The only drug approved to date for HS is adalimumab, a fact that was accomplished after the results of the trials PIONEER I and PIONEER II, with response rates at week 12 were significantly higher for the groups receiving adalimumab weekly than for the placebo groups: 41.8% versus 26.0% in PIONEER I (P=0.003) and 58.9% versus 27.6% in PIONEER II (P<0.001) and good safety profile.22,23,30,31 In non-responders or with a contraindication to adalimumab, the therapeutic range is wide, and there is no clear algorithm for its management. The good initial response in some patients, followed by secondary failure, prompted studies looking at adalimumab intensification from its standard dose 80mg/14 days to 80mg/7 days, with a proven rate of improvement.32,33 In addition to adalimumab, other anti-TNF agents have been studied for the treatment of HS. Infliximab has demonstrated its effectiveness in various studies.34,35 A recent systematic review and meta-analysis showed that the pooled response rate of HS patients to infliximab was 83% (95% CI, 0.71–0.91), with a favorable side effect profile.36 Parallel to the dose intensification that some authors suggest for adalimumab, there are other authors who have shown greater efficacy of infliximab when it is given at doses similar to those for inflammatory bowel disease: 7.5mg/kg every 4 weeks or even 10mg/kg every 4 weeks.37 Regarding etanercept, in the trial by Giamarellos-Bourboulis et al.,38 a reduction in disease burden was found at week 12, but the values were not specified. Subsequently, in the trial by Lee et al.,39 only 3 of 15 patients achieved the primary outcome, defined as 50% or greater improvement in PGA at week 12. Therefore, insufficient evidence has been reached for the recommendation of etanercept as a treatment of severe HS.40 Concerning certolizumab, we found few articles on the treatment of HS, most of them small case series, generally with favorable results, but with the possibility of publication bias characteristic of the small sample size. Due to its pharmacodynamics, it avoids the placental passage, which makes it an attractive option in pregnant patients with severe HS.41,42 Finally, in relation to anti-TNF agents, golimumab initially demonstrated its usefulness in small case reports and case series,43,44 a fact that was strengthened with the publication of a retrospective series with 13 patients who failed adalimumab and had good results with golimumab, therefore it could be an option in patients with failure to adalimumab.45

IL-17 has been implicated in numerous studies in the pathogenesis of HS.24 In the phase 3 clinical trials SUNSHINE and SUNRISE, secukinumab passed the primary end-point at week 16, with sustained responses at week 52. At 16 weeks, in the SUNSHINE trial, 45% of patients on secukinumab 300mg/14 days achieving HiSCR, compared with 41.8% of patients on secukinumab 300mg/28 days or 33.7% in the placebo group. In the SUNRISE trial, slightly better results at 16 weeks were found for secukinumab 300mg/14 days, with a HiSCR responder of 46.1%, compared with 42.3% in patients with secukinumab 300mg/28 days or 31.2% in the placebo group. The results at week 52 were recently published, with a percentage of patients achieving HiSCR of 56.4% with secukinumab 300mg/14 days and 56.3% with secukinumab 300mg/28 days in the SUNSHINE study, while the percentage of patients achieving HiSCR in the SUNRISE study was 65% with secukinumab 300mg/14 days and 62.2% with secukinumab 300mg/28 days. In both trials, the rate of side effects was mild, the most frequent being headache.46 A recent multicenter retrospective study of forty-seven patients with severe HS demonstrated a 48.9% (n=23/47) of patients achieved objective HiSCR, with adverse events in 6.4% (n=3/47) of the patients.47 This efficacy has been supported in some recent studies with longer observation periods.48 With the demonstration of the decrease in the disease burden of HS by blocking the IL-17A receptor, brodalumab began to be used in its treatment.49,50 Only small case series have been reported, the largest of them with 10 patients to whom 210mg was administered at weeks 0, 1 and 2 and subsequently every 2 weeks. In this study, all patients (100%) achieved target HiSCR, and 80% achieved IHS4 category change at week 12. HiSCR achievement occurred as early as week 2, with a favorable safety profile.51 Recently, therapeutic intensification with brodalumab has been proposed, with a weekly regimen instead of a biweekly regimen.52 Regarding ixekizumab, there are no studies with sufficient evidence to recommend its use in the treatment of severe HS, limiting the literature to small case reports and case series.53,54 Finally, in relation to this pathway, it is worth highlighting the results of bimekizumab, a dual inhibitor of IL 17-A and 17-F, were presented at the 2023 American Academy of Dermatology Annual Meeting, in its two phases 3 (BE HEARD I and BE HEARD II), achieving statistically significant and consistent clinically meaningful improvements over placebo in the signs and symptoms of HS at week 16, which were maintained to week 48, which positions it as a promising therapeutic weapon. At Week 16 in the trials, 47.8% of patients in BE HEARD I and 52% in BE HEARD II experienced the 50% reduction skin abscesses and inflammatory nodules. That compared with 28.7% and 32% for placebo, respectively. At week 48, clinical responses were maintained with continuous bimekizumab treatment, since over 75 percent of patients achieved HiSCR50, and over 55 percent achieved HiSCR75, at week 48. The safety profile of bimekizumab across BE HEARD I and BE HEARD II was consistent with previous studies with no new safety signals observed.55,56 CJM112, another monoclonal antibody that neutralizes soluble IL-17 and IL-17A/F has demonstrated in a phase II randomized controlled study HS-PGA response rate of 32.3% at week 16, compared to 12.5% in patients treated with placebo.57,58

Ustekinumab, a dual inhibitor of IL-12 and IL-23 by blocking their common p40 subunit, has demonstrated its efficacy in several HS.59 In addition, an increase in its efficacy has been postulated with intravenous administration with 90mg every 8 or even 6 or 4 weeks, doses like Crohn's disease,60–62 reaching in a retrospective study 50% (n=7/14) objective HiSCR and with a reduction in pain in 71.4% of patients at week 16.62

The interleukin-1 (IL-1) family is a complex involved in the correct functioning and regulation of the innate immune system, linking innate and adaptative immune responses and its failure is related with psoriasis, HS, and atopic dermatitis. Anakinra, an IL-1 receptor inhibitor, has been shown to be effective in some patient series, especially at doses of 200mg/day.63 In a placebo-controlled clinical trial, at week 12, a >50% decrease in disease activity score was used as the primary end-point, which was achieved by 78% of the treatment group and 30% of the placebo group. However, these results have not been subsequently verified in larger trials and, in addition, early and frequent relapses have been reported.64 Canakinumab, an anti-IL-1β monoclonal antibody, provides controversial data in HS, with small series with positive65 and other negative results.66 Bermekimab (also called MABp1), a specific antibody inhibitor of IL-1α, has demonstrated in a recent phase II clinical trial HiSCR target rates at week 12 of 61% in anti-TNF native patients and 63% in those who had failed to anti-TNF.67 Currently, a new randomized phase II trial (NCT04988308) with this drug is being recruited.68

As far as anti-IL-23 agents are concerned, guselkumab has been shown to be effective in some case series.69 In a phase IIb placebo-controlled, double-blind study (NOVA-trial, NCT03628924) comparing guselkumab at a dose of 200mg/4 weeks subcutaneously at weeks 0, 4, 8 and 12 versus 1200mg intravenously at weeks 0, 4, 8 followed by 200mg subcutaneously versus placebo, it was observed that HiSCR was achieved at week 16 in 50.8% of the patients treated with subcutaneous administration versus 45% of intravenous ones.70 A recent multicenter, phase IIa trial with guselkumab at 200mg s.c., every four weeks for 16 weeks shows that 65% (n=13/20) achieved HiSCR with also a significant decrease in the median IHS4-score (8.5–5.0, P=0.002) and the median AN-count (6.5–4.0, P=0.002).71 Risankizumab had demonstrated its possible therapeutic use in HS in small case series.72 However, the recently published randomized trial with 243 patients (risankizumab 180mg, n=80; risankizumab 360mg, n=81; placebo, n=82) demonstrated that HiSCR was achieved by 46.8% of patients with risankizumab 180mg, 43.4% with risankizumab 360mg, and 41.5% with placebo at week 16, with the primary end-point not achieved, so the study was early finished.73 Data with tildrakizumab are sparse. The largest series with 9 patients showed its potential therapeutic usage in HS.74

Apremilast, an oral phosphodiesterase-4 (PDE-4) inhibitor, demonstrated its efficacy in a 3:1 trial at a dose of 30mg/12h compared to placebo, reaching 53.3% the HiSCR objective versus 0% in the group placebo.75 These responses were confirmed at the two-year follow-up.76 These results have been supported by other small series but so far, we lack comparative prospective studies with more evidence to support its widespread use.

The involvement of the complement pathway in the pathogenesis of HS has been demonstrated. Vilobelimab (IFX-1), an anti-C5a monoclonal antibody, showed target HiSCR rates of 75% in an open-label trial.77 Subsequently, in a phase 2 trial (NCT03487276) it has shown a HiSCR of 51.5% at a dose of 800mg IV every 4 weeks, although the response with placebo was 47.1%.78 Avacopan, another oral C5a inhibitor already used in ANCA vasculitis and atypical hemolytic uremic syndrome, is being evaluated in a trial (NCT03852472) against placebo but the results of this study are yet to be published.79

With increasing use in dermatology, a key role of stress signaling and Janus Kinase (JAK)/Signal transducer and activator of transcription 1 (STAT1) activation in disease progression of HS has been described, turning this pathway into a possible therapeutic target. Tofacitinib has been described as a successful treatment of HS in isolated cases.80 In a recent real-life retrospective cohort study, upadacitinib demonstrated 75% (n=15/20) individuals achieved HiSCR50 at week 4, increasing to 100% at week 12 and maintained at week 24, promising results.81 There is an ongoing phase 2 clinical trial evaluating upadacitinib in HS (NCT04430855).82 Only one case of HS treatment with baricitinib has been reported in the literature.83 INCB054707 (povorcitinib) is a new JAK-1 inhibitor that is being evaluated in 3 clinical trials (NCT03569371, NCT03607487 and NCT04476043). In NCT03607487, higher response rates were demonstrated in the 90mg/day group (HiSCR 88%) versus placebo (HiSCR 57%), although the adverse effect rate was substantial, with up to one third of patients grade 3 or 4.84 Lately, its usefulness has also been postulated topically with ruxolitinib,85 as has already been postulated in other entities such as vitiligo or alopecia areata. Its efficacy is being tested in two clinical trials, one of which is in the recruitment phase and the other in progress, using 1.5% topical ruxolitinib.86

There are numerous new targets that are being evaluated for the treatment of HS.87,88 IRAK-4 is a multiple immune regulator, primarily of the innate immune system. KT-474, an IRAK-4 inhibitor, is being evaluated for the treatment of HS in a phase 1 trial (NCT04772885), as well as a phase 2 trial (NCT04092452), a trial with three anti-kinase drugs that also includes Ropasacitinib (PF-06826647), a tyrosine kinase 2 (TYK2) inhibitor, and Brepocitinib (PF-06700841) dual TYK2/JAK1 inhibitor.89 We have not found any studies evaluating tocilizumab or another anti-IL-6 drug in the treatment of HS. IL-36 has been implicated in the pathogenesis of autoinflammatory diseases, autoimmune diseases, and infectious diseases. Its elevation in hidradenitis suppurativa could represent a new therapeutic target for spesolimab and imsidolimab, two anti-IL-36 monoclonal antibodies employed in generalized pustular psoriasis. Both drugs are being evaluated in two phase 2 clinical trials (NCT04762277 spesolimab90 and NCT04856930 imsidolimab91). Rituximab, a monoclonal anti-CD-20 agent, is postulated as a possible therapeutic weapon, its effectiveness being postulated in 5 cases described in the literature.92 Iscalimab (CFZ533) is a monoclonal antibody that blocks the CD-40 pathway, and it is being studied in the treatment of the HS on a phase II trial (NCT03827798).93 LYS 006, an oral leukotriene A4 hydrolase (LTA4) inhibitor, is being evaluated in a phase II trial for the treatment of HS (NCT03827798).93 LY 3041658, a monoclonal antibody that blocks chemokines that bind to CXCR1 and CXCR2 receptors, is also being evaluated in a phase 2 trial (NCT04493502).94 Finally, CSL 324 is a phase 1 anti-G-CSF antibody for the treatment of HS and palmoplantar pustulosis (NCT03972280).95