Treatment of Hidradenitis Suppurativa

Lack of recognition leads to many ineffective treatments, but even when the diagnosis is made, there is a shortage of effective and approved treatment. Generally, it is recommended that patients are seen by dermatologists, and multiple mutually supporting treatments are initiated simultaneously. These include surgery of any fibrotic lesions, medical treatment of inflammation and super-infection, and supportive care.

Treatment is generally unsatisfactory for many patients, and HS specialty clinics there is a real and strong need for the development of safe and effective treatments that can be made available globally. Adding to the unmet need for treatment is the lack of disease recognition in the non-dermatological medical community.

Improving awareness through education and research

Within the dermatology realm, the past decade has seen a massive increase in HS research including existing work to expand available biologic treatment for moderateto-severe HS. Emphasis should be placed on educating other specialties on recognition and diagnosis of HS, providing them the ability and confidence to make appropriate referrals to dermatology and/or commence initial treatment, and manage subsequent flares. Guidance on medical and surgical management of HS can be reinforced through large annual dermatology meetings. Foundations focused on HS advocacy, education and research have also developed internationally through the years - including the Hidradenitis Suppurativa Foundation. These foundations play critical roles in educating patients and advanced practice providers through patient sharing sessions and dedicated meetings such as the Symposium on Hidradenitis Suppurativa Advances and the European Hidradenitis Suppurativa Foundation (EHSF) conference.

Providing opportunities through social media

Social media platforms, such as Facebook, Twitter, Instagram, and TikTok can provide HS patients opportunities to expose themselves to large HS communities from which they may seek education related to their disease. A study revealed that based on observations from the largest HS support group in 2017–2018, consisting of almost 13,000 members, over half of the posts were requests for information, predominantly about lifestyle changes, symptom management, and experiences with medications. Unfortunately, social media may also be tainted by misinformation. Authors suggest that although dermatologists cannot ”suppress” the opinions and voices of others on social media platforms, the active engagement of trained dermatologists can improve patients’ access to reliable information. Over time, continued accurate engagement may increase awareness, reduce stigma, and ultimately lead to faster diagnosis and treatment of HS.

Table 2

Triggers associated with HS

Principles of HS management

Few chronic skin conditions encompass impairments in such multifaceted areas of human health including physical, occupational, interpersonal and psychological domains of functioning. Despite the huge burden, there is a lack of uniformly effective therapies for HS patients. In order to optimize the management outcome and mitigate the high healthcare utilization cost, the timely treatment is critical.

The current approach to cases with HS is a multifaceted approach combining lifestyle modifications, addressing associated comorbidities and combined medical and surgical therapy. The goal of medical therapy is the control of existing inflammation and prevention of flares and new lesions, while the goal of surgical therapy is removal of irreversible damaged tissue and scaring. Medical therapy is often the first line of treatment particularly for high inflammatory and migratory lesions. Surgical therapy would be more effective for the lesions not responding to medical therapy, residual scars, tunnels and abscesses. This chapter delves into the fundamental principals in HS management by looking at the treatment of a person as a whole and not only skin manifestations.

Treating skin manifestations

The limited understanding of the pathologic mechanisms of HS has led to a critical lack of effective therapeutic interventions. HS is a multifactorial disease, encompassing genetic and environmental factors, lifestyle, hormonal status and microbiota. The treatment options are multifaceted including behavioral change, topical therapy, systemic therapy, surgical interventions, laser and light-based therapy. Table 3 summarizes commonly used treatment options.

Table 3

Treatment for HS

The first line of treatment in early stage of the disease include topical therapy and systemic antibiotics. The application of biologics and small molecules is an evolving area in management of HS. However; despite the increasing diverse therapeutic armamentarium, a substantial number of patients do not achieve or maintain disease remission. Surgical intervention has also an important role in management of HS.

Treating the whole person beyond the skin

HS is a dynamic disease, and various clinical scores are used to assess the severity of HS skin alterations. The chronic inflammatory state in HS is associated with upregulation of tissue and circulating cytokines. HS is associated with a huge burden and unsurprisingly multiple systemic conditions, whether skin alterations or extracutaneous inflammatory alterations occur first is currently unknown. The chronic pain and disfigurement from this disease is debilitating. Given the low QoL outcomes, it is not surprising that HS patients also suffer more frequently from psychological disorders, and engage in negative thought patterns (e.g., feeling unworthy) that potentiate existing vulnerabilities to mental health challenges (36,158). Comprehensive care strategies coordinated among multiple disciplines and particularly in a timely manner are critical in improving the care of patients with HS. Table 4 lists common comorbidities associated with HS.

Table 4

Common comorbidities associated with hidradenitis suppurativa

Horizon scanning of new drugs in the pipeline and phase 2/3 trials

Information on clinical trials in this section can be found via NCT number on www.clinicaltrials.gov

There are currently many therapeutic strategies for HS under development targeting varying components of HS pathogenesis. With the EMA and FDA approval of secukinumab, the IL-17 pathway has attracted prominent attention with several different drugs currently under investigation that target IL-17. Preliminary pooled results from two phase 3 RCTS (NCT04242446 and NCT04242498) evaluating the efficacy of bimekizumab, a humanized monoclonal trispecific antibody targeting both IL-17A and IL-17F, demonstrated significantly higher response rates over placebo. Recently announced results from a phase 2a study with sonelokimab (an anti-IL-17A/F nanobody; NCT05322473) showed superiority over placebo. An open label phase 2 study assessing Izokibep (a small protein inhibitor of IL-17A (NCT05355805)) has recently been completed with positive results, and a phase 3 study (NCT05905783) is currently ongoing. In contrast, two phase II studies targering IL-23 upstream of IL17, using guselkumab or risankizumab were prematurely terminated as the primary end point was not met and the overall findings do not support the efficacy of either drug in the treatment of HS. Other potntial upstream mechanism have been postulated including IL-1 (162), with lutikizumab, a dual IL-1α/β inhibitor, currently under investigation in a phase 2 trial (NCT05139602). A phase 2 trial with bermekimab (a IL-1a monoclonal antibody) was terminated terminated for futility. Studies targrying the IL1 recepter or IL-1 receptor-associated kinases (IRAK) have so far not demonstrated superiority over placebo (MEDI8968, an anti-IL-1 receptor antibody in NCT01838499, and zimlovisertib, an IRAK inhibitor in NCT04092452).

In addition, there is a strong theoretical basis for targeting JAK-STAT signaling in HS given its associations with Th17 cells, neutrophil chemotaxis, and B cell migration and activation. Several oral and topical Janus kinase (JAK) inhibitors are currently under investigation for HS. Upadacitinib, an oral JAK inhibitor, demonstrated superiority over placebo in a phase 2 trial (NCT04430855) and is now undergoing evaluation in a phase 3 study (NCT05889182). Povorcitinib, a specific JAK1 inhibitor, showed good tolerance in two small open-label phase 2 studies, and phase 3 studies are currently in progress (NCT05620836, NCT05620823). Ruxolitinib, a JAK1/2 inhibitor, is being tested topically compared to vehicle (NCT05635838) in a phase 2 trial. Additionally, a phase 2 study indicated that Brepocitinib (a JAK1/TYK2 inhibitor) was found to be superior to placebo, while PF-06826647, which blocks only TYK2, did not demonstrate clinical efficacy (NCT04092452).

Directing treatment at neutrophil recruitment and activation fits well in the pathogenic concept of HS. Eltrekibart, a humanized monoclonal antibody which neutralises chemokines that bind to the CXCR1 or CXCR2 receptors, showed good clinical response in a phase 2 clinical trial (NCT04493502) with a larger phase 2b trial underway (NCT06046729). However, another small phase 2 RCT investigating RIST4721 (a CXCR2 inhibitor, NCT05348681) was discontinued following safety findings. Spesolimab and imsidolimab, two anti-IL-36 monoclonal antibodies employed in generalized pustular psoriasis are being evaluated in phase 2 clinical trials (NCT04762277; spesolimab and NCT04856930; imsidolimab)..

An alternative approach involves targeting B cells. A phase 2 randomized, double-blind clinical trial is in progress to assess the efficacy of iscalimab, an antiCD-40 monoclonal antibody (NCT03827798). Additionally, the investigation of remibrutinib, an oral BTK inhibitor that inhibits B cells and other myeloid cells, is also underway in phase 2 clinical trials (NCT03827798).

While the involvement of the complement pathway in the pathogenesis of HS has been demonstrated, phase 2 studies with vilobelimab (IFX-1, an antiC5a monoclonal antibody, NCT03487276) and avacopan ( an oral C5a inhibitor, NCT03852472) were recently terminated as they both failed to meet their primary endpoint. A phase 2 study with BDB001, another anti-C5 antibody is still ongoing (NCT05103423).

Overall, while many promising phase 2 and 3 RCTs are currently ongoing, a large amount of trials have failed to meet their primary endpoint resulting in premature termination. This demonstrates the highly heterogeneous pathophysiology of HS, involving a multitude of inflammatory pathways and cell types as well as raise questions about currently used clinical endpoints.