Topical Ruxolitinib for the Treatment of Hidradenitis Suppurativa

Claire Fason, BA¹ and Stephen Tyring, MD, PhD, MBA^2,3

¹McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflicts of interest: The authors declare that there is no conflict of interest. Funding sources: None.

Abstract
Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin disease characterized by painful nodules, abscesses, sinus tracts, and scarring, with significant impact on quality of life. Although biologics have expanded treatment options for moderate to severe disease, there are currently no approved therapies specifically indicated for mild HS. Emerging evidence implicates dysregulation of the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway in HS pathophysiology, suggesting JAK inhibition as a promising therapeutic strategy. This review summarizes current evidence on JAK inhibition in HS, with a focus on topical ruxolitinib. Early clinical trials in patients with mild to moderate HS have demonstrated encouraging efficacy, including significant improvements in Hidradenitis Suppurativa Clinical Response (HiSCR) rates and histologic reductions in epidermal and dermal inflammation, alongside a favorable safety profile. Existing data support topical ruxolitinib as a promising, targeted, and potentially safer treatment option for early-stage HS.

Keywords: hidradenitis suppurativa, JAK/STAT pathway, Janus kinase inhibitors, topical ruxolitinib, mild hidradenitis suppurativa, inflammatory skin disease

Introduction

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory skin condition, characterized by painful nodules, abscesses, scarring, and sinus tracts. While HS most commonly affects apocrine gland-rich areas, such as the axillae, inguinal and anogenital regions, perineum, and the infra-mammary area, it can also less commonly affect the face, neck and extremities. The disease course consists of recurrent flares with increased suppuration and pain.¹ While various clinical scales exist, severity is most often graded using the Hurley scale.² The Hurley scale grades HS lesions from I-III: Hurley stage I consists of abscess formation without sinus tracts and scars; stage II presents widely separated lesions, recurrent abscesses with tract formation and scars; and stage III is characterized by diffuse or near diffuse involvement, or multiple interconnected abscesses.² While Hurley staging is often used to grade severity, Hidradenitis Suppurativa Clinical Response rate (HiSCR), which is defined as at least a 50% reduction in the total abscess and inflammatory nodule count, no increase in abscesses, and no increase in draining fistulas, is often used as a clinical endpoint.³

Treatment of HS consists of systemic and topical medical therapies, and surgery for more severe lesions. While treatment can lead to significant improvement, complete remission is often difficult to achieve. For Hurley stage I, or mild HS, treatment typically consists of topical clindamycin, topical antiseptics, and intralesional corticosteroids.² Adalimumab, a tumor necrosis factor (TNF) inhibitor, was the first biologic agent to receive US FDA approval for the treatment of moderate to severe HS.⁴ Recently, the FDA approved bimekizumab, an interleukin (IL)-17F and IL-17A inhibitor, and secukinumab, an IL-17A inhibitor, for the treatment of moderate to severe HS.^5,6 Despite the emerging treatments for moderate to severe HS, there are currently no approved treatments for mild HS.⁷ There is a large need for effective treatment options since achieving adequate disease control is often difficult and response rates vary greatly among patients. Additionally, many patients stop responding to treatment with biologic agents over time.⁸

While current biologic therapies act via IL and TNF inhibition, further research into Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibition for the treatment of HS is promising. This review will discuss topical ruxolitinib, a JAK inhibitor, that is currently being investigated for the treatment of HS.

Pathophysiology of HS

The pathophysiology of HS is complex and consists of an interplay between genetic, lifestyle, and immunological factors. The pathogenesis of HS is believed to be driven by multiple cytokines including IL‐1β, IL‐17, IL‐23 and IL‐10 and, TNF‐α, which mediate inflammation via the JAK-STAT signaling pathway. Transcriptional studies have found elevated JAK-dependent cytokines and overactivation of JAK signaling pathways in HS lesions.^4,9,10

Unlike currently available therapies that inhibit single cytokines, JAK inhibitors have the ability to broadly suppress various cytokines, interferons, and growth factors, thereby potentially offering more effective treatment.⁷

Recent research has suggested that epidermal keratinocytes have an early and sustained role in the inflammation that occurs in HS. Lesional keratinocytes have been found to be a primary source of chemokines, which leads to the recruitment of immune cells into the epidermis. Keratinocytes act with immune cells to drive the production of inflammatory cytokines that are associated with HS. Due to the epidermal involvement in the pathophysiology of HS, topical therapy could be effective.^10,11

Systemic JAK Inhibitors in HS

Recent investigations and case reports have explored the efficacy of various systemic JAK1 selective inhibitors, including updacitinib, for the treatment of moderate to severe HS. A small retrospective cohort study of 20 patients with moderate to severe HS who were treated with updacitinib 15 mg to 30 mg showed promising results. At week 4, 75% of patients reached HiSCR of 50% reduction in the number of inflammatory lesions (HiSCR50), and by week 12, 100% of patients met HiSCR50. Additionally, 95% of patients achieved HiSCR75, or a 75% reduction in the number of inflammatory lesions. There were minor adverse reactions, including varicella zoster reactivation, mild, transient transaminitis, and asymptomatic elevations in creatinine kinase.¹²

Similarly, a case report of a 15-year-old female with comorbid ulcerative colitis (UC) and HS showed significant HS improvement after initiation of 45 mg of updacitinib. The patient was trialed on multiple HS therapies, including doxycycline, spironolactone, an oral contraceptive agent, clindamycin, rifampin, intralesional triamcinolone, and surgical deroofing with no meaningful reduction in symptoms or lesions. After a UC flair, she was transitioned to upadacitinib which led to rapid and long-term improvement in both her UC and HS.¹³

Povorcitinib (formerly INCB054707), an oral small-molecule JAK1 selective inhibitor, has demonstrated preliminary efficacy for the treatment of moderate to severe HS. In both phase 2 trials, improvements in HiSCR, abscess and inflammatory nodule count, pain, and quality of life were seen. Adverse effects included dose dependent thrombocytopenia, fatigue, headache, and upper respiratory infections.⁴ Recent interim data from phase 3 trials reported sustained efficacy of povorcitinib through 24 weeks in moderate to severe HS, with nearly 60% of patients achieving HiSCR50 and meaningful proportions reaching HiSCR75-100, along with early and durable improvements in skin pain.¹⁴

Topical Ruxolitinib

Topical ruxolitinib, a JAK inhibitor, has been FDA approved for atopic dermatitis and non-segmental vitiligo. Additionally, research has shown that it is effective for other inflammatory skin conditions including psoriasis, alopecia areata, and lichen planus. Ruxolitinib is currently being investigated for its use in mild to moderate HS.

A pilot clinical trial studied patients with Hurley stage I HS treated with 1.5% ruxolitinib cream. Given that the pathophysiology of HS involves deep immune infiltrate, there is concern that topical therapy would not be sufficient to target the inflammatory pathways driving the disease. To investigate this, biopsies were taken before and after 16 weeks of treatment with topical ruxolitinib. After 16 weeks of treatment, the majority of patients (5 out of 6) achieved HiSCR50, and biopsies showed reduced epidermal and dermal inflammation with resolution of deeper inflammation. Biopsies also showed a reduction in neutrophils, lymphocytes, and other inflammatory markers after treatment. Although small, this trial shows the promise of ruxolitinib while also addressing the concern that topical therapy is unable to target deeper dermal inflammation.⁷

In a randomized double-blind vehicle-controlled phase 2 study, the safety and efficacy of twice daily topical ruxolitinib 1.5% was investigated in adult patients with mild to moderate HS, defined as Hurley stage I or II with no draining tracts. By week 16, 79.2% of the patients receiving ruxolitinib therapy had achieved HiSCR50, compared to only 50% in the vehicle group. Similarly, there was a statistically significant decrease in abscess and inflammatory nodule count in the treatment group compared to vehicle group.¹⁵ (ClinicalTrials.gov ID NCT05635838). There are multiple ongoing clinical trials investigating topical ruxolitinib cream for early or mild HS (Table 1).

Table 1:

Safety

While a wide range of severe adverse reactions, including malignancy, venous thromboembolic events, and major cardiovascular events have been reported with systemic JAK inhibitor usage, topical ruxolitinib is generally considered well tolerated and safe.¹⁶ While there is limited data regarding adverse reactions in ruxolitinib used in the treatment of HS specifically, studies have shown the long-term safety of ruxolitinib when used for other skin conditions. Results from two phase 3 studies investigating topical ruxolitinib 1.5% for the treatment of atopic dermatitis found that ruxolitinib was very well tolerated and safe for long-term use. In 52 weeks of therapy, there were no serious adverse events. Treatment related adverse events occurred in 4.4% of patients, and none discontinued therapy due to an adverse event. Most frequent adverse events were upper respiratory tract infections, nasopharyngitis, influenza, and headache. About 1.8% of patients reported application site reactions and an additional 1.8% of patients reported new onset or worsening acne vulgaris during treatment.¹⁷

Conclusion

The treatment of HS remains a challenge. While systemic therapies and biologics have shown promise for moderate to severe HS, their applicability and safety for long-term use in mild cases has not been investigated given the risk for adverse effects. The emerging role of JAK-STAT pathway dysregulation in HS pathophysiology has opened new avenues for treatment, particularly with JAK inhibitors such as ruxolitinib.

Topical ruxolitinib offers a novel, targeted, and potentially safer alternative for patients with Hurley stage I and II disease. Early trials, while limited, have demonstrated encouraging results, with significant reductions in inflammatory lesion counts and overall disease burden, as well as histological evidence of decreased deep dermal inflammation. Importantly, topical ruxolitinib appears to be well tolerated, with a favorable safety profile based on long-term data from its use in other inflammatory dermatoses.

Although further large-scale phase 3 trials are ongoing, current evidence supports the potential of topical ruxolitinib as a promising treatment option for mild to moderate HS. Its ability to modulate multiple pro-inflammatory cytokines via JAK inhibition, combined with its topical route of administration and minimal adverse reactions, makes it a valuable candidate in the evolving therapeutic landscape of HS. While continued research is needed, early data shows that topical ruxolitinib may help address an unmet need in the management of early-stage disease.

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