Discoid drug‐induced lupus erythematosus induced by antitumor necrosis factor agents is a very rare subtype of cutaneous lupus: Three cases and literature review

Dear Editor, Drug-induced lupus erythematosus (DILE) is a lupus-like autoimmune disorder, which usually occurs with chronic exposure to certain drugs and resolves after cessation of the culprit medication. The spectrum of DILE constantly evolves with that of the pharmacopeia. In a recent study of 12 166 DILE identified from theWHO pharmacovigilance database, 118 drugs were identified. This study showed that since 2007, antitumor necrosis factor (anti-TNF) agents have been the drugs most commonly associated with systemic DILE. Such as idiopathic lupus, DILE can be classified in systemic and cutaneous DILE. Among cutaneous DILE, subacute DILE has been mostly reported. In a case-control study, anti-TNF agents were also associated with occurrence of subacute DILE (odds ratio 8.0, 95% confidence interval 1.6-37.2). Discoid form of DILE has been rarely reported. We report three cases of discoid DILE induced by anti-TNF agents and we reviewed four cases previously published identified through a literature search from MEDLINE/PubMed and we describe clinical, immunological, and pathological features, potential association with systemic DILE and therapeutic management. Individual features of our three cases are presented in Table 1, and those from the literature review in Table 2. Discoid DILE occurred mostly in women (sex ratio 6:1). The median age at onset was 40 years (range 30-53). Underlying diseases were rheumatoid arthritis (n = 5) and Crohn's disease (n = 2) and triggering anti-TNF agents included infliximab (n = 3), adalimumab (n = 3), and certolizumab pegol (n = 1). Interestingly, in the case report of Spillane et al, discoid DILE occurred after the second injection of adalimumab, whereas no symptoms appeared during the 8 months of etanercept treatment. More importantly, etanercept was restarted without recurrence of discoid DILE suggestive that adalimumab may be more associated with the risk of discoid DILE. However, this remains to be confirmed. Time between initiation of the anti-TNF agent and the onset of discoid DILE ranged from 1 month to 4 years. Cutaneous lesions were disseminated in five cases (Figure 1, case 1) and restricted to the face in two cases. Pathological features showed in all cases basal vacuolar alteration of the epidermis and a deep perivascular lymphocytic infiltrate (Figure 2, case 2 and Figure 3C, case 3). Direct immunofluorescence was positive in 2/3 cases with available data. Immunologic features included positive antinuclear autoantibodies (ANA; n = 5), positive anti-doublestranded DNA (anti-dsDNA; n = 4). Systemic involvement was noted only in our case 3. This 53-year-old woman presented typical erythematous and hyperpigmented patches with a central atrophic clearing, localized on the ears associated with hyperkeratotic lesions and erosions of the fingers (Figure 3A,B) as well as typical discoid DILE pathological findings (Figure 3C). She also displayed inflammatory joint pain with synovitis of the hands as well as a pericardial effusion, positive ANA, 1/5120 (vs 1/640 6 years ago under infliximab), positive dsDNA antibodies, decreased complement levels and lymphopenia. Considering therapeutic management, cutaneous lesions resolved after cessation of the triggering anti-TNF and topical treatment or shortterm hydroxychloroquine use in 6/7 cases. For case 3, cutaneous lesions and systemic symptoms did not resolve after the discontinuation of adalimumab and hydroxychloroquine 400 mg/d; therefore, she was started on oral prednisone 1 mg/kg/d and rituximab. Rituximab was switched to belimumab because of a persistent articular and cutaneous activity after 6 months. Finally, she was included in a protocol with lowdose interleukin 2, which initially led to partial improvement of both cutaneous and articular features, but she eventually relapsed. The refractory features could raise the hypothesis of a classical systemic lupus erythematosus occurring under anti-TNF rather than a DILE. Indeed, the resolution of symptoms after cessation of the culprit drug is one of the key clues of the diagnosis of DILE. However, there are no validated criteria for the diagnosis of DILE. Moreover, in a systematic review of systemic DILE induced by anti-TNF agents, systemic corticosteroids and immunosuppressive drugs were needed in 31/77 (40%) and 7/77 (9%), respectively, including one case with refractory disease. Overall, discoid DILE is a very rare subtype of DILE with less than 30 published cases almost exclusively associated with 5-fluorouracil agents. We found that discoid DILE may be also induced by anti-TNF agents and have similar clinical and pathological features than classical discoid DILE. Of importance cutaneous lesions resolved after cessation of the triggering anti-TNF in 6/7 cases, but we report one case refractory to treatment.