin IgM+, +ANA | Prednisone (with some improvement) |
| 49, F | Trunk and extremities | Yes | C-ANCA+, PR3-ANCA+ | Conservative | |
| 27, F | Lower extremities | Yes | P-ANCA+, MPO- and PR3-ANCA+ | Prednisone (improved) | |
| 29, F | Left foot and b/l ears | No | P-ANCA+, MPO- and PR3-ANCA+, anticardiolipin IgM+ | Prednisone (improved) | |
| 55, F | Face, trunk and extremities | No | P-ANCA+, MPO- and PR3-ANCA+, anticardiolipin IgM+, thyroglobulin and thyroid peroxidase antibody+ | Steroids and cyclophosphamide (improved) | |
| Fthenakis and Klein | 48, F | Face, abdomen, legs | No | +ANA, mildly reduced protein C and protein S | Spontaneous remission with relapse |
| Bradford et al | 57, F | b/l cheeks and earlobes | Yes | P-ANCA+, anticardiolipin IgM+ | Filgrastim and spontaneous skin resolution |
| 22, F | Face, ears, legs, thighs, buttocks | Yes | P-ANCA+, anticardiolipin IgM+, serine IgM+ | Steroids (resolved) | |
| Muirhead and Eide | 54, F | Face, ears, breasts, extremities | Yes | P-ANCA+, C-ANCA+ | Steroids (unresolved) and debridement |
| Han et al | 52, F | Arms, legs, nose, cheeks, ears | Yes | P-ANCA+, PR3-ANCA+, anticardiolipin IgM+ | Steroids, dalteparin (improved) |
| Geller et al | 50, F | b/l arms, breasts, upper back, ears | Yes | Anticardiolipin IgM+, P-ANCA+, elevated CRP | N/A |
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