In a prospective cohort study, all consecutive patients with a diagnosis of RA according to the criteria of the American Rheumatism Association 16 who were starting on TNF-α-blocking therapy at the Department Of Rheumatology of the Radboud University Nijmegen Medical Centre were followed as part of a Biological Registry 17. Approval was obtained by the hospital's ethics committee.

Patients were required to meet the criteria set out in the Dutch guidelines for biological therapies: a moderate to high disease activity score (DAS) based on 28 joints (DAS28 ≥ 3.2), and failure or intolerability of at least two disease-modifying antirheumatic drugs (DMARDs), including methotrexate, in adequate dosage regimens. Besides therapy with registrated TNF-α-blocking agents – infliximab, etanercept, and adalimumab – some patients were treated in clinical trials with lenercept, a soluble p55 TNF-α-receptor 18.

The number and nature of dermatological conditions that led patients in this cohort to consult a dermatologist during follow-up were investigated. The RA patients treated with TNA-α-blocking agents who experienced dermatological events was compared with a control group of patients who had RA but had never had TNF-α-blocking therapy. The control patients were selected from the Nijmegen inception cohort, in which 500 RA patients have been followed since 1985 19. Each control was paired with a TNF-α-treated patient for duration and season of the follow-up period, within a 2-month window.

Data collected at the start of TNF-α-blocking therapy were age, sex, duration of disease, presence or absence of rheumatoid factor (measured by ELISA; considered positive if results showed >10 IU/ml), antinuclear antibody (tested for by immunofluorescence on Hep-2 cells), number of DMARDs previously used, and start date of TNF-α-blocking therapy. Baseline information obtained included erythrocyte sedimentation rate (ESR), 28-joint counts for swelling and tenderness, and general wellbeing as indicated on a visual analogue scale, and the disease activity score (DAS28) was calculated 20.

Variables about which information was collected during TNF-α-blocking therapy were the use of concomitant DMARDs and prednisolone, dose and interval changes of TNF-α-blocking agents and, if appropriate, date and reason for discontinuation.

All patients who visited a dermatologist during follow-up were identified. Clinically important dermatological events were defined as any new manifestation or any exacerbation of pre-existing skin disease during follow-up. A standardized chart review form was used to record the following: start date of event, dermatological history, medication, morphological description, localization, histopathological and immunohistological information if available, working diagnosis, additional investigations, topical and systemic therapeutic actions, outcome of event, and any available information on rechallenge.

Drug-related eruptions were defined as skin reactions with a probable or definite relation to the use of TNF-α-blocking agents, based on a time relation with the administration of the agent, morphological pattern, and/or histological information. Drug-related eruptions were classified morphologically according to the criteria of Fitzpatrick and colleagues 21. Events were also classified as major or minor, major events being any requiring hospitalization.

Patient-years of follow-up were calculated for total follow-up, time on active therapy, and time after discontinuation of therapy (time off therapy). The number of events per year of follow-up was calculated for each RA patient for total time of follow-up, time on active treatment, and time off treatment, if appropriate.

In the control group, the following baseline characteristics were collected: age, sex, disease duration, rheumatoid factor, antinuclear antibody, DAS28, the number of DMARDs previously used, and prednisolone use. All visits to a dermatologist during follow-up were identified. Events were not recorded in the control group.

The baseline characteristics of RA patients on TNF-α-blocking therapy were compared according to whether or not the patients experienced dermatological events. The chi-square test was applied for dichotomous variables and Student's t-test was used for continuous variables. Nonparametric tests were applied when appropriate. The Wilcoxon signed rank test was used to compare the number of events per patient-year of follow-up in patients receiving and patients not receiving active TNF-α-blocking therapy. Univariate and multivariate logistic regression analyses were performed to identify possible predictive factors for the occurrence of a dermatological visit (independent variable, dichotomous) in RA patients on TNF-α-blocking therapy. Dependent variables tested were sex, age at diagnosis, rheumatoid factor, antinuclear antibody, disease duration, DAS28 at baseline, prior number of DMARDs, use of prednisolone, and duration of follow-up. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

The number of patients who visited a dermatologist was compared between RA patients on TNF-α-blocking therapy and controls, using the chi-square test. P values and ORs were calculated.

All tests were two-sided, with P < 0.05 considered statistically significant. Statistical analyses were performed using SPSS statistical software (v 12.0.1, SPSS Inc, USA).

A total of 289 RA patients started TNF-α-blocking therapy between June 1994 and December 2003. Their baseline characteristics are shown in Table 1.

The median follow-up time was 2.3 years (range 0.02 to 9.6). The total follow-up time was 911 patient-years, with 627 patient-years representing active therapy. Seventy of the 289 RA patients (24%) received more than one TNF-α-blocking agent and 8 (3%) received more than two agents. Infliximab was administered to 167 patients, adalimumab to 108, etanercept to 78, and lenercept to 31.

Dermatological events were recorded in 72 of the 289 RA patients (25%) receiving TNF-α-blocking therapy and in 37 (13%) of the control group (n = 289). The odds ratio (OR) of TNF-α-blocking therapy for a dermatological referral was 2.26 (95%CI 1.46 to 3.50, P < 0.0005). In patients on TNF-α-blocking therapy fifty-six instances of dermatological conditions were recorded in 34 patients (47%) and included, among others, 10 drug reactions – while the patient was receiving gold (7), nonsteroidal anti-inflammatory drugs (2), or methotrexate (1) – 10 cases of eczema, 9 of mycosis, 3 of other infections, and 5 of chronic venous insufficiency.

In univariate analyses, duration of follow-up (OR 1.27, 95%CI 1.14 to 1.41, P < 0.0005) and of disease (OR 1.03, 95%CI 1.003 to 1.07, P < 0.05) were statistically significant predictive factors for a dermatological event. In a multivariate model, only duration of follow-up was a statistically significant predictive factor (OR 1.30, 95%CI 1.12 to 1.52, P < 0.001).

One hundred and twenty-eight dermatological events were recorded during follow-up in RA patients on TNF-α-blocking therapy (0.14 event per patient-year), as listed in Table 2. The event per patient-year ratio was 0.16 during active treatment and 0.10 off treatment (P < 0.001). The number of events recorded during or after treatment was 56 for adalimumab (0.12 event per patient-year), 49 for infliximab (0.14 per patient-year), 16 for etanercept (0.13 per patient-year), and 13 for lenercept (0.07 per patient-year). TNF-α-blocking therapy was permanently withdrawn because of dermatological events 21 times in 19 patients.

Thirty-three infections were recorded in 27 patients, consisting of 20 fungal, 11 bacterial, and 2 viral infections (see Table 3). Two patients had had a previous episode of dermatomycosis. None of the patients required hospitalization. One patient, who temporarily discontinued adalimumab monotherapy twice because of elective surgery, developed a bacterial superinfection of pre-existing eczema after every restart.

Eczema was diagnosed 20 times in 19 patients and appeared in various morphological patterns. Most events were described as erythematosquamous (n = 8) or erythematous (n = 3) lesions or plaques, localized on hands and feet (n = 3), arms and legs (n = 5), face (n = 1), neck (n = 1), and buttocks (n = 1). A vesicular rash on hands and feet was described five times. A papular rash was described in three cases, with localization around the eyes, on the back, and once on the back and lower legs. Diagnoses comprised dyshidrotic (n = 5), contact (n = 4), nummular (n = 1), atopic (n = 1), papular (n = 1), and nonspecific eczema (n = 8). Two patients had a prior history of dyshidrotic eczema.

Biopsies were performed in five events. Histology showed dermatitis and spongiosis in all cases, with high dermal perivascular infiltration in three. One biopsy also showed mild psoriasiform acanthosis and another showed additional keratinocyte necrosis.

Three patients stopped TNF-α-blocking therapy because of the dermatological event, after which the lesions resolved. Hospitalization was necessary for treatment of eczema in one patient. In another patient the eczematous lesions recurred after adalimumab therapy was restarted. Adalimumab was continued and topical steroids were applied with good effect. TNF-α-blocking therapy had already been stopped in 4 patients before the onset of eczema and was continued in 13 patients, of whom 7 had persisting or recurring lesions. Therapy consisted mostly of topical corticosteroids.

Drug-related eruptions occurred frequently during the first 5 months of TNF-α-blocking therapy and were caused by all four TNF-α-blocking agents (see Table 4). In two cases, a generalized drug-related eruption followed subcutaneous injection of etanercept. In two cases, the eruption developed during infusion (patients numbers 8 and 11, Table 4). In the other cases the time of onset ranged between 2 and 57 days after the most recent infusion.

Most drug-related eruptions consisted of a combination of morphological patterns, including exanthema, urticarial eruptions, lichenoid skin lesions, and purpura. In four patients, an eczematous drug-related eruption was seen. Classification as drug-related eruption was based on a time relation with administration of the TNF-α-blocking agent, the morphological pattern, and/or histological information. Two patients had experienced a previous drug-induced eruption (1 dermatitis in response to gold, 1 dermatitis after indomethacin).

The histological findings were compatible with the diagnosis in all cases. Perivascular infiltrations – predominantly lymphocytic – epidermal exocytosis, and hyperorthokeratosis were described. Interface dermatitis was described in three instances. One biopsy revealed focal infiltrations with marked vascular and endothelial proliferation.

Seven patients stopped and 8 patients continued therapy; 6 of them had a positive rechallenge and recurring lesions. One major event was recorded: an RA patient was hospitalized for an extensive eczematous eruption with urticaria on arms and legs (Fig. 1, and Patient no. 6 in Table 4). Treatment consisted mostly of topical application of corticosteroids and sometimes of systemic antihistamines.

Events of skin malignancies were recorded five times, in four patients. One RA patient developed three basal cell carcinomas simultaneously on her left arm, right nostril, and right eyelid after 2.7 years of adalimumab therapy, which was subsequently stopped. One 74-year-old RA patient developed Bowen's disease on his right hand 2 years after adalimumab therapy had been stopped. The same patient later developed a squamous cell carcinoma on the left earlobe after the start of etanercept therapy. Other skin malignancies recorded were a squamous cell carcinoma (earlobe) after 1.5 months of adalimumab therapy and a low-grade basalioma (Pinkus epithelioma) on the leg after 6 months of adalimumab therapy. In all cases, histology confirmed the diagnosis and therapy consisted of excision. No recurrences were seen.

Actinic keratosis was recorded in five patients (three receiving adalimumab, one infliximab, and one lenercept). Excision or cryotherapy was successful in four. One patient had recurring actinic lesions on the scalp.

Benign tumors were recorded seven times during TNF-α-blocking therapy. One patient experienced an increased growth of a facial telangiectatic nevus, present since childhood, 2 months after starting etanercept therapy. Seborrheic keratosis (n = 3), oral hyperkeratosis (n = 1), histiocytoma (n = 1), and fibroma (n = 1) were also recorded.

Vasculitis was recorded five times: four during and one after cessation of TNF-α-blocking therapy. The diagnosis was confirmed by biopsy in four cases. One patient developed a superficial necrotizing leukocytoclastic vasculitis with ulceration after 7 months of infliximab therapy, with complete recovery after discontinuation of infliximab. One patient developed a papular erythema in the groins after 5 years of adalimumab therapy. Histological examination was compatible with vasculitis with infiltration of mononuclear cells and presence of eosinophilic granulocytes. One patient developed a purpuric vasculitis on the legs after 1.5 months of lenercept therapy, improving spontaneously despite continuation of lenercept. One patient developed isolated digital vasculitis on his toes after one year of adalimumab therapy, which was continued. The lesions persisted. No biopsy was performed. One patient developed a generalized urticarial exanthema after therapy with etanercept 2 years earlier. Current therapy consisted of hydroxychloroquine and prednisolone. Histology showed a mild leukocytoclastic vasculitis.

The nine events with ulcers included four pressure ulcers, two ulcers due to dependency edema, one traumatic ulcer, one ulcer secondary to an unguis incarnatus, and one ulcer without further specification. Biopsies were taken in two patients, but no signs of vasculitis were found. A patient had a pressure ulcer with secondary infection and a fistula on his ankle, which contained osteosynthetic material. The patient was admitted to the hospital for intravenous antibiotic therapy and infliximab was stopped for several months. After recovery, the patient restarted infliximab without recurrence of his skin problems. TNF-α-blocking therapy was continued in the other eight patients, and in four of these the ulcers recovered; follow-up was missing in the other four.

In 10 patients, a dermatological consultation was recorded for stasis dermatitis (n = 3), edema (n = 3), varices (n = 2), or chronic venous insufficiency (n = 2). In one patient with extensive varices, infliximab therapy was stopped temporarily because of a complicating thrombophlebitis. One patient had edema of both legs of unknown cause, with livid discoloration and induration. One patient had lymphedema secondary to RA. All other events were considered to be related to comorbidity, other than RA.

Psoriatic or psoriasiform eruptions were recorded in three RA patients. One developed a vesiculopustular erythematosquamous rash on hands and feet after 9 months of adalimumab therapy. Histology showed a mixed psoriasiform and spongiotic dermatitis. A second RA patient developed psoriasis guttata-like eruptions on her lower legs after 4 years of therapy with adalimumab. The lesions diminished after adalimumab was withdrawn. A third patient developed a psoriasiform eruption on arms and legs after 16 months of adalimumab therapy. Histology obtained in the latter two patients was consistent with psoriasis.

Other dermatological conditions that occurred during or after TNF-α-blocking therapy included, among others, dermatomyositis (1), drug-induced systemic lupus erythematosus (1), and lymphomatoid papulosis-like eruption (1). Details are shown in Table 5.

One RA patient developed a macular rash on the inner sides of the upper arms and legs after 2.5 months of lenercept monotherapy. A skin biopsy showed a nonspecific chronic dermatitis. A soft-tissue biopsy, including skin, fascia, and muscle, showed fascial and muscular infiltration, consistent with dermatomyositis.

One RA patient developed a drug-induced systemic lupus erythematosus after 20 months of infliximab therapy in combination with methotrexate, consisting of discoid lupus erythematosus lesions on her hands and scalp, aphthous lesions, conversion to antinuclear antibody positivity, and a positive anti-double stranded-DNA (titer 60 U/L). The skin lesions flared within one week after infusion and disappeared after discontinuation of infliximab.

A third RA patient developed macular erythematosquamous lesions on her lower arms, upper legs and trunk after 2.6 months of adalimumab monotherapy. Histology showed a dermal infiltration with CD30-positive atypical T cells. Although the lesions appeared to be lymphomatoid papulosis, they completely disappeared within 6 weeks. Adalimumab was not stopped. This patient developed a large-cell anaplastic non-Hodgkin lymphoma 2 years later.