title: Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.
abstract: OBJECTIVE
  Vitiligo-like depigmentation in patients with melanoma may be associated with more favorable clinical outcome. We conducted a systematic review of patients with stage III to IV melanoma treated with immunotherapy to determine the cumulative incidence of vitiligo-like depigmentation and the prognostic value of vitiligo development on survival.
  
  
  METHODS
  We systemically searched and selected all studies on melanoma immunotherapy that reported on autoimmune toxicity and/or vitiligo between 1995 and 2013. Methodologic quality of each study was appraised using adapted criteria for systematic reviews in prognostic studies. Random-effect models were used to calculate summary estimates of the cumulative incidence of vitiligo-like depigmentation across studies. The prognostic value of vitiligo-like depigmentation on survival outcome was assessed using random-effects Cox regression survival analyses.
  
  
  RESULTS
  One hundred thirty-seven studies were identified comprising 139 treatment arms (11 general immune stimulation, 84 vaccine, 28 antibody-based, and 16 adoptive transfer) including a total of 5,737 patients. The overall cumulative incidence of vitiligo was 3.4% (95% CI, 2.5% to 4.5%). In 27 studies reporting individual patient data, vitiligo development was significantly associated with both progression-free-survival (hazard ratio [HR], 0.51; 95% CI, 0.32 to 0.82; P < .005) and overall survival (HR, 0.25; 95% CI, 0.10 to 0.61; P < .003), indicating that these patients have two to four times less risk of disease progression and death, respectively, compared with patients without vitiligo development.
  
  
  CONCLUSIONS
  Although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, our findings suggest clear survival benefit in these patients. Awareness of vitiligo induction in patients with melanoma is important as an indicator of robust antimelanoma immunity and associated improved survival.
authors.affiliation: Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. h.e.teulings@amc.uva.nl.
authors.forename: Hansje-Eva
authors.initials: HE
authors.lastname: Teulings
authors.affiliation: Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Limpens
authors.affiliation: Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Jansen
authors.affiliation: Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.affiliation: Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Reitsma
authors.affiliation: Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Phyllis I
authors.initials: PI
authors.lastname: Spuls
authors.affiliation: Hansje-Eva Teulings, Jacqueline Limpens, Sophia N. Jansen, Aeilko H. Zwinderman, Johannes B. Reitsma, Phyllis I. Spuls, and Rosalie M. Luiten, Academic Medical Centre, University of Amsterdam, Amsterdam; Johannes B. Reitsma, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Rosalie M
authors.initials: RM
authors.lastname: Luiten
mesh_terms: D018572:Disease-Free Survival; D006801:Humans; D017496:Hypopigmentation / Q000453:epidemiology / Q000276:immunology; D007167:Immunotherapy; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000276:immunology / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D009367:Neoplasm Staging; D016017:Odds Ratio; D011379:Prognosis; D012878:Skin Neoplasms / Q000276:immunology / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D014820:Vitiligo / Q000453:epidemiology / Q000276:immunology; D000096142:Cutaneous Malignant Melanoma