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Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure.

ABSTRACT: BACKGROUND:Vitiligo is an autoimmune disease in which cutaneous depigmentation occurs. Existing therapies are often inadequate. Prior reports have shown benefit of the Janus kinase (JAK) inhibitors. OBJECTIVE:To evaluate the efficacy of the JAK 1/3 inhibitor tofacitinib in the treatment of vitiligo. METHOD:This is a retrospective case series of 10 consecutive patients with vitiligo treated with tofacitinib. Severity of disease was assessed by body surface area of depigmentation. RESULTS:Ten consecutive patients were treated with tofacitinib. Five patients achieved some repigmentation at sites of either sunlight exposure or low-dose narrowband ultraviolet B phototherapy. Suction blister sampling revealed that the autoimmune response was inhibited during treatment in both responding and nonresponding lesions, suggesting that light rather than immunosuppression was primarily required for melanocyte regeneration. LIMITATIONS:Limitations include the small size of the study population, retrospective nature of the study, and lack of a control group. CONCLUSION:Treatment of vitiligo with JAK inhibitors appears to require light exposure. In contrast to treatment with phototherapy alone, repigmentation during treatment with JAK inhibitors may require only low-level light. Maintenance of repigmentation may be achieved with JAK inhibitor monotherapy. These results support a model wherein JAK inhibitors suppress T cell mediators of vitiligo and light exposure is necessary for stimulation of melanocyte regeneration.

SUBMITTER: Liu LY

PROVIDER: S-EPMC6233876 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure.

Liu Lucy Y LY Strassner James P JP Refat Maggi A MA Harris John E JE King Brett A BA

Journal of the American Academy of Dermatology 20170818 4

<h4>Background</h4>Vitiligo is an autoimmune disease in which cutaneous depigmentation occurs. Existing therapies are often inadequate. Prior reports have shown benefit of the Janus kinase (JAK) inhibitors.<h4>Objective</h4>To evaluate the efficacy of the JAK 1/3 inhibitor tofacitinib in the treatment of vitiligo.<h4>Method</h4>This is a retrospective case series of 10 consecutive patients with vitiligo treated with tofacitinib. Severity of disease was assessed by body surface area of depigmenta ...[more]

PMID: 28823882

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Project description:This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10?mg twice daily for 4?weeks and were followed for 4?weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4?weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-? production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-? production were decreased up to 42% 1?month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4?weeks after withdrawal.

Project description:IntroductionIn Australia, there is an unmet need for improved treatments for rheumatoid arthritis (RA). Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. To provide an overview of key study outcomes for tofacitinib in Australian patients, we analyzed the efficacy and safety of tofacitinib in the Australian subpopulation of global RA phase III and long-term extension (LTE) studies.MethodsData were pooled from the Australian subpopulation of four phase III studies and one LTE study (database not locked at cut-off date: January 2016). Patients in the phase III studies received tofacitinib 5 or 10 mg twice daily (BID), placebo (advancing to tofacitinib at months 3 or 6), or adalimumab, with background methotrexate or conventional synthetic disease-modifying antirheumatic drugs. Patients in the LTE study received tofacitinib 5 or 10 mg BID. Efficacy endpoints were American College of Rheumatology (ACR) 20/50/70 response rates, and change from baseline in the Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Safety endpoints included incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs. AEs of special interest and laboratory parameters were analyzed in the LTE study.ResultsAcross phase III studies (N = 100), ACR response rates and improvements in DAS28-4(ESR) and HAQ-DI scores were numerically greater with tofacitinib vs. placebo at month 3, and increased until month 12. The results were sustained in the LTE study (N = 99) after 60 months' observation. In general, the efficacy and safety profiles of tofacitinib were similar to those of the global RA population.ConclusionsIn Australian patients with RA, tofacitinib therapy demonstrated sustained efficacy and consistent safety over ≥ 60 months' treatment.FundingPfizer Inc. TRIAL REGISTRATION NUMBERS (ALL CLINICALTRIALS.GOV): NCT00960440; NCT00847613; NCT00856544; NCT00853385; NCT00413699.

Project description:Most psoriasis patients have mild to moderate disease, commonly treated topically. Current topical agents have limited efficacy and undesirable side effects associated with long-term use. Tofacitinib is a small molecule Janus kinase inhibitor investigated for the topical treatment of psoriasis.This was a 12-week, randomized, double-blind, parallel-group, vehicle-controlled Phase 2b study of tofacitinib ointment (2 % and 1 %) applied once (QD) or twice (BID) daily in adults with mild to moderate plaque psoriasis. Primary endpoint: proportion of patients with Calculated Physician's Global Assessment (PGA-C) clear or almost clear and ?2 grade improvement from baseline at Weeks 8 and 12. Secondary endpoints: proportion of patients with PGA-C clear or almost clear; proportion achieving Psoriasis Area and Severity Index 75 (PASI75) response; percent change from baseline in PASI and body surface area; change from baseline in Itch Severity Item (ISI). Adverse events (AEs) were monitored and clinical laboratory parameters measured.Overall, 435 patients were randomized and 430 patients received treatment. The proportion of patients with PGA-C clear or almost clear and ?2 grade improvement from baseline at Week 8 was 18.6 % for 2 % tofacitinib QD (80 % confidence interval [CI] for difference from vehicle: 3.8, 18.2 %) and 22.5 % for 2 % tofacitinib BID (80 % CI: 3.1, 18.5 %); this was significantly higher vs vehicle for both dosage regimens. No significant difference vs vehicle was seen at Week 12. Significantly more patients achieved PGA-C clear or almost clear with 2 % tofacitinib QD and BID and 1 % tofacitinib QD (not BID) at Week 8, and with 2 % tofacitinib BID at Week 12. Pruritus was significantly reduced vs vehicle with 2 % and 1 % tofacitinib BID (starting Day 2), and 2 % tofacitinib QD (starting Day 3). Overall, 44.2 % of patients experienced AEs, 8.1 % experienced application site AEs, and 2.3 % experienced serious AEs. The highest incidence of AEs (including application site AEs) was in the vehicle QD group.In adults with mild to moderate plaque psoriasis, 2 % tofacitinib ointment QD and BID showed greater efficacy than vehicle at Week 8, but not Week 12, with an acceptable safety and local tolerability profile.NCT01831466 registered March 28, 2013.

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Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure.

Publications

Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure.

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