JAK Inhibitors in Dermatology: A Focus on the Lower Extremities

Janus kinase (JAK) inhibitors represent a class of medications that have significantly reshaped the landscape of inflammatory disease treatment. Originally developed for treating autoimmune diseases such as rheumatoid arthritis, JAK inhibitors have gained traction in dermatology due to their ability to modulate various inflammatory pathways that contribute to skin diseases. With increasing research on their efficacy, safety, and versatility, JAK inhibitors have become particularly relevant in treating conditions affecting the lower extremities, an interest for clinicians who frequently manage patients with complex dermatological manifestations.

This article will explore the mechanisms of JAK inhibitors, their applications in dermatology, the specific evidence surrounding their use for conditions affecting the lower extremities, and their potential in podiatric care.

Understanding JAK Inhibitors: Mechanisms of Action

JAK inhibitors target a group of intracellular tyrosine kinases known as Janus  kinases. These kinases play a critical role in the signaling pathways of various cytokines and growth factors that regulate immune cell activity, hematopoiesis, and inflammatory responses. The JAK family consists of 4 members: JAK1, JAK2, JAK3, and TYK2. These kinases function by transmitting signals from cytokine receptors on the cell surface to the nucleus, leading to the activation of signal transducers and activators of transcription (STAT) proteins, which subsequently modulate gene expression.¹

In dermatology, JAK inhibitors are particularly important because they can interrupt the signaling of pro-inflammatory cytokines such as interleukin (IL)-2, IL-6, IL-12, IL-23, and interferon-gamma, all of which are implicated in the pathogenesis of several skin disorders.¹ By inhibiting these pathways, JAK inhibitors reduce inflammation and help restore the balance of immune responses in affected skin tissues.

At the time of this writing, all JAK inhibitors are dispensed orally: tofacitinib (Xeljanz, Pfizer), baricitinib (Olumiant, Eli Lilly), ruxolitinib (Jakafi, Incyte), upadacitinib (Rinvoq, AbbVie), fedratinib (Inrebic, Impact Biomedicines), abrocitinib (Cibinqo, Pfizer), ritlecitinib (Litfulo, Pfizer).¹ There is one exception of a topical cream: ruxolitinib (Opzelura, Incyte Dermatology).¹ This fact is a relief for many needle-phobic patients who do not want to pursue biologic therapy that relies on mostly subcutaneous injections.

JAK Inhibitors in Dermatology: An Overview

JAK inhibitors have demonstrated effectiveness in treating a variety of dermatologic conditions. Some of the most well-studied uses include:

Atopic dermatitis. JAK inhibitors, particularly baricitinib and upadacitinib, have shown promising results in clinical trials for moderate to severe atopic dermatitis (AD).^2,3 These medications are for patients who do not respond to topical therapies or systemic corticosteroids, providing a targeted approach to reduce inflammation and improve skin barrier function.

Alopecia areata. This autoimmune disorder, characterized by patchy hair loss, has been another focus of JAK inhibitor research. Tofacitinib and ruxolitinib have shown efficacy in promoting hair regrowth by inhibiting the immune attack on hair follicles.^4,5

Psoriasis. Psoriasis, a chronic inflammatory skin condition that affects various parts of the body, including the lower extremities, has also been a target of JAK inhibitor therapy. Researchers have studied tofacitinib, which inhibits JAK1 and JAK3, for its ability to reduce the inflammatory cascades responsible for psoriatic lesions.6 Deucravacitinib (Sotyktu, Bristol-Myers Squibb), a tyrosine kinase 2 (TYK2) inhibitor, recently received Food and Drug Administration (FDA) approval to treat adults with moderate-to-severe plaque psoriasis.⁷

Vitiligo. Researchers have explored JAK inhibitors such as ruxolitinib for treating vitiligo, a condition that destroys melanocytes, leading to depigmented patches on the skin.⁸ These inhibitors help to modulate the immune response against melanocytes and can lead to repigmentation in some patients.

Possible Application of JAK Inhibitors in the Lower Extremities

For podiatrists, understanding the role of JAK inhibitors in managing dermatologic conditions is paramount, especially for patients with refractory or chronic conditions, as specialists are utilizing these medications more and more.

Atopic dermatitis on the lower extremities. Atopic dermatitis frequently affects the lower extremities, both in pediatric and adult patients. The ankles, plantar feet, and dorsum of the feet are common areas for eczema flares due to increased sweat retention and friction from clothing or footwear. JAK inhibitors such as baricitinib and upadacitinib have shown significant efficacy in controlling widespread or localized AD on the lower extremities, reducing both itching and inflammation.^2,3

A study published in the British Journal of Dermatology showed that baricitinib led to significant improvements in patients with moderate to severe atopic dermatitis involving multiple body regions, including the lower extremity. The study demonstrated reductions in the Eczema Area and Severity Index (EASI) and improvements in quality-of-life scores. Such results are crucial for patients who suffer from severe treatment-resistant AD, which affects mobility and daily activities due to lesions on the legs and feet.²
 
Acral psoriasis. Plaque psoriasis may manifest on the lower extremities, particularly around the knees, anterior legs, and plantar feet. The involvement of the feet is challenging to treat due to the hyperkeratotic stratum corneum and mechanical stress in these areas which lends itself to the Koebner phenomenon.

JAK inhibitors, particularly tofacitinib, have shown effectiveness in treating psoriasis involving the lower extremities. A phase 3 clinical trial published in the British Journal of Dermatology demonstrated that tofacitinib significantly improved psoriasis symptoms, including on the lower extremity, when compared to a placebo.⁶ Patients given tofacitinib experienced reductions in the PASI scores, with some achieving complete or near-complete clearance of plaques in the affected areas.⁶

For podiatric physicians, this is significant as patients with psoriasis on the lower extremities often face mobility issues due to pain, hyperkeratosis, and fissuring, and JAK inhibitors could offer a more targeted and less invasive treatment option than traditional systemic therapies.

Wound healing following orthopedic surgery. A recent retrospective study suggests that JAK inhibitors “seem to be safe” from a wound healing perspective following orthopedic surgery by modulating inflammatory responses and maintaining control of the underlying rheumatoid arthritis.⁹ There were no instances of surgical site infections and only one delayed wound healing patient in 32 patients undergoing 49 orthopedic procedures, which included several lower extremity cases.⁹

Alopecia of the lower extremities. Alopecia areata typically presents as hair loss on the scalp; however, it can affect hair-bearing areas of the lower extremities. This condition can cause psychological distress due to its unpredictable nature and disfigurement. JAK inhibitors, such as ruxolitinib and tofacitinib, have been shown to promote hair regrowth in alopecia areata by suppressing the immune attack on hair follicles.⁴

A study published in Journal of the American Academy of Dermatology demonstrated that tofacitinib was effective in inducing hair regrowth in patients with alopecia areata.⁴ Practitioners may encounter patients with alopecia universalis, which can affect the legs (and the rest of body hair). JAK inhibitors could be an effective option for these patients, especially when cosmetic concerns or functional impairments arise. More research is needed in lower extremity hair loss, but JAK inhibitors could be a promising treatment for alopecia universalis or focal alopecia areata of the lower extremity.

Vasculitis and autoimmune conditions affecting the lower extremities. Several autoimmune conditions that affect the lower extremities, such as vasculitis, have responded to JAK inhibitors.¹⁰ Vasculitis in the form of polyarteritis nodosa can lead to painful ulcers, purpura, and nodules on the legs, often requiring systemic immunosuppressants to control the inflammation.

JAK inhibitors, by modulating the immune response, offer an alternative to systemic corticosteroids and other immunosuppressants. A case study showed that baricitinib use led to improvements in patients with vasculitis affecting the lower extremities.¹⁰ This utilization has potential implications for patients with complex autoimmune skin conditions that manifest on the legs.

Safety Considerations and Side Effects of JAK Inhibitors

While JAK inhibitors have demonstrated efficacy across a range of dermatologic conditions, they are not without risks. Common side effects include upper respiratory infections, headaches, and gastrointestinal symptoms. More serious risks include thromboembolic events, reactivation of viral infections (such as herpes zoster), and the potential for increased malignancy risk due to immunosuppression.⁹

In 2021, the FDA published the results of its findings from a large clinical trial that stated JAK inhibitors showed an “increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death with the arthritis and ulcerative colitis medicine tofacitinib.”¹¹ This also extended to medications not part of that trial, baricitinib and upadacitinib, which resulted in a black box warning for this drug class. That said, the original study included older patients who had an extensive medical history. Physicians prescribe JAK inhibitors, especially when used for atopic dermatitis and alopecia areata, more frequently in younger patients due to the age range affected in those dermatologic conditions.

Future Directions and Potential Applications in Podiatry

The role of JAK inhibitors in dermatology continues to expand, with ongoing reports exploring their use in conditions such as ulcerative lichen planus and nail lichen planus.^12,13 As research progresses, podiatric physicians will encounter more patients who are currently taking JAK inhibitors or are candidates for JAK inhibitors, either as primary therapy or as part of a multidisciplinary approach to managing complex skin conditions.

In Conclusion

JAK inhibitors represent a promising advancement in dermatology, offering targeted therapy for a range of inflammatory skin conditions. For podiatric physicians, knowledge of these medications, their indications, and their potential side effects is important as increasing numbers of patients are placed on these therapies. While more research is needed to fully understand their potential in podiatric care, the evidence thus far suggests that JAK inhibitors will play an increasingly important role in managing dermatologic conditions of the lower extremity, particularly for patients with refractory disease.

Dr. Vlahovic is a Professor at Samuel Merritt University College of Podiatric Medicine in Oakland, CA. 

References

1.    Beard A, Trotter SC. JAK 1-3 inhibitors and TYK-2 inhibitors in dermatology: Practical pearls for the primary care physician. J Family Med Prim Care. 2024 Oct;13(10):4128-4134. doi: 10.4103/jfmpc.jfmpc_112_24. Epub 2024 Oct 18. PMID: 39629448; PMCID: PMC11610805.ferences
2.     Simpson EL, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br J Dermatol. 2020 Aug;183(2):242-255. doi: 10.1111/bjd.18898. Epub 2020 Mar 5. PMID: 31995838.
3.     Guttman-Yassky E, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021 Jun 5;397(10290):2151-2168. doi: 10.1016/S0140-6736(21)00588-2. Epub 2021 May 21. Erratum in: Lancet. 2021 Jun 5;397(10290):2150. doi: 10.1016/S0140-6736(21)01214-9. PMID: 34023008.
4.     Craiglow BG, Liu LY, King BA. Tofacitinib for the treatment of alopecia areata and variants in adolescents. J Am Acad Dermatol. 2017 Jan;76(1):29-32. doi: 10.1016/j.jaad.2016.09.006. Epub 2016 Nov 2. PMID: 27816292.
5.     Nohria A, Desai D, Shapiro J, Bordone L, Lo Sicco K. Review of the use of Janus kinase inhibitors in the treatment of scarring alopecia. Int J Dermatol. 2024 Jun;63(6):e105-e110. doi: 10.1111/ijd.17153. Epub 2024 Apr 3. PMID: 38571280.
6.     Papp KA, et al; OPT Pivotal 1 and OPT Pivotal 2 investigators. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015 Oct;173(4):949-61. doi: 10.1111/bjd.14018. PMID: 26149717.
7.     Kingston P, Blauvelt A, Strober B, Armstrong AW. Deucravacitinib: a novel TYK2 inhibitor for the treatment of moderate-to-severe psoriasis. J Psoriasis Psoriatic Arthritis. 2023 Oct;8(4):156-165. doi: 10.1177/24755303231201336. Epub 2023 Sep 5. PMID: 38188537; PMCID: PMC10768812.
8.     Hamzavi I, et al Efficacy of ruxolitinib cream in vitiligo by patient characteristics and affected body areas: Descriptive subgroup analyses from a phase 2, randomized, double-blind trial. J Am Acad Dermatol. 2022 Jun;86(6):1398-1401. doi: 10.1016/j.jaad.2021.05.047. Epub 2021 Jun 2. PMID: 34089797.
9.     Nishida K, Harada R, Nasu Y, et al. Influence of Janus kinase inhibitors on early postoperative complications in patients with rheumatoid arthritis undergoing orthopaedic surgeries. Mod Rheumatol. 2024;34(3):466-473. doi:10.1093/mr/road047
10.     Zhou S, Zhang Z, Yao Z, Guo Y. Successful treatment of cutaneous polyarteritis nodosa with baricitinib. J Dermatolog Treat. 2024 Dec;35(1):2417965. doi: 10.1080/09546634.2024.2417965. Epub 2024 Nov 7. PMID: 39510529.
11.     Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. Available at  https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death. Accessed Dec. 11, 2024.
12.     Bazargan AS, Jafarzadeh A, Nobari NN. Successful treatment of resistant plantar ulcerative lichen planus with tofacitinib: A case report and comprehensive review of the literature. Clin Case Rep. 2023 Oct 17;11(10):e8066. doi: 10.1002/ccr3.8066. PMID: 37854265; PMCID: PMC10580686.
13.     He J, Yang Y. Janus kinase 1 inhibitor abrocitinib for isolated nail lichen planus: a case report and literature review. J Dermatolog Treat. 2024 Dec;35(1):2434094. doi: 10.1080/09546634.2024.2434094. Epub 2024 Nov 27. PMID: 39603658.