Combination therapies for hidradenitis suppurativa: Narrative review of current strategies and emerging perspectives

Abstract

Hidradenitis suppurativa (HS) is a chronic, recurrent, and debilitating inflammatory dermatosis affecting approximately 1% of the population, with a female predominance and substantial psychosocial burden. Clinically, it presents with painful nodules, abscesses, and draining tunnels that often progress to fibrosis and long-term disability. Pathogenesis is multifactorial, encompassing follicular occlusion and rupture, dysbiosis, neutrophil-rich inflammation, and cytokine networks driven by tumor necrosis factor-alpha and interleukin-17 (IL-17), and despite advances, major challenges persist, including phenotypic heterogeneity, diagnostic delays, and the limited durability of monotherapies. This narrative review critically synthesizes evidence on combination strategies in HS following a systematic search of PubMed, Embase, and Cochrane (2009–July 2025), including randomized and nonrandomized trials, cohorts, and case series (⩾10 patients) that evaluated multimodal approaches (antibiotics plus biologics, biologics within surgical pathways, small molecules in combination, laser/light-based therapies, and structured wound care). Outcomes of interest included Hidradenitis Suppurativa Clinical Response, International Hidradenitis Suppurativa Severity Score System (IHS4)/IHS4-55, tunnel resolution, patient-reported measures (Dermatology Life Quality Index), flare frequency, and safety; qualitative synthesis was performed according to Scale for the Assessment of Narrative Review Articles criteria. Antibiotics remain valuable for induction or bridging: clindamycin–rifampicin and multidrug regimens (rifampin–moxifloxacin–metronidazole, ertapenem) yield meaningful but time-limited benefit, optimally used as preparatory steps toward long-term interventions. Biologics form the backbone of durable disease control (adalimumab, secukinumab, bimekizumab), with enhanced outcomes when initiated alongside antibiotics or integrated perioperatively with surgery for tunnel eradication. Among small molecules, Janus kinase inhibitors (e.g., upadacitinib) show promising efficacy; apremilast and IL-36 blockade are exploratory options; sirolimus and conventional immunosuppressants retain niche utility in syndromic or refractory phenotypes. Adjunctive measures, including laser/light therapies, structured wound care, metabolic interventions (notably glucagon-like peptide-1 receptor agonists), smoking cessation, and psychological support, further consolidate disease control, while multidisciplinary care models optimize sequencing, comorbidity management, and recurrence reduction. In conclusion, combination therapy has emerged as the organizing principle of modern HS management: integrating antibiotic induction, biologics for long-term modification, targeted surgery, and adjunctive measures enables deeper and more durable responses. Future priorities include treat-to-target strategies, biomarker-guided selection, antimicrobial stewardship, and pragmatic real-world evaluations to advance toward near-clearance in a broader patient population.

Plain language summary

How using multiple therapies can improve care for hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory skin condition characterized by painful nodules, abscesses, and deep skin tunnels, typically occurring in intertriginous areas such as the armpits, groin, and buttocks. Affecting approximately 1% of the global population, HS significantly impairs patients’ quality of life due to chronic pain, irreversible scarring, and its profound impact on mental health and daily activities. This review highlights the clinical benefits of “combination therapy”, the strategic use of multiple, complementary treatments, to better manage HS. Traditional standalone treatments, including systemic antibiotics, surgery, or biologic therapies (such as adalimumab or secukinumab), often provide incomplete or temporary relief when used in isolation. However, when integrated strategically, these modalities can rapidly control inflammation, prevent the recurrence of skin tunnels, and promote better wound healing. Examples include starting biologic drugs together with a short course of antibiotics, combining surgery with biologic therapy to reduce relapse, and adding supportive measures like laser therapy, wound care, lifestyle changes, and psychological support. New treatments such as JAK inhibitors and GLP-1 receptor agonists are also being studied as part of combination approaches. Ultimately, combination therapy is emerging as the optimal organizing principle for modern HS management, offering patients a higher likelihood of durable disease control and substantially improved well-being.

Introduction

Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory dermatosis that affects nearly 1% of the global population, with consistent female predominance and a high burden across all age groups. ¹ Beyond its cutaneous manifestations, HS exerts a profound psychosocial impact, encompassing pain, impaired quality of life, stigmatization, and reduced work productivity. The disease is also strongly associated with systemic comorbidities, including metabolic syndrome, inflammatory bowel disease, depression, and anxiety, underscoring its relevance as a multisystem condition. ²

The clinical presentation of HS is characterized by painful inflammatory nodules, abscesses, and recurrent draining sinus tracts or tunnels, which are typically localized to intertriginous regions such as the axillae, inguinal folds, and anogenital areas. These lesions often progress to fibrotic scarring and contractures, contributing to long-term disability. The disease course is unpredictable, with alternating phases of exacerbation and partial remission, and the cumulative morbidity increases with disease duration. ²

Pathogenetically, HS is a multifactorial disorder driven by an interplay between follicular, microbial, and immunologic mechanisms. Follicular occlusion followed by rupture is considered the initiating event, leading to dermal exposure of keratin and microbial antigens. This triggers secondary bacterial colonization and dysbiosis, amplifying an innate immune response dominated by neutrophilic infiltration and activation of inflammasome pathways. Adaptive responses further perpetuate inflammation through the tumor necrosis factor-alpha (TNF-α) and interleukin-17/interleukin-23 (IL-17/IL-23) axes, creating a self-sustaining cytokine network.^2,3 These mechanistic insights have provided the rationale for the development of targeted therapies and have positioned HS as a disease of dysregulated innate and adaptive immunity.

Despite advancements in our understanding of disease biology, clinical challenges persist. HS is distinguished by its phenotypic heterogeneity, which manifests in variable patterns of lesion morphology, tunnel burden, and anatomical distribution. This heterogeneity poses a significant challenge to the development of standardized approaches to treatment. ² Diagnostic delay is another consistent issue: patients frequently experience years of symptoms before receiving a correct diagnosis, during which time irreversible tissue damage accumulates and therapeutic windows are missed.^2,4,5 In addition, therapeutic responses remain highly variable, and traditional monotherapies, whether systemic antibiotics, biologic agents, or surgical procedures, have repeatedly demonstrated limited capacity to induce durable remission, especially in tunnel-dominant phenotypes.^4–6 (Figure 1).

Figure 1.

Graphical representation of the integrated multimodal treatment pathway for hidradenitis suppurativa. The algorithm illustrates how combination therapies are applied sequentially: antibiotics for induction, biologics and surgery for consolidation, and maintenance strategies including biologics, wound care, lifestyle interventions, metabolic management, and adjunctive therapies.

These limitations have given rise to a growing interest in combination approaches. Mechanistically, cross-category combinations are appealing in HS because distinct modalities address complementary disease dimensions: microbial dysbiosis/secondary infection, cytokine-driven inflammation, and established structural disease (tunnels and scarring). Finite antibiotic courses may rapidly reduce inflammatory and microbial load, functioning as induction or bridging. While biologics are often viewed as slower-acting in advanced disease, rapid clinical improvements can be seen within the first 2–4 weeks when introduced early in the disease course before significant tunnel formation. Likewise, integrating systemic immunomodulation into surgical pathways targets both the inflammatory milieu and the anatomic nidus, with the potential to reduce perioperative disease activity, support wound healing, and lower local recurrence. Finally, pairing biologics with small-molecule inhibitors may theoretically broaden pathway coverage (upstream cytokine neutralization together with downstream signal-transduction blockade), providing a testable basis for synergy in selected refractory phenotypes and informing future trial designs focused on sequencing (induction–consolidation–maintenance). Recent guidelines and consensus statements from European, North American, and international expert panels converge on the principle that optimal HS management requires multimodal integration rather than reliance on a single modality.^4–6 The present review builds on this perspective, providing a narrative synthesis of the available evidence on combination therapies for HS, with particular attention to induction, consolidation, and maintenance strategies across medical, surgical, and supportive domains.

Methods

This narrative review aimed to critically appraise and contextualize evidence on combination therapies for HS. A comprehensive search of MEDLINE (PubMed), Embase, and the Cochrane Library covered January 2009 to July 21, 2025.

We included randomized and nonrandomized trials, prospective and retrospective cohorts, and case series with ⩾10 patients that evaluated multimodal or combination approaches (e.g., antibiotics plus biologics; biologics within surgical pathways; small molecules; laser/light as adjuncts). To ensure comprehensive context, we also incorporated systematic reviews, meta-analyses, and evidence-based guidelines/consensus statements. Only English-language publications were considered. Two reviewers (An.Ca., St.Bi.) independently screened titles/abstracts and assessed full texts for relevance; disagreements were resolved by discussion.

Outcomes of interest prioritized clinically meaningful domains: Hidradenitis Suppurativa Clinical Response (HiSCR), International Hidradenitis Suppurativa Severity Score System (IHS4) and its 55% reduction threshold (IHS4-55), tunnel count/resolution, and patient-reported outcomes (PROs) as Dermatology Life Quality Index, along with flare frequency and pain where reported. Safety endpoints included serious adverse events, infections, and surgical morbidity (e.g., delayed healing, recurrence). Given heterogeneity in design, interventions, comparators, and endpoints, we conducted a qualitative synthesis without quantitative meta-analysis.

When weighing evidence, we assigned greater interpretive value to studies with larger samples, longer follow-up, prespecified endpoints, and comparators; smaller or exploratory studies were used to highlight signals in areas with limited data. We appraised clarity, methodological transparency, and clinical applicability using Scale for the Assessment of Narrative Review Articles criteria, ⁷ explicitly acknowledging constraints inherent to narrative reviews (selection bias, publication bias, and outcome heterogeneity). Where appropriate, we triangulated findings across study types (trial → cohort → guideline) to support practice-oriented conclusions.

Antibiotic-based combinations

Systemic antibiotics are one of the longest-established therapeutic options in HS. Their widespread use reflects their antimicrobial effects and well-documented anti-inflammatory properties, which can provide meaningful, albeit often transient, clinical benefits. Tetracyclines and the combination of clindamycin with rifampicin have historically been the mainstay regimens and continue to be frequently prescribed for mild-to-moderate and moderate-to-severe disease. More recently, multidrug schedules such as rifampin–moxifloxacin–metronidazole (RMoM) and intravenous ertapenem have expanded the therapeutic armamentarium, particularly in refractory patients. However, these regimens should be viewed less as definitive solutions and more as time-limited tools within broader combination strategies aimed at stabilizing inflammation, reducing the microbial burden, and creating favorable conditions for long-term interventions such as biologics or surgery.

Tetracyclines, primarily doxycycline, minocycline, and lymecycline, are often used as the first-line systemic therapy for mild-to-moderate HS. Advantages include favorable tolerability, oral administration, and modest anti-inflammatory activity through the inhibition of neutrophil chemotaxis and matrix metalloproteinase activity. Prospective European cohort data demonstrated that tetracyclines achieved significant symptomatic improvement, with reductions in inflammatory lesion counts and improvements in quality of life. However, the magnitude of the response was lower than that observed with clindamycin–rifampicin. ⁸ These findings confirm their usefulness as a safe induction regimen, while also highlighting their limitations in achieving sustained control in more severe cases.

The dual regimen of clindamycin and rifampicin (CLN + RIF) is one of the most widely studied antibiotic combinations for HS. Typically administered for 10–12 weeks, CLN + RIF has provided consistent clinical benefits in both prospective and retrospective studies. Patients treated with this regimen exhibit reductions in inflammatory nodules and abscesses, improved HiSCR and IHS4 outcomes, and an enhanced quality of life overall.^8,9 Nevertheless, variability in response remains considerable, and relapse after discontinuation is common. Importantly, rifampicin’s significant induction of hepatic cytochrome P450 enzymes can lead to clinically relevant drug–drug interactions, particularly with oral contraceptives and certain immunosuppressants. Therefore, careful patient counseling and monitoring are essential. Despite these limitations, the regimen remains a cornerstone of treatment for moderate-to-severe disease, particularly as a bridge to biologic therapy or surgery.

For patients with refractory HS, the RMoM regimen, combining rifampicin, moxifloxacin, and metronidazole, has emerged as an attractive option. A prospective trial involving 28 patients with severe disease reported high short-term remission rates, with many patients experiencing continued clinical improvement after 1 year. ¹⁰ Importantly, the RMoM regimen is often used in sequential strategies, such as induction with ertapenem followed by consolidation with RMoM. This provides rapid disease debulking before transitioning to biologics or surgery. This sequential approach highlights the increasing focus on using antibiotics as integral, time-limited components of multimodal treatment algorithms rather than as standalone therapies.

Ertapenem has been studied as a treatment for the most severe HS flare-ups, particularly in patients with widespread suppuration and a high tunnel burden. Although the available evidence is limited to case reports and small case series, the outcomes have been encouraging. In one illustrative report, intravenous ertapenem rapidly reduced inflammation, alleviated pain, and improved quality of life, enabling a subsequent transition to oral or biologic therapy. ¹¹ Due to its parenteral route of administration and concerns regarding resistance, it is unlikely that ertapenem will be widely adopted. However, its ability to rapidly control otherwise intractable flare-ups highlights the potential of antibiotics as crisis management tools in HS.

Additional antibiotic-based strategies have also been explored. A prospective comparison showed that lymecycline produced comparable improvements in clinical and ultrasonographic parameters to those observed with CLN + RIF. This suggests that tetracyclines could be a viable alternative for patients who are unable to tolerate or are contraindicated for rifampicin. ¹² Safety concerns are growing in importance, as shown by the reassuring data that revealed no higher rate of Clostridium difficile infection among HS patients treated with prolonged clindamycin, thus reducing one of the major concerns about long-term use. ¹³ Trimethoprim–sulfamethoxazole combined with cephalexin has been reported as an alternative oral regimen in selected moderate-to-severe HS patients, although evidence is currently limited to small retrospective series. ¹⁴

In addition to established treatments, exploratory approaches have investigated the potential of combining nonantibiotic agents to boost anti-inflammatory effects. A retrospective case series indicated that combining colchicine with tetracyclines improved IHS4 scores, alleviated symptoms, and improved quality of life, compared with tetracyclines alone. ¹⁵ Similarly, acitretin combined with macrolide pulse therapy has been proposed as a treatment option for patients who are not eligible for biologics. Small case series have indicated a potential benefit, though inconsistent efficacy and limited adverse effects have restricted its broader application. ¹⁶ While such regimens remain in the preliminary stages and are supported only by low-level evidence, they underscore the ongoing efforts to diversify antibiotic-based strategies and customise treatment for specific patient subsets.

These data suggest that, although antibiotics are valuable, they are inherently limited in the management of HS. They are most effective when used in short courses to rapidly control the disease, as a bridge to biologic therapy, or to stabilize patients before surgery. However, prolonged or repeated use is associated with diminishing returns and increasing risks, including antimicrobial resistance, microbiome disruption, and cumulative toxicity. Accordingly, both European and North American guidelines now emphasize strict antimicrobial stewardship, advocating careful patient selection, finite treatment durations, and an early transition to disease-modifying strategies wherever feasible.^4,5 Within this framework, systemic antibiotics remain indispensable; however, their role is best understood as part of a broader therapeutic continuum rather than as definitive long-term solutions.

Biologic-based combinations

The advent of biologic therapy has transformed the management of HS, providing the first targeted options capable of modifying disease trajectory rather than delivering transient symptomatic relief. Adalimumab, a TNF-α inhibitor, was the first biologic therapy to be formally approved for HS. Its efficacy was established in the pivotal phase III PIONEER I and II trials. ¹⁷ These studies demonstrated significant reductions in inflammatory lesion counts and improvements in PROs, as well as an acceptable safety profile. However, the trials also revealed the limitations of biologic monotherapy, as only a subset of patients achieved HiSCR, with many continuing to experience relapses or persistent tunnel disease despite treatment.

The range of therapeutic options has expanded with the development of IL-17 inhibitors. Secukinumab, an IL-17A inhibitor, was evaluated in the SUNSHINE and SUNRISE trials, which enrolled patients with moderate-to-severe HS and demonstrated clinically meaningful efficacy at both 16 and 52 weeks. ¹⁸ These findings reinforced the central role of IL-17A in the inflammatory cascade of HS. More recently, the BE HEARD I and II trials of bimekizumab, a dual IL-17A/F inhibitor, confirmed the relevance of this pathway and achieved significant response rates across multiple endpoints. This provides evidence that broader IL-17 blockade may confer an additional benefit. ¹⁹ Sonelokimab, a trivalent nanobody targeting IL-17A and IL-17F, also showed efficacy versus placebo in phase II. ²⁰ Early readouts from the phase III development program have been communicated, and full peer-reviewed reporting will be important to clarify the consistency of benefit across study populations and design settings. Together, these programs have established IL-17 inhibition as a validated alternative to TNF blockade, marking a new era in biologic therapy for HS.

Although these advances are significant, biologic therapies have historically been characterized by a relatively slow onset of action in patients with advanced disease, typically requiring several weeks to produce a clinical effect. However, faster clinical responses are possible if introduced early in the disease course. This delay has stimulated growing interest in combined regimens, particularly the integration of biologics with systemic antibiotics during induction. The rationale is that antibiotics can rapidly debulk the inflammatory and microbial load, alleviating symptoms and reducing the risk of secondary infections while the biologic exerts its slower, disease-modifying effects. Evidence supporting this approach comes from both trial design and real-world studies. In PIONEER II, where the use of concomitant oral tetracyclines was permitted, efficacy rates were higher than in PIONEER I, where antibiotic washout was mandated. ¹⁷ Further corroboration came from a matched cohort study showing that patients who initiated adalimumab alongside a 12-week course of clindamycin–rifampicin achieved greater IHS4 reductions, lower tunnel counts, and a higher proportion of IHS4-55 responders compared to those who took adalimumab alone. ²¹ These findings highlight the potential for synergy between finite antibiotic courses and biologics at the time of initiation and illustrate how integrated regimens can accelerate and deepen therapeutic responses without undermining antimicrobial stewardship.

Beyond antibiotics, surgery remains the other indispensable pillar of HS care. This is particularly so for the eradication of chronic sinus tracts and fibrotic scarring. Combining biologics with surgery has emerged as a rational strategy to improve both short- and long-term outcomes. The SHARPS randomized trial demonstrated that adalimumab administered perioperatively significantly improved HiSCR rates compared with surgery alone, without increasing postoperative complications such as delayed wound healing or infection. ²² This high-quality evidence confirmed the perioperative safety of adalimumab in the surgical setting and supported its integration into perioperative pathways. Real-world data from multiple centers in Asia and Europe reinforce these results, showing that patients receiving adalimumab alongside surgery achieved better IHS4 responses, superior quality-of-life improvements, and lower local recurrence rates than those managed surgically without systemic optimization. Mechanistically, perioperative biologic therapy likely reduces the inflammatory milieu, enabling more conservative resections and improved wound healing. Continued postoperative treatment suppresses residual activity and prevents new tunnel formation.^23–25

Another area of exploration involves combining biologics with conventional immunosuppressants. This approach is based on the experience with other immune-mediated diseases, where agents such as methotrexate are used to reduce antidrug antibody formation and prolong biologic persistence. In HS, these regimens have primarily been used to treat syndromic or highly refractory variants, such as PASH (pyoderma gangrenosum, acne, HS) or PAPASH (pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa). Anecdotal evidence suggests that they stabilize the disease and improve long-term biologic efficacy.^26–28 However, controlled studies are lacking, and concerns about additive toxicity limit their broader application.

Dual biologic therapy is a concept that has been proposed on the basis of mechanistic synergy between pathways such as TNF and IL-17, or TNF and IL-1/IL-36. Preclinical data support the rationale, showing that the simultaneous blockade of redundant inflammatory axes can suppress the initiation and propagation of disease activity. ²⁹ However, the current evidence base for HS is limited to case reports and small case series, which are often focused on syndromic or refractory patients. While enhanced control has been suggested by some reports, possible risks of additive immunosuppression, infection, malignancy, and prohibitive cost remain. For now, dual biologic therapy cannot be recommended outside of experimental settings and should be confined to specialized centers with rigorous monitoring.

The available evidence suggests that, while biologics are essential for long-term HS management, their integration alongside other strategies is particularly vital for severe disease. If treated early, combination therapy is rarely needed, which aligns with current biologic approval labels. Initial antibiotic treatment helps to rapidly control the disease, while surgery combined with biologics reduces recurrence and improves healing. The adjunctive use of conventional immunosuppressants or experimental dual biologic regimens may offer solutions in highly selected cases. As treatment paradigms evolve, the guiding principle is shifting from whether to combine biologics with other interventions, to how these combinations can be sequenced and integrated most effectively to achieve durable and meaningful outcomes for patients (Table 1).

Table 1.

Summary of combination and adjunctive therapeutic regimens in HS.

Combination regimen	Dosage and duration	Indications/setting	Efficacy outcomes	AEs	Notes/evidence
Clindamycin + Rifampicin	Clindamycin 300 mg BID plus Rifampicin 300 mg BID (or 600 mg OD), 10–12 weeks	Moderate–severe HS; bridge to biologics	HiSCR-50 48% at 12 weeks; initial response 73% decreasing to 41% at 1 year; reduction of inflammatory nodules; improvement in QoL	GI upset, rash, hepatotoxicity, drug–drug interactions (CYP450)	Prospective European cohort 8
RMoM	Rifampicin 10 mg/kg/day plus Moxifloxacin 400 mg/day plus Metronidazole 250–500 mg TID for 6 weeks, then Rifampicin plus Moxifloxacin for 4 weeks	Severe or refractory HS; bridge to surgery or biologics	Remission rate 75% at 12 weeks; sustained benefit at 1 year; 57% CR in refractory cases	GI upset, candidiasis; tendonitis or rupture (rare); risk of neurotoxicity with Metronidazole beyond 6 weeks	Prospective trial, 28 patients 10
Ertapenem (IV)	1 g/day IV, 6–12 weeks	Severe flares with high tunnel burden	Rapid reduction in pain and inflammation; improvement in QoL	Infusion-related AEs; resistance risk	Rescue induction; case reports and small series 11
Tetracyclines (Doxycycline, Minocycline, Lymecycline)	Doxycycline 100 mg/day; Minocycline 100 mg/day; Lymecycline 300 mg BID; 8–12 weeks	Mild–moderate HS	Symptom relief; reduction in lesion counts; lower efficacy compared to Clindamycin plus Rifampicin	GI upset, photosensitivity, dizziness (Minocycline)	Cohort data8,12; safety confirmed 13
TMP–SMX + Cephalexin	TMP–SMX 800–160 mg twice a day plus Cephalexin 500 mg twice a day for 3 months	Hurley stage II/III HS	75% (12/16) and 68.8% (11/16) had improvement based on physician and patient report	Diarrhea, pruritic rash	Case series 14
Tetracyclines + Colchicine	Minocycline 100 mg/day plus Colchicine 0.5 mg BID for 6 months followed by Colchicine maintenance for 3 months	Moderate HS; patients unfit for biologics	Reduction in IHS4 and DLQI; trend toward greater efficacy compared to Colchicine alone	GI intolerance (rare)	Retrospective study 15
Azithromycin + Acitretin	Azithromycin 500 mg/day for 3 consecutive days every 4 weeks plus Acitretin 25–35 mg/day (0.4 mg/kg/day)	Moderate–severe HS; biologic-contraindicated	IHS4 score decreased from 8.1 to 4.6; DLQI from 16 to 4.4; VAS pain from 6 to 2.1 after 8 weeks	GI upset in 2 of 15 patients	Small series 16
Adalimumab + Clindamycin/Rifampicin	Adalimumab standard dosing plus Clindamycin and Rifampicin for 12 weeks	Moderate–severe HS, especially with tunnels	IHS4 reduction of 20 vs 9 with monotherapy; tunnel reduction of 4 vs 2; HiSCR90 achieved in 36% vs 0%	Comparable to monotherapy; rifampicin interactions	Retrospective cohort 21
Adalimumab + Surgery (perioperative use)	Adalimumab continued perioperatively; wide excision or deroofing	Advanced HS with tunnel-dominant phenotype	HiSCR 48% vs 34% with surgery alone; recurrence lower; disease-free interval 18.5 vs 6 months	No increase in postoperative infection or delayed healing	RCT (SHARPS) 22 ; real-world23–25
Infliximab/Ustekinumab + Surgery	Biologic maintained for at least 6 months postoperatively	Severe or refractory HS	Recurrence 13.8% vs 38.5% with surgery alone; lesion reduction ⩾75% in some patients	Comparable to surgery alone	Retrospective studies24,25
Sonelokimab (IL-17A- and IL-17F-targeting Nanobody)	120 mg	Moderate-to-severe HS	Mean abscesses and draining tunnels reduction at weeks 12: −59%; weeks 24: −67%	Overall favorable benefit–risk profile	Phase II MIRA trial 20
Dual biologics (e.g., TNF + IL-17, TNF + IL-1/36)	Not standardized (case reports)	Syndromic or refractory HS	Anecdotal enhanced control	Additive immunosuppression, infections, high cost	Conceptual reports26,29
Sirolimus + TNF inhibitors	Oral Sirolimus combined with Infliximab or Adalimumab; variable duration	Severe Hurley III refractory HS	Minimal or complete response achieved in 78% at 24 weeks (small series)	Cytopenia, mucositis, metabolic AEs	Small case series 40
Upadacitinib (JAK1 inhibitor)	30 mg/day oral; phase II RCT	Moderate–severe HS	Significant reduction in disease activity compared to placebo; improved PROs	Infections, acne, increase in lipids	Phase II trial 31
Povorcitinib (JAK1 inhibitor)	15, 45, or 75 mg once daily; phase II RCT	Moderate–severe HS	Significant reduction in abscess and inflammatory nodule count at week 16	Mild acne, CPK elevation, infections	Phase II RCT 32
Ruxolitinib (topical JAK1/JAK2 inhibitor)	Twice daily for 16 weeks	Mild-to-moderate HS	Significant reduction in abscess and inflammatory nodule: −3.61 (ruxolitinib 1.5%) vs −2.42 (vehicle)	Well tolerated, contact dermatitis	Phase II RCT 33
Apremilast (PDE4 inhibitor)	30 mg BID oral	HS with psoriasis or IBD comorbidity	Modest improvement; inconsistent efficacy	GI upset, headache	Review and case series34,35
Roflumilast (PDE4 inhibitor)	500 μg once daily oral	Moderate–severe HS	Mean IHS4 reduction 9.7; DLQI −6.3; VAS 10 overall −2.0; HiSCR50 50%	Nausea, vertigo, disease worsening	Real-world cohort 36
Lutikizumab (IL-1α/IL-1β antagonist)	300 mg every week; 300 mg every other week; 100 mg every other week	Moderate-to-severe HS	Mean change from baseline in draining tunnels count (16 weeks): 300 mg EW: −3.0; 300 mg EOW: −4.2; 100 mg EOW: −2.5	Not reported	Phase II RCT 37
Anakinra (IL-1 receptor antagonist)	100 mg daily	Severe HS	Clinical response at Week 12: 78% (anakinra) vs 30% (placebo)	Diarrhea, swelling at the injection site, candidiasis	RCT, small sample size (20 pts) 38
Spesolimab (IL-36 antagonist)	IV dosing; phase II PoC trial	Moderate-to-severe HS	Reduction in inflammatory lesions; improved severity scores	Infusion reactions, infections	Proof-of-concept RCT 39
Methotrexate, Azathioprine, Cyclosporine, Dapsone	Standard systemic dosing	Syndromic HS (PASH, PAPASH) or refractory cases	Stabilization in small retrospective series; limited efficacy in classical HS	Hepatotoxicity, nephrotoxicity, hematological AEs	Retrospective data 35
Vilobelimab (anti-C5a monoclonal IgG4 antibody)	IV dosing, 7 weeks	Severe HS	HiSCR response: 75% at Day 50; 83.3% at Day 134	6/12 patients experienced AEs. 5 serious AEs (all HS exacerbations or infections)	Phase IIa study, single arm 51
GLP-1 receptor agonists (Liraglutide, Semaglutide, Dulaglutide)	Standard antidiabetic dosing; weekly or monthly SC injection	Obese or refractory HS	Improvement in lesions and symptoms in 50%–60% of patients; additional metabolic benefits	GI upset, weight loss	Systematic reviews54,55

AEs: Adverse Events; BID: Bis in die (twice a day); CPK: Creatine Phosphokinase; DLQI: Dermatology Life Quality Index; EOW: Every Other Week; EW: Every Week; GLP-1: glucagon-like peptide-1; HiSCR: hidradenitis Suppurativa Clinical Response; HS: hidradenitis suppurativa; IBD: Inflammatory Bowel Disease; IHS4: International Hidradenitis Suppurativa Severity Score System; IL: interleukin; JAK: Janus kinase; OD: optical density; PDE4: phosphodiesterase-4; PROs: patient-reported outcomes; QoL: Quality of Life; RCT: Randomized Controlled Trial; RMoM: Rifampicin + Moxifloxacin + Metronidazole; SMX: sulfamethoxazole; TID: Ter in die (three times a day); TMP: trimethoprim; TNF: tumor necrosis factor; VAS: Visual Analogue Scale.

Small molecules and immunosuppressants

While biologic agents remain the cornerstone of long-term disease modification in HS, the therapeutic spectrum has expanded in recent years with the advent of selective small molecules and renewed interest in conventional immunosuppressants. These agents are particularly relevant in refractory patients, in those with contraindications to biologics, or as adjuncts in syndromic variants where disease severity demands broader immunomodulation. ³⁰

The most compelling evidence to date comes from the inhibition of Janus kinase (JAK). In a phase II randomized, placebo-controlled trial, the selective JAK1 inhibitor upadacitinib demonstrated clinically meaningful improvement in moderate-to-severe HS, with significant reductions in disease activity and PROs compared to placebo. ³¹ Povorcitinib, a selective JAK1 inhibitor, has shown promising results in HS. In a phase II trial, it significantly reduced inflammatory lesions and nearly doubled HiSCR response rates compared to placebo, with a safety profile similar across groups. ³² Building on these findings, the global phase III program (STOP-HS1/STOP-HS2) has been designed to confirm efficacy and safety with a primary assessment at week 12 and continued longer-term follow-up, which will better define the magnitude and durability of benefit and inform its positioning as an oral alternative to biologics. The results confirm the mechanistic importance of the JAK/STAT axis in HS pathogenesis and suggest that JAK inhibitors may emerge as valuable components of future treatment algorithms. Their oral administration supports their use as alternatives or complements to biologic therapy. While JAK inhibitors demonstrate rapid onset in other conditions like atopic dermatitis, caution is needed when generalizing this to HS, where improvements may not be seen within the first few days of treatment. Furthermore, long-term safety and efficacy data are still needed. Topical therapies represent an additional emerging development area in HS, aiming to control localized inflammatory activity while minimizing systemic exposure. In this context, topical ruxolitinib cream has been evaluated in a 16-week clinical trial in mild HS, with week-16 outcomes reported. ³³ The phase III ruxolitinib trial evaluated the drug as a monotherapy. If the ongoing phase III program is successful, it would likely be approved as a monotherapy for patients with limited disease activity. Its utilization as an add-on option for patients on other treatments, or as part of maintenance strategies within broader multimodal pathways, would represent an off-label application.

Beyond JAK inhibition, the therapeutic pipeline for small molecules remains broad, but it is preliminary. A comprehensive overview of emerging strategies highlights the diversity of investigational approaches, ranging from targeted kinase inhibition to modulation of inflammatory mediators. ³⁴ Among available agents, apremilast, a phosphodiesterase-4 (PDE4) inhibitor approved for psoriasis and psoriatic arthritis, has been variably employed in HS, particularly in patients with comorbid psoriatic disease or inflammatory bowel disease. Its efficacy in HS, however, has been inconsistent, with modest improvements at best, underscoring its role as a niche therapy rather than a broadly applicable option. ³⁵ Nevertheless, its favorable safety profile, oral formulation, and potential for combination with biologics position apremilast as a pragmatic alternative in selected patients. Roflumilast, an oral PDE4 inhibitor, approved for chronic obstructive pulmonary disease, has recently been investigated in HS. In a small real-world cohort, it led to improvements in disease activity, quality of life, and PROs, with about half of patients achieving HiSCR50. However, treatment discontinuation was frequent due to adverse events or limited efficacy. Larger controlled studies are warranted to define its role in HS management. ³⁶

Attention has also shifted toward the IL-1 cytokine family, which is closely linked to neutrophil-rich inflammation and inflammasome activation in HS.^37,38 Beyond IL-36, clinical proof-of-concept exists for broader IL-1 pathway modulation: in a randomized clinical trial, IL-1 receptor blockade with anakinra demonstrated efficacy signals in severe HS. ³⁸ More recently, dual inhibition of IL-1α/IL-1β with lutikizumab (ABT-981) has shown improvements in draining tunnels in patients with difficult-to-treat disease and the program has advanced into phase III development. ³⁷ In parallel, IL-36 receptor antagonism has also been clinically explored; a randomized placebo-controlled trial of spesolimab provided encouraging reductions in inflammatory burden versus placebo, supporting IL-36 as an actionable axis within the IL-1 family network. ³⁹ Together, these data position IL-1-pathway interventions (IL-1α/β and IL-36) as rational candidates for future combination strategies with TNF or IL-17 blockade, particularly in refractory or tunnel-dominant phenotypes.

Conventional immunosuppressants, once the mainstay of systemic therapy for HS, now occupy a more restricted but still meaningful role. Methotrexate, cyclosporine, and dapsone continue to be used in syndromic or highly refractory phenotypes, especially in cases such as PASH ⁴⁰ or PAPASH, ⁴¹ where systemic inflammation is particularly pronounced. Their efficacy in classical HS remains limited, with most evidence derived from small retrospective series. Importantly, these agents carry risks of hepatotoxicity, nephrotoxicity, and hematological adverse events, requiring close monitoring. As such, their current role is adjunctive mainly, either in experimental combinations or when biologics and small molecules are unavailable or contraindicated. ³⁵

Experimental use of mechanistic target of rapamycin (mTOR) inhibition further illustrates the potential of repurposed immunomodulators. Small case series have reported that sirolimus, when added to TNF inhibitors, achieved high rates of disease control in patients with severe, refractory HS. ⁴² The mechanistic rationale lies in sirolimus’s ability to modulate both T-cell activity and metabolic pathways implicated in chronic inflammation. While preliminary, these results suggest that mTOR blockade could complement cytokine inhibition in highly selected scenarios. Broader validation in prospective studies will be required before sirolimus can be considered a standard option.

Taken together, the landscape of small molecules and immunosuppressants in HS is rapidly evolving. JAK inhibitors represent the most promising class, supported by randomized evidence and a strong mechanistic rationale. Apremilast, although less effective, provides a safe oral option for patients with comorbid conditions. IL-36 blockade and mTOR inhibition remain at the exploratory stage but point to exciting future avenues for combination therapy. Conventional immunosuppressants retain niche value in syndromic or refractory cases but are increasingly supplanted by targeted agents. Ultimately, these therapies highlight the principle that durable disease control in HS is most likely to arise not from isolated interventions, but from rationally designed regimens that combine complementary mechanisms to address the complex immunopathogenesis of the disease.

Multimodal treatment stacking and adjuncts

The complexity of HS increasingly necessitates structured multidisciplinary models of care. Traditional dermatology-led approaches, while indispensable for diagnosis and initiating systemic therapy, are often insufficient to address the diverse clinical, surgical, metabolic, and psychosocial needs of this patient population. Recent consensus statements and real-world experiences converge on the principle that integrated, multidisciplinary frameworks are fundamental to optimizing outcomes. ⁴³

At the core of these models lies an operational team composed of dermatologists, surgeons, radiologists, or ultrasonographers, and specialized wound-care nurses. Dermatologists typically coordinate systemic therapy, while surgeons address tunnel eradication and scarring through procedures ranging from deroofing to wide excision. Radiologists and dermatologists, particularly those skilled in high-resolution ultrasonography, offer valuable diagnostic and monitoring tools that inform both medical decision-making and surgical planning. ⁴⁴ Wound-care nurses contribute by standardizing dressing regimens, providing patient education, and ensuring continuity of care, thereby reducing postoperative morbidity and reinforcing adherence.^45,46 While standardized principles help ensure consistency and measurable targets, wound care in HS should remain individualized according to drainage volume, maceration risk, anatomical site, pain, infection/colonization features, and the postoperative context.

Laser- and light-based modalities can be useful adjuncts in selected HS phenotypes. Laser hair removal, particularly with long-pulsed 1064-nm Nd:YAG systems, targets the follicular unit and has been evaluated in controlled studies, with evidence syntheses supporting improvements in disease severity, especially in mild-to-moderate, hair-bearing disease where follicular occlusion is a key driver.^47,48 For chronic, tunnel-dominant disease, CO₂ laser deroofing/excision has been used as a procedural alternative within multimodal pathways, with comparative data suggesting high rates of tunnel healing at follow-up and an acceptable safety profile. ⁴⁹

Beyond this core team, an extended consultant panel is required to manage the frequent comorbidities associated with HS. Gastroenterologists contribute expertise in inflammatory bowel disease, while endocrinologists and nutritionists address obesity, metabolic syndrome, and dietary interventions. Rheumatologists are involved in systemic inflammatory and autoinflammatory syndromes. Infectious disease specialists and microbiologists guide antibiotic stewardship, ensuring finite treatment durations and minimizing the risk of antibiotic resistance. Psychologists and psychiatrists provide essential support for the high prevalence of depression, anxiety, and psychosocial distress among HS patients. Additional input from cardiologists, gynecologists, urologists, and primary care physicians further strengthens holistic care, addressing reproductive health, cardiovascular risk, and preventive strategies. ⁵⁰

Evidence supporting these models extends beyond theoretical rationale. Consensus-based guidelines emphasize that coordinated care accelerates transitions between therapeutic modalities, reduces surgical recurrence rates, and improves both clinical and PROs. ³⁹ Early experiences with structured multidisciplinary pathways in European centers have demonstrated greater efficiency in treatment sequencing, enhanced patient satisfaction, and reduced healthcare fragmentation.^46,47 Importantly, these benefits are achieved not by introducing novel drugs or devices, but by reorganizing existing resources into cohesive networks that align treatment decisions with patient needs across the disease course.

In summary, multidisciplinary care in HS represents more than an organizational refinement; it is a determinant of therapeutic success. By integrating diverse specialties within structured pathways, healthcare systems can provide timely, comprehensive, and patient-centered management. Such models exemplify the shift from fragmented, episodic interventions toward coordinated, pathway-driven care, ensuring that advances in pharmacology and surgery translate into durable and meaningful improvements in the lives of HS patients.

Future directions

Despite remarkable therapeutic advances, the management of HS continues to be characterized by partial responses, unpredictable relapses, and persistent structural disease. While biologics, antibiotics, and surgery provide valuable benefits, many patients fail to achieve sustained remission, particularly those with tunnel-dominant or refractory phenotypes. Future progress in HS management will depend on moving beyond incremental refinements of monotherapies toward precision-driven, multidimensional strategies that integrate emerging agents, novel endpoints, and real-world implementation frameworks (Figure 2).

Figure 2.

Schematic representation of current and future systemic therapeutic strategies for hidradenitis suppurativa. Present approaches rely mainly on TNF and IL-17 inhibitors. Next-generation therapies include selective JAK inhibitors and IL-36 antagonists, while emerging strategies focus on GLP-1 receptor agonists, complement inhibition, and mTOR blockade.

One key frontier is the expansion of therapeutic targets. Current biologics primarily target TNF-α and IL-17; however, mechanistic research underscores the complexity of HS immunopathogenesis and highlights additional pathways suitable for intervention. Among the most promising are the IL-1 family cytokines, especially IL-1β and IL-36. A proof-of-concept trial of spesolimab, an IL-36 receptor antagonist, demonstrated meaningful reductions in inflammatory lesion counts and disease activity, validating the role of this axis in HS and suggesting that IL-36 blockade could be integrated into future treatment algorithms, either as monotherapy or in combination with TNF or IL-17 inhibitors. ³⁹ More broadly, the therapeutic pipeline includes JAK/STAT inhibitors, complement pathway modulators, and metabolic regulators, all of which could diversify available strategies and enable more precise tailoring of treatment to individual patient biology. ²⁶ Emerging data also support a potential role for complement inhibition, particularly targeting C5a, given its contribution to neutrophil recruitment and amplification of tissue inflammation. Vilobelimab (IFX-1; InflaRx), an anti-C5a monoclonal antibody, was evaluated in the phase IIb SHINE trial in moderate-to-severe HS. While the primary week-16 HiSCR endpoint was not met versus placebo, post hoc analyses suggested signals of benefit at the highest tested dose, particularly on draining-tunnel burden and IHS4-based outcomes. ⁵¹ Furthermore, bispecific antibodies are being explored to concurrently modulate complementary inflammatory pathways and may represent a future alternative to empiric dual-biologic combinations. Although HS-specific clinical evidence remains limited, single-molecule dual targeting could broaden pathway coverage while preserving a defined single-agent safety and pharmacologic profile, and warrants monitoring as the HS development pipeline evolves. Additional molecules, such as IL-1 receptor-associated kinase 4 inhibitors, are also in early development. Although efficacy data in HS are not yet available, their role in upstream signaling of the IL-1 family suggests potential relevance for future investigation.^3,26

The concept of dual or combination targeted therapy is also gaining traction. While current clinical practice rarely employs more than one biologic at a time, the rationale for simultaneously blocking synergistic pathways, such as TNF and IL-17, or IL-17 and IL-1/IL-36, is strong. Experimental reports in other inflammatory conditions suggest that such combinations can overcome primary nonresponse and reduce the likelihood of relapse. In HS, expert commentary has emphasized the potential of these regimens to “raise the bar” for efficacy, enabling more profound and more durable disease suppression. ²⁹ However, rigorous clinical evaluation is essential before such strategies can move into standard care, given concerns about additive immunosuppression, safety, and cost. Adaptive or platform trial designs, which allow multiple regimens to be tested simultaneously, will be particularly valuable in generating comparative data and defining the most effective combinations.

Equally important is the refinement of treatment endpoints. Traditional measures, such as HiSCR, while valuable for clinical trial standardization, are insufficiently comprehensive in capturing tunnel resolution, flare frequency, malodor, and PROs that more accurately reflect disease burden. Future directions must continue to focus on treating early within the “window of opportunity” to prevent irreversible tissue damage. ⁵² Furthermore, future frameworks will likely adopt a formal treat-to-target approach, ⁵³ incorporating multidimensional metrics such as IHS4 trajectories, validated quality-of-life indices, and composite symptom scores. This approach would allow clinicians to escalate, de-escalate, or switch therapy based on objective milestones aligned with patient priorities, rather than relying solely on global lesion counts. ²⁶

Biomarker discovery and validation represent another critical frontier. Advances in high-resolution ultrasound, transcriptomics, proteomics, and microbiome profiling offer the potential to stratify patients based on tunnel biology, inflammatory signatures, or microbial dysbiosis. Such biomarkers could predict treatment responsiveness, identify individuals at the highest risk of relapse, and inform the selection of targeted interventions. Prospective cohorts that systematically integrate biospecimen collection with standardized imaging protocols will be essential to advancing precision medicine in HS. ²⁶

Alongside innovation in therapeutic targets and endpoints, antimicrobial stewardship must be institutionalized as a formal component of HS management. The repeated use of broad-spectrum antibiotics poses risks of resistance, microbiome disruption, and cumulative toxicity, yet antibiotics remain indispensable for short-term induction and bridging strategies. Future guidelines must therefore codify stop rules, promote rotation principles to minimize resistance, and embed regular microbiological reassessment within clinical algorithms. Stewardship frameworks will help balance the immediate need for disease control against the long-term public health imperative of preserving antimicrobial efficacy. ²⁶

Lifestyle and metabolic interventions will also play an increasingly prominent role in future treatment paradigms. The strong association between obesity, metabolic dysfunction, and HS severity underscores the importance of addressing systemic inflammatory drivers. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for the treatment of diabetes and obesity, have shown promising results in HS, with more than half of treated patients experiencing reductions in lesion burden or symptom improvement. ⁵⁴ Their dual capacity to improve metabolic parameters and attenuate inflammation positions them as ideal candidates for integration into combination regimens, particularly for obese patients with severe or refractory disease. Evaluating GLP-1 RAs in controlled HS trials will clarify their potential as standard adjuncts and may establish them as a bridge between dermatologic and metabolic care.

Given the strong association between obesity, metabolic dysfunction, and HS severity, metabolic therapies are likely to become integral to combination strategies. GLP-1 RAs, already used in the treatment of diabetes and obesity, have shown promise in HS, with both metabolic improvements and attenuation of inflammatory pathways, including TNF-α inhibition.^54–56 Their dual impact positions GLP-1 RAs as ideal candidates for integration into multimodal regimens, particularly for obese patients with severe or refractory disease.

Finally, real-world implementation science will be crucial to translating innovation into practice. Pragmatic studies must evaluate not only clinical outcomes but also cost-effectiveness, quality-adjusted life years, time to biologic initiation, hospitalization rates, and healthcare utilization. Structured multidisciplinary pathways, already shown to improve coordination and reduce fragmentation, require systematic evaluation across diverse health systems to determine scalability and sustainability.^26,50 At a global level, updated prevalence estimates and resource assessments will inform equitable access to advanced therapies, ensuring that therapeutic advances benefit patients across diverse socioeconomic contexts. ¹

In summary, the future of HS management lies in transitioning from fragmented, partially effective interventions to precision-driven, combination-based strategies. By expanding therapeutic targets, adopting multidimensional endpoints, embedding antimicrobial stewardship, integrating metabolic interventions such as GLP-1 RAs, and institutionalizing multidisciplinary frameworks, clinicians can aim not merely for partial control but for near-clearance and durable remission. Achieving this vision will require sustained collaboration across clinical, translational, and policy domains, but the momentum now building in HS research offers realistic grounds for optimism.

Conclusion

The therapeutic paradigm of HS is shifting from fragmented, monotherapeutic approaches toward integrated strategies that address the multifactorial nature of the disease. Decades of clinical experience and emerging high-quality evidence converge on the recognition that monotherapies, whether systemic antibiotics, biologics, or surgery, rarely achieve durable remission, particularly in patients with tunnel-dominant or refractory phenotypes. By contrast, strategically combined regimens that integrate complementary mechanisms of action provide more rapid, deeper, and longer-lasting control of disease activity.

Within this framework, systemic antibiotics remain indispensable for short-term induction of disease control, but their use should be judicious and finite, aligned with principles of antimicrobial stewardship. Biologics constitute the backbone of long-term management, and their full potential is realized when embedded within structured algorithms that combine them with antibiotic induction or surgical eradication of structural niduses. Surgery remains essential for definitive tunnel management, and perioperative integration of biologics has been shown to improve both safety and efficacy. Small molecules, including JAK inhibitors and investigational IL-36 antagonists, represent promising additions to the therapeutic armamentarium, while conventional immunosuppressants and experimental strategies such as mTOR inhibition retain niche applications in syndromic or refractory cases. Adjunctive measures, including laser- and light-based interventions, optimized wound care, lifestyle modification, and psychosocial support, further consolidate therapeutic gains and enhance patient adherence.

Taken together, these insights establish combination therapy not as an optional adjunct, but as the organizing principle of modern HS management. Through coordinated, multimodal, and multidisciplinary care pathways, it is now possible to move beyond partial symptom control and aspire to durable remission, reduced recurrence, and meaningful improvements in patient quality of life.