How do different drug classes work in treating Hidradenitis Suppurativa?
Overview of Hidradenitis Suppurativa
Hidradenitis Suppurativa (HS) is a chronic, debilitating, inflammatory skin disorder that primarily affects apocrine gland-bearing regions such as the axillae, groin, perianal, and inframammary areas. The hallmark clinical features include recurrent, painful nodules, abscesses, and draining sinus tracts that eventually lead to extensive scarring. Patients frequently suffer from malodor, physical discomfort, and psychological distress due to the unpredictable nature of the disease and its impact on quality of life. The severity of HS is often described in terms of stages (e.g., Hurley staging), with early stages featuring isolated nodules and later stages showing extensive sinus tract formation and scarring.
Current Treatment Landscape
The treatment of HS is multifaceted and tailored to disease severity, lesion distribution, and patient-specific factors. Because the pathogenesis remains incompletely understood, management typically involves a combination of medical and surgical approaches. Medical therapies include topical and systemic antibiotics, hormonal treatments, and biologic agents that target specific inflammatory mediators. Over the past decade, the use of biologics has gained prominence for moderate to severe cases, while antibiotics remain the cornerstone of first-line therapy for their anti-inflammatory and antimicrobial properties. Hormonal therapies also play a significant role, particularly in female patients with evidence of androgenic influence. As our understanding of the inflammatory cascades in HS increases, treatment strategies continue to evolve with ongoing clinical trials and emerging drug classes.
Drug Classes Used in Treatment
The main drug classes in the treatment of HS are divided into antibiotics, biologics, and hormonal treatments. Each category is designed to target different aspects of the disease’s pathogenesis, which is multifactorial and includes microbial dysbiosis, dysregulated immune responses, and hormonal influences.
Antibiotics
Antibiotics have been the traditional mainstay of HS therapy due to their dual ability to reduce bacterial colonization and exert anti-inflammatory effects. Systemic antibiotics are typically used in cases where microbial dysbiosis and biofilm formation within the sinus tracts are implicated. For instance, tetracyclines (including tetracycline, doxycycline, and lymecycline) are favored as they exhibit anti-inflammatory properties in addition to antimicrobial activity. The rifampicin–clindamycin combination is recommended as first-line therapy for moderate to severe HS in many European guidelines, although concerns regarding prolonged rifampicin use have driven studies on rifampicin-sparing regimens such as clindamycin monotherapy. The antibiotics work by reducing the burden of diverse bacterial populations—often polymicrobial in HS lesions—and by inhibiting pro-inflammatory cytokine release.
Biologics
Biologic drugs represent a newer approach, targeting specific immunological pathways implicated in HS. The most well‐studied biologic in HS is adalimumab, a fully human monoclonal antibody that inhibits tumor necrosis factor-alpha (TNF-α). Other biologics include infliximab (another TNF-α inhibitor) and newer agents targeting interleukin pathways such as IL-17 and IL-23. For example, secukinumab (an IL-17A inhibitor) and bimekizumab (a dual IL-17A and IL-17F blocker) have shown promising results in reducing inflammatory lesions and improving clinical scores in HS. Biologics are generally used when antibiotic therapies have proven insufficient, particularly in patients with moderate to severe HS, as these agents specifically target key pro-inflammatory mediators that drive the recurrent and chronic inflammatory state in HS.
Hormonal Treatments
Hormonal therapies are primarily used in female patients where an underlying hyperandrogenic state is suspected to contribute to disease pathogenesis. Many women with HS experience flares in line with their menstrual cycle or present with concomitant endocrine disorders, such as polycystic ovary syndrome (PCOS), which further influence HS severity. Drugs such as combined oral contraceptives, spironolactone (an androgen receptor blocker), finasteride (a 5α-reductase inhibitor), and dutasteride have been employed to modulate the androgenic milieu, thereby reducing sebaceous gland activity and mitigating inflammatory responses in the skin. Hormonal treatments are particularly attractive because they may address the metabolic and endocrine contributors to the disease, improving both skin symptoms and systemic metabolic parameters.
Mechanisms of Action
The specific mechanisms by which each drug class exerts its therapeutic effects in HS differ according to the underlying pathology targeted.
How Antibiotics Work
Antibiotics treat HS by two primary mechanisms: (1) antimicrobial activity and (2) anti-inflammatory effects.
• Antimicrobial Action:
HS lesions are associated with a polymicrobial flora that may include anaerobic bacteria, actinomycetes, and streptococcal species. By reducing bacterial load, antibiotics help to minimize the perpetuation of local inflammation and the formation of biofilms within sinus tracts. With decreased bacterial colonization, the burden on the innate immune system is lessened, leading to fewer inflammatory signals and reduced lesion exacerbation.
• Anti-inflammatory Effects:
Many antibiotics, notably tetracyclines, have intrinsic anti-inflammatory properties independent of their antimicrobial actions. These agents inhibit metalloproteinases and pro-inflammatory cytokines (like IL-1β and TNF-α), thereby reducing tissue destruction and the chronic inflammatory state seen in HS. This dual mechanism is particularly beneficial because it addresses both the possibility of subclinical infection and the dysregulated immune responses contributing to the lesions.
How Biologics Work
Biologics are designed to specifically interfere with the inflammatory cascade that characterizes HS.
• TNF-α Inhibition:
Adalimumab and infliximab bind to TNF-α, a pivotal cytokine that orchestrates the inflammatory response in HS. By neutralizing TNF-α, these drugs decrease the activation and recruitment of immune cells, reduce the expression of adhesion molecules, and subsequently diminish the inflammatory embers that lead to nodule formation and fistulae.
• Interleukin Inhibition:
Other biologics target interleukins involved in the pathogenesis of HS. IL-17, for example, plays a significant role in recruiting neutrophils and propagating chronic inflammation. Agents like secukinumab block IL-17A, while bimekizumab targets both IL-17A and IL-17F to reduce the activity of T-helper 17 cells that are elevated in HS lesions. Similarly, emerging therapies targeting IL-23 work by modulating the differentiation and maintenance of Th17 cells, thereby indirectly reducing IL-17 production and the subsequent inflammatory cascade. These targeted mechanisms allow for precise modulation of the immune response, often leading to rapid improvement in clinical symptoms in patients with moderate–to-severe HS.
How Hormonal Treatments Work
Hormonal treatments address the endocrine component of HS.
• Anti-androgen Effects:
HS in women is often associated with higher levels of circulating androgens or heightened sensitivity of androgen receptors. Drugs like spironolactone, finasteride, and dutasteride function by inhibiting androgen receptor activity or reducing androgen production. Spironolactone blocks androgen receptors in the skin, leading to decreased sebum production and reduced follicular occlusion—factors that are thought to contribute to the inflammatory cycle in HS. Finasteride and dutasteride inhibit 5α-reductase, thereby reducing the conversion of testosterone to dihydrotestosterone (DHT), a more potent androgen that promotes sebaceous gland activity.
• Hormone Regulation via Contraceptives:
Combined oral contraceptives provide a multifaceted mechanism: they reduce the synthesis of androgens by the ovaries, increase levels of sex hormone-binding globulin (thus reducing the free, active fraction of testosterone), and stabilize cyclical hormonal fluctuations. This stabilization of hormone levels can be particularly effective in reducing premenstrual flares, a common complaint among women with HS.
Comparative Efficacy and Safety
A comparative evaluation of how these drug classes perform in HS treatment provides important insights into their clinical use, limitations, and role in treatment algorithms.
Clinical Trial Results
Multiple randomized controlled trials and observational studies have demonstrated variable efficacy among the three classes of drugs.
• Antibiotics:
Clinical trials assessing the use of antibiotics, particularly combination regimens such as rifampicin–clindamycin and monotherapies like tetracyclines, have demonstrated significant reductions in inflammatory lesion counts, improvements in pain scores, and better quality-of-life measures. Although antibiotics are widely used as first-line agents, the overall clinical response may diminish over time due to increasing antimicrobial resistance and treatment fatigue.
• Biologics:
Adalimumab was the first biologic approved for HS by both the FDA and EMA, with pivotal phase III trials (such as the PIONEER studies) showing a significant improvement in Hidradenitis Suppurativa Clinical Response (HiSCR) compared to placebo. Other biologics, including secukinumab and bimekizumab, have shown promising results in early-phase trials by rapidly reducing inflammatory lesions and improving pain and quality-of-life scores. The targeted nature of biologics has led to improvements that are often more sustained than those seen with antibiotics, although placebo response rates and variability between patients remain a concern.
• Hormonal Treatments:
Several studies have underscored the benefit of hormonal treatments, especially in female patients with evidence of hormonal disturbances or menstrual-related flares. These studies, although not as numerous or uniform as those involving biologics, indicate that hormone-modulating therapies can significantly reduce lesion counts and inflammation over extended periods (often requiring treatment durations of at least 12 months for full benefit). Hormonal treatments also offer the potential to improve associated systemic conditions, such as insulin resistance and metabolic syndrome, which are common in HS patients.
Side Effects and Safety Profiles
Each drug class carries its own risk profile, influencing clinical decision-making in individualized care.
• Antibiotics:
The safety profile of antibiotics is generally favorable in the short term; however, long-term use raises concerns about antimicrobial resistance, gastrointestinal disturbances, and alterations in the skin microbiome. The rifampicin–clindamycin combination, while effective, poses the risk of hepatotoxicity and drug–drug interactions, and prolonged use of rifampicin in particular is discouraged. Alternative antibiotic regimens, such as monotherapy with clindamycin or tetracyclines, are being explored to mitigate these risks.
• Biologics:
Biologics usually have a higher cost and require parenteral administration, which can be a barrier for some patients. They also carry risks inherent to immune modulation such as an increased risk of infections, injection site reactions, and rarely, paradoxical inflammatory events. Nonetheless, the long-term safety data for adalimumab in HS are encouraging, and the targeted approach of these agents means that systemic side effects are often less pronounced than those seen with traditional immunosuppressants.
• Hormonal Treatments:
Hormonal therapies are generally well tolerated but require careful patient selection since they can exacerbate or precipitate thromboembolic events, particularly in patients with pre-existing cardiovascular risk factors. Side effects may include menstrual irregularities, weight gain, and, in rare cases, an increased risk of certain cancers. Because they are mainly used in women, considerations regarding pregnancy, lactation, and long-term endocrine effects are extremely important. Monitoring and a multidisciplinary approach are therefore essential when employing hormonal treatments in HS.
Future Directions and Research
The current treatment landscape is continually evolving as new therapeutic targets are identified and novel drugs are developed. Research efforts are aimed at both optimizing existing therapies and introducing new treatment modalities.
Emerging Treatments
Emerging treatments in HS often focus on novel molecular targets and refined pharmacological approaches. For example, recent patents describe the use of LTA4H inhibitors for treating HS, which target leukotriene A4 hydrolase to reduce neutrophilic inflammation—a key feature in HS pathophysiology. Additionally, small molecule inhibitors, such as JAK inhibitors, and other agents targeting IL-1 or complement pathways represent promising directions for future therapies. These emerging agents are designed to fill gaps where current treatments—such as biologics and antibiotics—fall short, particularly for patients with refractory disease. The development of dual inhibitors, such as bimekizumab which blocks both IL-17A and IL-17F, is another example of evolving strategies to more broadly dampen the inflammatory milieu present in HS.
Ongoing Clinical Trials
A large number of clinical trials are currently underway to explore both new indications for existing drugs and entirely novel therapies for HS. ClinicalTrials.gov lists numerous ongoing studies assessing the efficacy and safety of biologic agents, including IL-17 inhibitors (e.g., secukinumab and bimekizumab), anti-IL-23 therapies (e.g., guselkumab, risankizumab, tildrakizumab), and other emerging agents. These trials are essential in refining patient selection criteria, optimizing dosing regimens, and determining long-term safety profiles. The evolving clinical trial landscape reflects the urgency of addressing the unmet needs of patients with HS and is expected to contribute data that not only support regulatory approvals but also guide real-world treatment strategies.
In addition to novel targets, there is an increasing interest in combination therapies—using biologics with antibiotics or hormonal treatments—to achieve synergistic effects that can better control severe or refractory disease. Recent studies on neoadjuvant biologic therapy combined with surgery also highlight how integrating multiple treatment modalities can improve outcomes, particularly in patients with long-standing HS.
Conclusion
In summary, the treatment of Hidradenitis Suppurativa utilizes a diverse array of drug classes—antibiotics, biologics, and hormonal treatments—each addressing distinct aspects of the disease’s multifactorial pathogenesis. Antibiotics function through antimicrobial action and anti-inflammatory effects, which help reduce bacterial colonization, biofilm formation, and cytokine release. Biologics offer a targeted approach by inhibiting specific inflammatory mediators, particularly TNF-α, IL-17, and IL-23, thereby directly modulating the immune system’s overactive response in HS. Hormonal therapies, mainly used in female patients with a hyperandrogenic profile, work by reducing the influence of androgens on the skin, thereby minimizing sebaceous gland activity and follicular occlusion.
Clinically, antibiotics remain an effective first-line strategy, although concerns about resistance and long-term efficacy persist. Biologics have demonstrated considerable promise in moderate to severe disease, with robust clinical trial data supporting their use, but their safety profiles require diligent monitoring. Hormonal treatments provide an additional therapeutic option, particularly for patients with endocrine influences worsening their skin symptoms, and can offer benefits that extend beyond mere disease control to also address metabolic comorbidities.
Looking ahead, ongoing clinical trials and emerging therapeutics are expected to further refine treatment strategies for HS. Advances such as LTA4H inhibitors, dual cytokine inhibitors like bimekizumab, and combination therapy protocols are at the forefront of current research and could provide more durable and holistic management options for patients with this challenging condition. The integration of clinical trial findings into real-world practice continues to enhance our understanding of HS, bringing us closer to individualized treatment regimens that optimize efficacy while minimizing adverse effects.
Ultimately, the future of HS treatment lies in a multidisciplinary approach that combines an understanding of inflammatory pathways, hormonal influences, and microbial factors with ongoing innovations in pharmacotherapy. With improved patient selection, novel interventions, and comprehensive management strategies, the quality of life for patients with HS is poised to improve significantly.
This detailed exploration highlights that each drug class plays a unique role through specific mechanisms of action and yields variable yet complementary effects on the disease process. The general principle is to tailor treatment regimens—whether through antibiotics to control infection and inflammation, biologics to down-modulate inflammatory cytokines, or hormonal therapies to regulate underlying endocrine disturbances—to the individual needs of patients. As research continues and our understanding deepens, combination therapies and emerging drug classes will provide further opportunities to close the treatment gaps in HS and deliver more precise and effective care.
In conclusion, the multi-pronged approach in treating Hidradenitis Suppurativa is essential due to the disease’s complexity. By integrating antibiotics, biologics, and hormonal treatments into personalized therapy plans, clinicians can approach HS from general, specific, and then re-integrated perspectives. This ensures that patients receive the benefits of each modality while mitigating risks and anticipating future therapeutic advancements. The emphasis on continued research, multidisciplinary care, and patient-specific strategies is a critical path forward in transforming HS treatment into a more effective and sustainable clinical practice.
For an experience with the large-scale biopharmaceutical model Hiro-LS, please click here for a quick and free trial of its features！
