Department of Internal Medicine, Section on Rheumatology, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, LA, USA
SIR, Since the addition of tumour necrosis factor (TNF) inhibitors to the armamentarium of drugs used to treat rheumatoid arthritis (RA) in 1998, little has been described in terms of cutaneous vasculitis associated with these medications. We describe a case of cutaneous vasculitis in which symptom onset directly coincided with the institution of TNF inhibitors, and symptom resolution occurred promptly upon drug withdrawal. To our knowledge, this is the first case of cutaneous leucocytoclastic vasculitis occurring with the separate use of etanercept and infliximab in the same patient.
Etanercept, a recombinant soluble human TNF receptor protein, and infliximab, a chimeric anti-TNF- monoclonal antibody, have been promoted for use in patients with moderate to severe RA in whom failure with other disease-modifying anti-rheumatic drugs (DMARDs) has been documented. More recently, etanercept has also been promoted for patients with early active RA in whom joint symptoms are less severe. The most common side-effects reported with etanercept have included mild injection site reactions and infections, mainly mild upper respiratory infections (colds) or sinusitis [1, 2]. Adverse events reported with infliximab have included headache, infections (mainly upper respiratory and urinary) and, rarely, infusion reactions, including fever, urticaria, dyspnoea and hypotension [3]. Theoretical concerns of malignancy risk and provocation of autoimmune disease secondary to TNF inhibition have been suggested in the current literature, but few cases have been clinically proven thus far [4]. We describe a case of cutaneous vasculitis presumed to be secondary to the introduction of two different TNF inhibitors into a patient's medical regimen.
A 73-yr-old female was diagnosed with seropositive RA in 1994 and subsequently underwent trials of multiple different DMARDs to control her disease, with no success. In February 1999, etanercept (25 mg subcutaneous injections twice weekly) was added to the regimen with dramatic beneficial effects on the synovitis. However, within the same month of starting therapy, the patient returned to our clinic with complaints of a rash on her chest and feet bilaterally. The rash consisted of multiple erythematous papular and nodular lesions 23 cm in diameter, some with central clearing, on the dorsums of her feet bilaterally, her distal fingertips and the central chest area. Etanercept was continued with addition of cetirizine and Temovate cream for symptoms. Four months later, the rash had spread to her hips bilaterally and, in addition, there was a large ecchymotic lesion at her right elbow.
Etanercept was stopped and the skin manifestations resolved. Two separate trials of etanercept later the same year again resulted in palpable purpura of the hands, legs and feet bilaterally. A 3 mm punch biopsy at that time was consistent with leucocytoclastic vasculitis.
Laboratory evaluation revealed that, with each reintroduction of etanercept, the erythrocyte sedimentation rate and C-reactive protein concentration fell from approximately 120 mm/h and 11 mg/dl to ranges of 70100 mm/h and 1.05.0 mg/dl. Laboratory tests during the same month as the biopsy revealed an antinuclear antibody (ANA) titre of 1:320 and a positive test for perinuclear antineutrophil cytoplasmic antibodies (ANCA) with a myeloperoxidase of less than 0.5 EU/ml. The patient was negative for double-stranded DNA antibodies, anti-Sm antibodies, anti-SS-A (RO) antibodies, anti-SS-B (La) antibodies and ribonucleoprotein (RNP) antibodies. Complement levels were within normal limits. The only previous ANA test prior to TNF- blockade for comparison was positive, with a titre of 1:80 and a negative profile.
Recently, the patient underwent a trial of yet another TNF-inhibiting agent: infliximab, co-administered with low-dose methotrexate. Her synovitis again improved dramatically. Interestingly, however, after the third infusion of 200 mg of infliximab, cutaneous vasculitic lesions again developed on her lower extremities that were identical to the lesions she acquired while on etanercept.
We believe that the above case suggests a relationship between the introduction of therapy with TNF inhibitors and anti-drug antibody production. The resulting immune complexes and recruitment of inflammatory mediators led to cutaneous vasculitis.
In previous studies, 16% of patients who have started therapy with etanercept have developed non-neutralizing antibodies to the soluble receptor. Eleven per cent have developed new ANA positivity and 15% have developed new anti-double-stranded DNA positivity compared with 5 and 4% respectively with placebo [1, 2, 5, 6]. In addition, there have been several reports of patients who developed human anti-chimeric molecule antibodies was receiving therapy with infliximab [7]. The number of patients who developed these antibodies was reported to be significantly higher for those receiving infliximab than for those receiving placebo.
Our patient did have ANA test while on etanercept and the titre increased from its previous level; in addition, para-nuclear ANCA was detected, which can be seen in RA vasculitis or lupus.
Three other cases of autoimmune skin rash associated with etanercept have been documented (Table 1). These included one case of discoid lupus [8] and two cases of necrotizing vasculitis [8, 9]. To our knowledge, no other cases of cutaneous vasculitis with the use of infliximab have been documented, and there have been no reports of a single RA patient experiencing leucocytoclastic vasculitis with two different TNF-
blockers.
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Notes
Correspondence to: R. Quinet, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA 70121, USA.
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