<scp>JAK</scp> inhibitor treatment for non‐infectious granulomatous skin diseases—A retrospective case study

Beyond glucocorticoids, there are almost no effective treatment options for non-infectious granulomatous skin diseases (NIGDs) such as the granuloma annulare (GA), the necrobiosis lipoidica (NL) and sarcoidosis (SA) available. Therefore, disseminated and/or long-standing lesions pose a therapeutic challenge.1 Currently, the pathophysiological mechanisms of NIGDs remain largely unknown, which, unlike other skin diseases such as atopic dermatitis and psoriasis, have hindered the development of effective cytokine-targeted therapies.1-3 The main pathophysiological mediators of granuloma formation are believed to signal via the JAK–STAT pathway.4, 5 Thus, januskinase inhibitors (JAKi) are regarded as promising therapeutic options for these difficult-to-treat conditions. Nineteen patients with chronic NIGDs who had not responded to topical glucocorticoids and some of whom had received systemic therapies such as azathioprine, methotrexate, balneophototherapy, hydroxychloroquine or adalimumab were treated with oral JAKis (abrocitinib, upadacitinib, baricitinib or tofacitinib) and followed up every 4 weeks for 12 (GA) or 16 (NL, SA) weeks from May 2020 to December 2024 at the outpatient clinic of the Department of Dermatology at Duesseldorf University Hospital. Eight of them were treated for GA, six for NL and five for cutaneous SA. Endpoints were the absolute and proportional (∆25, −50, −67 and −75%) improvement of disease-specific scores. The Granuloma Annulare Severity Index (GASI),6 the Necrobiosis Lipoidica Lesion Score (NLLS) and the Cutaneous Sarcoidosis Activity and Morphology Index (CSAMI)7 were used. Additionally, the Dermatology Life Quality Index (DLQI) was assessed, with an improvement of 4 points considered significant. Adverse events (AEs) as well as serious AEs (SAEs) were closely monitored. In GA the mean GASI before treatment was 31.3. After JAKi treatment, it was significantly reduced to 12.7 (p < 0.01, Figure 1a). The mean GASI reduction was 60%. All but one patient (87.5%) achieved a 50% reduction in their baseline GASI (GASI-50), 75% of them reached a GASI-67 and 25% reached a GASI-75 response (Figure 1a). Apart from one patient, all these patients reached a significant DLQI improvement. In NL, the mean NLLS before treatment was 7.8. After JAKi treatment, it was significantly reduced to 2.3 (p < 0,05, Figure 1b). The mean NLLS reduction was 71%. All patients achieved a NLLS-50, 66.67% of them reached a NLLS-67 and 33.33% reached a NLLS-75 response (Figure 1b). Seventy-five percent reached a significant DLQI improvement. In SA the mean CSAMI before treatment was 25. After JAKi treatment, it was reduced to 11.8, which was borderline significant (p = 0.0625, Figure 1c). The mean CSAMI reduction was 58%. All but one patient (80%) achieved a CSAMI-50, 40% of them reached a CSAMI-67 as well as a CSAMI-75 response (Figure 1c). Eighty percent reached a significant DLQI improvement. One patient showed a peripheral lymph node affection by sarcoidosis. A marked reduction of the lymphadenopathy on ultrasound examination was observed during treatment with baricitinib (Figure 2d). All other previously reported systemic sarcoidosis manifestations showed no activity at baseline. No changes were reported during follow-up. The treatment was overall well tolerated; adverse events included mild infections, herpes zoster and elevations of serum creatine kinase levels as well as liver enzymes. One patient developed newly diagnosed stable coronary artery disease. Since there was no hospitalization, the event did not meet SAE criteria. No SAEs were reported and no major adverse cardiac event (MACE) or new onset of malignancies occurred in our patients. Here, we show that various oral JAKi, mainly licensed for type 1 and 2 inflammatory responses,8 were able to induce a significant improvement in granulomatous conditions that did not respond to various treatments (Figure 2a–c). The safety profile was comparable to that of JAKi in other skin conditions. The retrospective design and lack of a control group limit the validity of the presented data. Larger prospective and placebo-controlled trials are necessary to further evaluate the efficacy and safety of this promising treatment option for these rare and difficult-to-treat skin conditions. The authors have nothing to report. RS reports congressional funding from Janssen Cilag, AbbVie, Celltrion Healthcare, Kyowa Kirin and Sanofi. SB reports personal fees from BMS, Novartis, Johnson and Johnson and Sanofi, and received travel expenses from Pierre Fabre, Sun Pharma, Kyowa Kirin and Lilly Pharma. BH reports personal fees and/or grants from Novartis, LEO Pharma, AbbVie, Sanofi, UCB, Eli Lilly, Janssen Cilag, Union Pharma, Galderma and Pfizer. SM reports personal fees and/or grants from Novartis, LEO Pharma, Almirall, Galderma, AbbVie, Sanofi, UCB, BMS, Lilly, Janssen Cilag, AstraZeneca, Bencard and Pfizer. All COI are outside the present work. AM and Péter Oláh did not report any conflicts of interest. This study was approved by the local ethics committee of the medical faculty of the Heinrich-Heine-University Duesseldorf (No.: 2024–3074). The patients in this manuscript have given written informed consent to the publication of their case details. The data that support the findings of this study are available from the corresponding author upon reasonable request.