ÌÇÐÄvlog

Granulomatous cheilitis (of Miescher) (GC), a rare nonnecrotizing granulomatous inflammatory disorder, is part of the orofacial granulomatosis spectrum.^1,2 It is characterized by intermittent or persistent swelling of the upper and/or lower lip, resulting in functional disability and cosmetic impairment. Despite various hypotheses, including factors such as food allergy, genetics, infection, and atopy, its exact cause remains unknown.² Granulomatous cheilitis is an exclusion diagnosis, and most cases remain isolated; however, it can be associated with systemic diseases such as Crohn disease (CD),³ sarcoidosis, or Melkersson-Rosenthal syndrome. Current treatment primarily involves topical or intralesional corticosteroids, with severe cases often requiring systemic agents such as biologics, with variable outcomes and frequent relapses.⁴ The evidenced role of the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway in granuloma formation has brought interest in using JAK inhibitors for granulomatous skin diseases⁵; to our knowledge, their effectiveness in GC remains unexplored.

This retrospective case series was conducted from June 1, 2023, to March 1, 2024, at a tertiary university hospital in Belgium, involving patients with biopsy-proven GC resistant to systemic treatments and subsequently treated with the JAK 1 inhibitor upadacitinib, 30 mg daily. All patients underwent standardized diagnostic work-up with complete cutaneous and extracutaneous examination, lip biopsy, chest radiograph, and colonoscopy. Objective clinical improvement in lip swelling and infiltration was assessed, with either complete response, partial response, or no response as the primary end point. Effectiveness on CD activity in patients with concomitant GC and CD was the secondary end point. All treatment-induced adverse events were reported during the study. We followed the . The study and data collection were approved by the institutional review boards of Cliniques universitaires Saint-Luc and Université catholique de Louvain. Written informed consent was obtained from all study participants for publication of their case details.

Five patients (4 women; median age, 30 years [range, 20-48 years]) were included. Demographic and clinical characteristics are detailed in the Table. All patients were previously treated with biologics in an attempt to control GC, CD, or both. Three patients had concomitant quiescent CD. Upadacitinib was added, but ustekinumab was maintained for patient 5 because of history of very severe CD with coloprotectomy.

The median follow-up duration was 7.2 months (range, 3.6-7.9 months). Upadacitinib treatment was associated with complete response in 4 of 5 patients (80%) within a median of 3.8 months (range, 3.1-5.0 months) (Figure); 1 patient showed partial response. Crohn disease remained quiescent in 3 of 3 patients with concomitant GC and CD. The treatment was well tolerated with no serious adverse events reported. Headaches, acne, mild lipid profile modifications, and/or transaminitis were observed in 2 patients.

JAK inhibitors have emerged as promising therapeutic options for various inflammatory disorders, including granulomatous diseases.⁵ Granulomatous cheilitis is a rare and debilitating granulomatous disorder that often represents a therapeutic challenge. All 5 patients in our study with longstanding recalcitrant GC showed meaningful clinical response within a median follow-up of 7.2 months when treated with high-dose (30 mg/d) upadacitinib. Crohn disease remained quiescent in 3 of 3 patients with concomitant GC and CD, despite discontinuing biologic treatment in 2 patients and despite a lower-dose regimen of upadacitinib than the one recommended for CD.⁶ The safety profile was favorable, with no serious adverse events. Combining a biologic and upadacitinib for 1 patient was effective and well tolerated.

Limitations of our study are the small sample size and the short follow-up duration, which may limit generalization of the findings to the broader population of patients with GC. Upadacitinib was effective in treating patients with recalcitrant and long-lasting granulomatous cheilitis, even in cases of concomitant CD, which could substantially improve the quality of life of affected patients. Safety data are reassuring. Further studies are needed to confirm these data in larger cohorts, over longer periods, and with other JAK inhibitors.

Accepted for Publication: May 28, 2024.

Published Online: July 31, 2024. doi:10.1001/jamadermatol.2024.2378

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2024 De Greef A et al. JAMA Dermatology.

Corresponding Author: Axel De Greef, MD, Department of Dermatology, Cliniques universitaires Saint-Luc (UCLouvain), Avenue Hippocrate 10, B-1200 Brussels, Belgium (axel.degreef@saintluc.uclouvain.be).

Author Contributions: Drs De Greef and Baeck had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: De Greef, de Montjoye, Baeck.

Acquisition, analysis, or interpretation of data: De Greef, Peeters, Dewit, Baeck.

Drafting of the manuscript: De Greef, Baeck.

Critical review of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Baeck.

Supervision: Peeters, Dewit, de Montjoye, Baeck.

Conflict of Interest Disclosures: Drs De Greef, Dewit, and Baeck reported receiving personal fees from AbbVie outside the submitted work. Dr de Montjoye reported receiving nonfinancial support from Lilly and Sanofi and personal fees from Novartis outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See the Supplement.

Additional Contributions: We thank Mariana Andrade, MD, Andrade-Evrard SRL, who provided editorial assistance. She was compensated for her contribution. We also thank the patients for granting permission to publish this information.