JAK inhibitors battle in the heavyweight class

By Warren R. Heymann, MD, FAAD
Nov. 12, 2025
Vol. 7, No. 45

JAK inhibitors (JAKi) have catapulted to such prominence in dermatologic therapeutics that I could write a weekly commentary about them. For dermatologic indications, JAKi are only FDA–approved for alopecia areata, atopic dermatitis), and vitiligo. Identical box warnings — serious infections, mortality, malignancies, major adverse cardiac events, and thrombosis — exist for baricitinib, ritlecitinib, deuruxolitinib, upadacitinib, abrocitinib, and topical ruxolitinib. These warnings stem from the Oral Rheumatoid Arthritis Trial Surveillance study, in which enrolled patients with rheumatoid arthritis (RA) treated with tofacitinib were at least 50 years old, had active RA, were receiving methotrexate, and had at least one cardiovascular risk factor. For most dermatologic patients at minimal risk, JAK inhibitors may be prescribed with confidence. (1)

Once dermatologists get through the box warning conversation with their patients, other adverse reactions, such as acne (JAKne), warrant discussion. (2) What may be most distressing for patients, however, are recent reports of notable weight gain attributed to JAKi.

Masood and Moorthy note, “Over the past three decades, researchers have found that biopsychosocial factors determine weight gain much more than personal choices and responsibility.” The impact of physical inactivity, excessive caloric intake, intrauterine environment, postnatal influences, insufficient sleep, drugs, medical conditions, socioeconomic status, ethnicity, psychosocial stress, endocrine-disrupting chemicals, and the gastrointestinal microbiome are all factors in the pathogenesis of obesity. Drugs associated with obesity include antidepressants (amitriptyline, nortriptyline, phenelzine, citalopram), antipsychotics (lithium, clozapine, quetiapine, haloperidol), antidiabetics (thiazolidinediones, sulfonylureas, insulin), α2-adrenergic agonists (clonidine), β2- adrenergic agonists (atenolol), and steroids. (3)

JAKi joins the august group of drugs that may cause weight gain. There are now multiple articles in the literature; the following is a sampling. Shah et al. reported 6 cases of tofacitinib‑induced weight gain in patients with ankylosing spondylitis, RA, and vasculitis. In this case series, the mean increase in the patient’s weight was 9.6 kg, ranging from 5 to 19 kg. Four patients showed a significant weight gain of more than 10%. (4) A study of 179 patients with myeloproliferative neoplasms (MPNs) treated with ruxolitinib was performed by Mollé et al. Patients received ruxolitinib for a median of 120 weeks, during which 124 (69%) gained weight. The median weight gain among all patients was 6.7% of the starting weight, with the average weight gain being 12% among patients gaining any weight. Although weight gain may be viewed favorably in cachectic patients as they improve, the authors state, “we found that patients with both indolent and more morbid MPNs gained considerable weight suggesting that this weight gain did not solely result from correction of MPN-linked symptoms.” (5) In their review of weight gain attributed to JAKi, Ch'en et al. concluded that weight gain has been reported as a treatment-emergent adverse event with all dermatologic JAKi-approved drugs in the U.S., except for abrocitinib. (6)

Xiong studied the incidence and characteristics of weight changes associated with using JAKi in a systematic review of 90 studies covering 16,000 patients. Their analysis found a notable incidence of weight gain with JAKi usage. Overall, 5.9% (947/16,000) of patients reported weight again. In randomized control trials, weight gain was observed in 7% of patients, while weight loss was observed in 1%. This paradox of weight loss was attributed to potential gastrointestinal adverse reactions such as nausea and/or increased mobility of patients with severe rheumatologic disease. Patients with dermatologic indications had lower weight gain rates (4%) than those with nondermatologic indications. These findings underscored the importance of appropriate counseling and weight monitoring. The authors concluded that further long-term studies are needed to better understand the mechanisms and management of JAKi-related weight changes. (7)

Multiple factors are likely involved in the pathophysiology of weight gain in patients receiving JAKi. Mollé et al. assert, “Appetite is elaborately regulated, and leptin signaling is centrally involved in a complex homeostatic mechanism controlling hunger, satiety, metabolism, and body weight. Leptin serves as a feedback signal reporting nutritional state to the brain. After feeding, leptin levels rise and this reduces appetite and feeding.” (5) Leptin dysregulation may play a role in JAK inhibitor-induced weight gain, as JAK2 inhibition interferes with the JAK2/STAT3 pathway, potentially impairing appetite regulation and reducing energy expenditure. (8) Xiong et al. suggest that patients may experience more significant weight gain when the JAK/STAT pathway is inhibited due to reduced muscle wasting (and possibly increased skeletal muscle mass), especially in patients with muscle and metabolic issues, as seen inflammatory conditions such as RA and myelofibrosis. (7)

In conclusion, JAKi may be associated with significant weight gain. This has important implications related to the adverse effects of the boxed warning. Patients should be aware of this risk, be monitored appropriately, and consider dietary counseling and lifestyle modification if weight gain is observed.

Point to Remember: JAK inhibitors may cause weight gain. Although the precise pathomechanism is unknown, leptin dysregulation may be involved. Dermatologists must counsel patients treated with JAK inhibitors about the risk of weight gain and provide them with appropriate counseling.

Our expert’s viewpoint

Mohannad Abu-Hilal, MD, MRCP (UK), FRCPC
Associate Professor, and Head of Dermatology Division
McMaster University, Hamilton, Ontario, Canada

Weight gain with Janus kinase inhibitors (JAKi) is increasingly recognized, though the exact mechanism remains elusive. In our systematic review and meta-analysis, we found that approximately 6% of patients treated with JAK inhibitors reported weight gain — a figure that notably varied by indication, with patients treated for dermatologic conditions experiencing a somewhat lower incidence compared to those with systemic inflammatory diseases.

Emerging hypotheses center around leptin dysregulation: inhibition of the JAK2/STAT3 pathway may impair appetite regulation and energy homeostasis, favoring weight gain. In addition, the mitigation of chronic inflammation and muscle wasting in certain diseases could contribute to a restoration of lean body mass and overall weight increase. While this may be beneficial in cachectic patients, it presents a challenge for a subset of patients, where weight gain could impact comorbidities such as cardiovascular risk, worsen skin disease burden, or lead to a reduced overall quality of life. Additionally, awareness of this potential side effect may influence a patient’s decision to start treatment. For many patients — particularly those who are concerned about weight or body image — the risk of weight gain could be a significant deterrent.

In my view, the potential for weight gain with JAK inhibitors, though not a contraindication, is an important consideration in patient counseling and monitoring. Discussing lifestyle interventions proactively can help mitigate unwanted weight changes and optimize long-term outcomes for our patients.

References

1. Heymann WR. Getting JAKed up about deep vein thrombosis risk. J Am Acad Dermatol. 2024 May;90(5):933-934. doi: 10.1016/j.jaad.2024.02.027. Epub 2024 Feb 23. PMID: 38403130.

2. Heymann WR. JAKne is on the horizon. Dermatology World Insights and Inquiries. Vol 4, No 30, July 27, 2022. https://staging.aad.org/dw/dw-insights-and-inquiries/archive/2022/jakne-is-on-the-horizon

3. Masood B, Moorthy M. Causes of obesity: a review. Clin Med (Lond). 2023 Jul;23(4):284-291. doi: 10.7861/clinmed.2023-0168. PMID: 37524429; PMCID: PMC10541056.

4. Shah K, Shukla D, Patel M, Malhotra S. A case series on tofacitinib-induced weight gain. Indian J Pharmacol. 2023 Jul-Aug;55(4):263-265. doi: 10.4103/ijp.ijp_158_23. PMID: 37737080; PMCID: PMC10657621.

5. Mollé N, Krichevsky S, Kermani P, Silver RT, Ritchie E, Scandura JM. Ruxolitinib can cause weight gain by blocking leptin signaling in the brain via JAK2/STAT3. Blood. 2020 Mar 26;135(13):1062-1066. doi: 10.1182/blood.2019003050. PMID: 32047890.

6. Ch'en PY, Ng J, Song EJ. Weight gain secondary to the use of Janus kinase inhibitors. Arch Dermatol Res. 2023 Dec;315(10):2773-2774. doi: 10.1007/s00403-023-02710-6. Epub 2023 Aug 23. PMID: 37610624.

7. Xiong G, Yu E, Heung M, Yang J, Lowe M, Abu-Hilal M. Weight gain secondary to the use of oral Janus kinase inhibitors: A systematic review and meta-analysis. JAAD Int. 2024 Dec 19;19:1-9. doi: 10.1016/j.jdin.2024.11.009. PMID: 39872731; PMCID: PMC11763511.

8. Ibba L, Gargiulo L, Bianco M, Di Giulio S, Cascio Ingurgio R, Alfano A, Vignoli CA, Valenti M, Facheris P, Perugini C, Narcisi A, Costanzo A. Potential Role of Leptin in JAK2 Inhibitor-Associated Weight Gain: A Monocentric Retrospective Study. Clin Exp Dermatol. 2025 Apr 2:llaf144. doi: 10.1093/ced/llaf144. Epub ahead of print. PMID: 40172062.