Alopecia y otros anti tnf(5)
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This report summarizes 5 new cases of alopecia areata (AA) that developed in patients being treated with tumor necrosis factor-alpha (TNF-α) blocker agents, and reviews 11 additional cases reported in literature. Most patients presented with rapid, extensive AA involving the scalp and sides. One third had a personal or family history of AA. Prognosis was generally poor, with minimal response to treatments. While rare, the authors conclude AA may be more common than reports suggest during anti-TNF-α therapy, especially in those with autoimmune disease history.
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Alopecia y otros anti tnf(5)
- 1. SHORT REPORT Alopecia areata as another immune-mediated disease developed in patients treated with tumour necrosis factor-a blocker agents Report of five cases and review of the literature M Ferran,†, * J Calvet,‡ M Almirall,‡ RM Pujol,† J Maymo´ ‡ Departments of † Dermatology and ‡ Rheumatology, Hospital del Mar, IMAS, Barcelona, Spain *Correspondence: M Ferran. E-mail: mferran@hospitaldelmar.cat Abstract Background Tumour necrosis factor antagonists (anti-TNF-a) have demonstrated the efficacy in different chronic immune inflammatory disorders. Within the spectrum of adverse events, autoimmune diseases have been observed, including cases of alopecia areata (AA). Objectives The objective of the study is to characterize AA developed during anti-TNF-a therapy. Methods We present five new cases and review all the cases reported in the literature (eleven). Results One third of the cases had a positive (personal or family) history of AA. Most of them presented with rapid extensive AA, usually involving the ophiasis area. Prognosis was usually poor, with slight response to treatments. In the cases where anti-TNF-a therapy was maintained, the course did not seem to change. Conclusions Although rare, AA developed during anti-TNF-a therapy might be more frequent than suggested by reports of isolated cases. Personal and family history of autoimmune disease might alert clinicians to their possible development or relapse once the anti-TNF-a therapy is started. Received: 24 January 2010; Accepted: 27 May 2010 Keywords adalimumab, alopecia areata, anti-TNFa, autoimmune, etanercept, infliximab Conflict of interest None. Funding sources None. Introduction In the last decades, tumour necrosis factor antagonists (anti-TNF-a) have demonstrated efficacy in the treatment of different chronic immune inflammatory disorders. Anti-TNF-a therapies seem to be safe and well-tolerated drugs, but with their increasing use and longer follow-up periods of treatment, a new spectrum of adverse events, including some immune-mediated diseases, has been observed. Leucocytoclastic vasculitis, lupus-like syndrome, systemic lupus erythematosus (SLE) and interstitial lung disease are the prin- cipal reported immune-mediated associated diseases,1–3 as well as paradoxical psoriasiform eruption.4 In the last 4 years, isolated cases of localized or extensive alopecia areata (AA) developing in patients under treatment with anti-TNF-a agents have been described.5–13 Material and methods Five new cases of AA appeared during anti-TNF-a therapy are described. In addition, a Medline search from 2005 until December 2010 has been performed to identify all the cases described in the literature. The terms used in Medline were alopecia and anti-TNF- a, infliximab, etanercept or adalimumab. A review of all the cases is presented. Results Case reports Our five cases are described in Table 1 and shown in Fig. 1. In summary, they are three women and two men, all with rheumatic ª 2010 The Authors JEADV 2011, 25, 479–484 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology DOI: 10.1111/j.1468-3083.2010.03770.x JEADV
- 3. immune-mediate inflammatory diseases other than SLE, being treated with etanercept (3) or adalimumab (2). One of them had family history of AA and another one, a personal history of mild AA in early childhood. Three of these patients developed AA between 3 and 5 months after anti-TNF-a introduction and coin- cided with disease-modifying antirheumatic drugs (DMARD) withdrawal. ANA and other immunological test were negative. Clinically, all the female cases developed an ophiasis pattern, whereas men presented with patchy AA. Anti-TNF-a therapy was withdrawn in two patients, one of whom had evolved to AA uni- versalis. However, the evolution of the clinical picture was not modified by maintenance or withdrawal of anti-TNF agent. Review of the literature We found 11 cases of AA induced by anti-TNF-a therapies in the literature,5–15 which are summarized in Table 1. There were no differences among genders. Past history of AA was present in three cases, whereas family history was either negative or non-available. The anti-TNF-a agent associated with AA was more frequently a monoclonal antibody (four cases of infliximab, five adalimumab and two etanercept). The time for AA to develop once the anti- TNF-a agent had been introduced was between a few weeks and 3.5 years. There were not any conclusive triggers that could be associated with the development or recurrence of AA; although in one case, the flare of AA developed after reducing the concomitant immunosuppressive treatment. Seven cases presented with rapid extensive AA, usually involving the sides and occiput (ophiasis area). Three cases developed AA involving other hair-bearing areas and, in two cases, AA precipi- tated coincident with another immune-mediated phenomenon (multiple halo nevi,10 psoriasiform eruption15 ). Prognosis was usually poor, with slight response to treat- ments and even worsening of the AA. Although the anti-TNF-a therapy was discontinued in five cases, only two cases showed improvement with complete regrowth (one after treatment with cyclosporine15 ), two other cases progressed into AA totalis or universalis and evolution was not reported in one case. In the cases where anti-TNF-a therapy was maintained, the course did not seem to change (a slight improvement was recorded in two cases). Discussion Alopecia areata is a non-scarring hair loss, which can involve any hair-bearing area. Clinically, AA can present with different clinical manifestations, from reversible patchy hair loss to complete baldness (AA totalis) or complete body hair loss (AA univer- salis).16 AA is considered an organ-specific autoimmune disease, which might be associated with other autoimmune conditions, such as thyroid disease, vitiligo, SLE and other collagen- vascular diseases.16 In rheumatic immune-mediated inflammatory diseases other than SLE (RA, PsA, AS), no data can be found in the literature. Table1Continued Age=gender Diagnosis Immunologyand geneticmarkers Personalhistory ofAA Familyhistory ofAA Anti-TNF agentðdoseÞ Monthsof treatment Concomitant DMARDs Possibletriggers Clinicalpicture Anti-TNF discontinuation Treatments Evolution 15Katoulisetal.14 30$RANANoNoADA(40mg eow) 9LEF CsA StressPatchyhairlossNoTopicalandsystemic steroids Stable,minimal hairregrowth 16Nakagomi etal.15 69$RANANANAINF(NA)24NANAPatchyhairloss Psoriasiformeruption withPPP YesTopicalCP CsA Hairregrowth ⁄w,everyweek;AA,alopeciaareata;ADA,adalimumab;AS,ankylosingspondylitis;CCP,anticitrulinatedpeptides;CJA,chronicjuvenilearthritis;CP,clobetasolpropionate;CQ,cloroquine; CsA,cyclosporine;DXM,dexametasone;eow,everyotherweek;ETA,etanercept;INF,infliximab;LEF,leflunomide;MPDN,methylprednisolone;MTX,methotrexate;NA,notavailable;PDN, prednisone;PPP,palmoplantarpustulosis;PsA,psoriaticarthritis;PsP,psoriasispustulosa;PsV,psoriasisvulgaris;RA,rheumatoidarthritis;RAc,retinoicacid;RF,rheumatoidfactor;TA, triamcinoloneacetonide;x2⁄w,twiceaweek. ª 2010 The Authors JEADV 2011, 25, 479–484 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology Alopecia areata developed during anti-TNF-alpha therapy 481
- 4. Data on the role of TNF-a on the etiopathogenesis of AA are scarce. A gene polymorphism for the TNF-a gene or a close-linked locus within the major histocompatibility complex was found in patients with patchy AA.17 However, given multiple reported cases of developing AA while on anti-TNF-a agents either de novo or recurrently, and the lack of efficacy of etanercept as a treatment,17 it seems that the immunological cascade responsible for AA is not dependent on TNF-a. We propose that TNF-a blocking switches (a) (b) (c) (d) (e) Figure 1 Clinical pictures of patients (a–e). The first three cases present with confluent alopecic patches involving ophiasis area. Last cases show a small and patchy alopecia areata (AA) on the beard and moustache, as well as the scalp. ª 2010 The Authors JEADV 2011, 25, 479–484 Journal of the European Academy of Dermatology and Venereology ª 2010 European Academy of Dermatology and Venereology 482 Ferran et al.
- 5. off the primary disease inflammatory pathway, but could move the unblocked proximal inflammatory response into an alternative signalling pathway. Depending on the individual genetic suscepti- bility, this pathway could clinically manifest as one or another immune-mediated disease states, for instance, psoriasiform para- doxical eruptions or AA. AA might be associated with all three anti-TNF-a agents and can present with different degrees of involvement, typically involving the ophiasis pattern. Considering the evolution of all the patients, it seems that the clinical picture is milder and with better prognosis in patients on etanercept. A third of all the patients had a positive (personal or family) history of AA, but it was not associated with differences in clinical manifestations or evolution. However, in those cases with a personal history, the clinical picture during anti-TNF-a therapy was more severe than previous episodes. In three of our cases plus one from the literature, AA devel- oped coinciding not only with the anti-TNF-a agent introduc- tion but also with the dosage decrease of concomitant used immunosuppressive agents, which might mean that the later could be acting as a curb. Once the immunosuppressant is reduced or withdrawn, AA triggered by anti-TNF-a therapy would not find any impediment to develop. Actually, methotrex- ate, as well as other immunosupressants, has been reported as a useful therapy for AA,18,19 which may explain this curb effect. However, some immunosupressants have also been implicated as a cause of AA, for instance leflunomide or cyclosporine.20,21 Two of our cases were being treated with leflunomide; however, patient 3 had been taking it for a long time, without developing any adverse event, and patient 2 was progressively decreasing its dose when AA developed, so leflunomide causality is doubtful in both cases. Regarding alopecia caused by methotrexate, it usually presents as anagen effluvium. As far as we have determined, no cases of AA induced by methotrexate have been described in the literature. The causality of anti-TNF-a agents is difficult to establish. Drug induced alopecia should be diagnosed if improvement of the alopecia occurs after cessation of the suspected drug. Although the anti-TNF agent was discontinued in seven of 16 cases, only two cases showed improvement with complete re- growth of hair. In addition, considering the increased risk for autoimmune disease in these rheumatic patients, the possibility that the use of an anti-TNF-a drug and the development of AA might have been coincidental cannot be excluded. However, immune-mediated diseases induced by anti-TNF-a do not follow the patterns of most adverse drug reactions and do not fit the classic criteria for adverse effect. For instance, they might last longer in spite of drug withdrawal,3,4 and it might be unethical to perform a challenge test. Therefore, taking into consideration other autoimmune diseases developed during anti-TNF-a ther- apy and temporal association, a causative effect more than a coincidental effect seems to be likely. The decision to continue the therapy, in some patients, was taken to avoid a major flare of the underlying disease, as AA was tolerated by the patient with the prescribed treatment. In summary, we report five new cases of AA in patients treated with anti-TNF-a, which increases the total to 16 published cases, proving additional evidence for a causal relationship. All three anti-TNF-a agents seem to be associated to development or exac- erbation of AA. Although AA is a prevalent disease, especially in patients with other autoimmune disease, association with articular rheumatic inflammatory diseases has not been previously described without anti-TNF-a therapy. Our five cases in a short series of articular inflammatory diseases suggest that the incidence of AA might be higher than reported in this subgroup of patients. Considering that some cases had a personal or family history of AA, a complete personal and family medical history is suggested before starting an anti-TNF-a agent. References 1 Ramos-Casals M, Brito-Zero´n P, Mun˜oz S et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86: 242–251. 2 Ramos-Casals M, Brito-Zero´n P, Soto MJ, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNF-targeted therapies. Best Pract Res Clin Rheumatol 2008; 22: 847–861. 3 Exarchou S, Voulgari P, Markatseli T, Zioga A, Drosos A. Immune-mediated skin lesions in patients treated with anti- tumour necrosis factor alpha inhibitors. Scand J Rheumatol 2009; 4: 1–4. 4 Collamer AN, Guerrero KT, Henning JS, Battafarano DF. 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