A systematic review of vitiligo onset and exacerbation in patients receiving biologic therapy

To the Editor: Biologic therapies have improved outcomes in patients with immune-mediated inflammatory diseases due to their ability to inhibit specific proinflammatory cytokines, such as tumor necrosis factor-alfa (TNF-α) and interleukins (IL).1Rider P. Carmi Y. Cohen I. Biologics for targeting inflammatory cytokines, clinical uses, and limitations.Int J Cell Biol. 2016; 2016: 1-11Crossref Scopus (85) Google Scholar An infrequent side effect of biologic therapy is the onset of vitiligo. This systematic review aimed to comprehensively summarize the existing literature on new-onset and exacerbations of vitiligo after biologic use. Twenty-one studies were included after the OVID Embase and MEDLINE databases were systematically searched on July 13, 2020, in accordance with the PRISMA guidelines. The following search keywords were used: “vitiligo” and “specific biologics.” Overall, 140 patients (mean age, 46.7 years; males, 59.5% [50 of 84 patients]) reported vitiligo-related complications while on biologics (Table I).Table ISummary of characteristics and clinical outcomes of vitiligo in patients on biologic therapyCharacteristicsParticipantsTotal (n)140Age (y) Mean age ± standard deviation46.7 ± 9.1 Age range21-83 Reported total (n)58Sex (n, %) Female34 (40.5) Male50 (59.5) Reported total84Prior use of biologics (n, %) Yes3 (27.3) No8 (72.7) Reported total11Biologics (n, %) TNF-α inhibitor71 (82.6)Adalimumab32Infliximab26Etanercept11Certolizumab2 CD52 inhibitor6 (7.0)Alemtuzumab6 IL-12/23 inhibitor4 (4.7)Ustekinumab4 IL-17A inhibitor2 (2.3)Secukinumab1Ixekizumab1 CD20 inhibitor1 (1.2)Rituximab1 IL-6 receptor inhibitor1 (1.2)Tocilizumab1 CTLA-4 inhibitor1 (1.2)Abatacept1 Reported Total86Indication (n, %) Ankylosing spondylitis25 (29.1) Psoriasis19 (22.1) Crohn's disease12 (14.0) Rheumatoid arthritis11 (12.8) Ulcerative colitis6 (7.0) Multiple sclerosis6 (7.0) Psoriatic arthritis4 (4.7) Hidradenitis suppurativa1 (1.6) Pan uveitis1 (1.6) SAPHO1 (1.6) Reported total86Vitiligo outcome (n, %) Induction118 (84.3) Exacerbation22 (15.7) Reported total140Latency period (mo) Mean duration ± standard deviation13.1 ± 8.4 Duration range1.4-60 Reported total (n)58Cutaneous distribution (n, %) Extremities30 (38.5) Trunk26 (33.3) Face10 (12.8) Entire body4 (5.1) Knees2 (2.6) Elbows2 (2.6) Groin1 (1.3) Neck1 (1.3) Leucotrichia1 (1.3) Poliosis1 (1.3) Reported total (n)78Drug discontinuation (n, %) Yes38 (82.6) No8 (17.4) Reported total46Treatment (n, %) Corticosteroids7 (22.6) Topical tacrolimus6 (19.4) Excimer laser and topical tacrolimus3 (9.7) Oral prednisone2 (6.5) Clobetasol2 (6.5) Secukinumab1 (3.2) Clindamycin1 (3.2) Cyclophosphamide1 (3.2) Calcipotriol/betamethasone dipropionate1 (3.2) Methotrexate1 (3.2) Triam1 (3.2) Plasma infusions1 (3.2) Minox1 (3.2) Polipodium leucotomos1 (3.2) Vitamin E1 (3.2) Topical phenylalanine1 (3.2) Reported total31Clinical outcomes (n, %) Complete resolution2 (4.5) Partial resolution13 (29.5) No recovery20 (45.5) Worsening9 (20.5) Reported total44Resolution period (mo) Mean duration ± standard deviation28.6 ± 8.4 Duration range1-32 Reported total (n)42Drug switches (n, %) Etanercept2 (66.7) Secukinumab1 (33.3) Reported total3 Open table in a new tab Of the 140 patients, 84.3% (118 patients) experienced de novo vitiligo and 15.7% (22 patients) experienced exacerbation of pre-existing vitiligo after the administration of the following reported biologics: anti–TNF-α (82.6% [71 of 86 patients]), anti-CD52 (7.0% [6 of 86 patients]), anti–IL-12/23 (4.7% [4 of 86 patients]), anti–IL-17A (2.3% [2 of 86 patients]), anti-CD20 (2.3% [2 of 86 patients]), and anti–IL-6 (1.2% [1 of 86 patients]); specific biologics were not reported in 54 patients. The most common biologic indications were: ankylosing spondylitis (29.1% [25 of 86 patients]), psoriasis (22.1% [19 of 86 patients]), and Crohn's disease (14.0% [12 of 86 patients]). Of the locations of depigmentation that the authors reported, the trunk and/or extremities (60.4% [32 of 53 patients]) were most commonly affected. The mean duration of exposure to biologics before vitiligo development or exacerbation was 13.1 months (range: 1.4-60 months). Vitiligo treatment was reported for 31 patients, which included topical corticosteroids (22.6% [7 of 31 patients]), topical tacrolimus (19.4% [6 of 31 patients]), and a combination of excimer laser and topical tacrolimus (9.7% [3 of 31 patients]) (Table II). Complete resolution of vitiligo was observed in 4.5% of cases (2 of 44 patients) after biologic discontinuation, with a mean resolution period of 12 months. A partial resolution was achieved in 37.1% of cases (13 of 35 patients): after biologic discontinuation and treatment (3 of 13 patients), treatment only (2 of 13 patients), and biologic discontinuation only (1 of 13 patients), with the mean resolution period of 6.5 months; the treatment and biologic discontinuation regimen for partial resolution in 22 patients were not reported. Additionally, 3 patients switched to an alternate biologic for their primary indication: etanercept (n = 2) and secukinumab (n = 1); no vitiligo-related adverse events were reported after the switch.Table IISummary of outcomes and treatment regimensManagement strategiesResolution outcomeMean resolution period (mo)Discontinuations onlyCR: 112PR: 0N/AWorsening: 0N/ANo resolution: 0N/AReported total: 1Discontinuation and treatmentCR: 0N/APR: 36.5Worsening: 0N/ANo resolution: 0N/AReported total: 3Treatment onlyCR: 0N/APR: 26.5Worsening: 0N/ANo resolution: 112Reported total: 3NoneCR: 0N/APR: 0N/AWorsening: 0N/ANo resolution: 1N/AReported total: 1NRCR: 1NRPR: 832Worsening: 932No resolution: 1832Reported total: 36CR, Complete resolution; N/A, not applicable; NR, no resolution; PR, partial resolution. Open table in a new tab CR, Complete resolution; N/A, not applicable; NR, no resolution; PR, partial resolution. In patients that experienced vitiligo development or exacerbations, the most common biologic class was anti–TNF-α. A retrospective study documented a 2-fold increased risk of developing vitiligo among patients on anti–TNF-α as compared to the general population.2Bae J.M. Kim M. Lee H.H. et al.Increased risk of vitiligo following anti-tumor necrosis factor therapy: a 10-year population-based cohort study.J Invest Dermatol. 2018; 138: 768-774Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Long-term TNF-α inhibition may give rise to cytokine shifts and the subsequent recruitment of autoreactive T cells to the epidermis, leading to the destruction of melanocytes.3Palucka A.K. Blanck J.P. Bennett L. Pascual V. Banchereau J. Cross-regulation of TNF and IFN-α in autoimmune diseases.Proc Natl Acad Sci U S A. 2005; 102: 3372-3377Crossref PubMed Scopus (407) Google Scholar,4Silva L.C. Ortigosa L.C. Benard G. Anti-TNF-α agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls.Immunotherapy. 2010; 2: 817-833Crossref PubMed Scopus (165) Google Scholar In addition to being an adverse effect of biologics, vitiligo development or exacerbation can also be seen as a cutaneous manifestation incidentally associated with chronic immune-mediated inflammatory diseases. For instance, Snook et al5Snook J.A. De Silva H.J. Jewell D.P. The association of autoimmune disorders with inflammatory bowel disease.QJM. 1989; 72: 835-840PubMed Google Scholar reported vitiligo in 1.1% of adults with ulcerative colitis and 0.5% of patients with Crohn's disease compared with 0.3% in the control population. Limitations of this review include a small sample size, observational nature of the studies, and a mean Naranjo score of 3 (possible). Despite the need for further studies, our systematic review demonstrates that vitiligo-related complications can be associated with biologic use, especially anti–TNF-α.

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