Secukinumab Plus Upadacitinib for the Treatment of Severe Hidradenitis Suppurativa and Associated Immune-Mediated Comorbidities: A Case Series

Abstract

Introduction

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease frequently associated with other immune-mediated inflammatory diseases (IMIDs), such as systemic lupus erythematosus (SLE) and psoriasis. Although advanced therapies have improved HS outcomes, many patients continue to experience suboptimal control, particularly when managing concurrent comorbidities. Combination therapy with biologics and small molecules may offer an effective strategy in select complex cases.

Methods

We present three female patients with moderate-to-severe HS and systemic comorbidities (two with paradoxical palmoplantar psoriasis, one with SLE) who were treated with a combination of secukinumab and upadacitinib. All had previously failed at least two conventional systemic therapies. Secukinumab 300 mg was initiated first, followed by the addition of upadacitinib (15–30 mg) after 5–6 months.

Results

The combination achieved significant improvement in HS activity and complete or near-complete resolution of comorbid conditions. Treatment was well tolerated, with no discontinuations or adverse events reported over 3–6 months of follow-up.

Conclusion

Our findings suggest that dual targeted therapy may represent a viable approach for patients with refractory disease and multiple immune-mediated conditions, warranting further investigation in larger cohorts.

Key Summary Points

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that may coexist with other immune-mediated conditions, such as systemic lupus erythematosus (SLE) or psoriasis.

In patients with severe or refractory HS and associated comorbidities, combining biologic and targeted synthetic therapies may offer clinical benefit.

This case series reports the first clinical experience using secukinumab plus upadacitinib in patients with HS and systemic comorbidities, specifically SLE or psoriasis, demonstrating favorable outcomes and tolerability.

Introduction

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease with a significant symptom burden [1]. Improved understanding of its pathogenesis has led to the development and approval of effective targeted biological therapies such as adalimumab, secukinumab, and, more recently, bimekizumab, as well as the exploration of novel therapeutic targets, including interferon-γ (IFNγ), complement, JAK-STAT pathway, and interleukin-1 (IL-1) [1, 2]. Beyond cytokine dysregulation, the pathogenesis of HS is increasingly recognized as multifactorial, involving epigenetic regulation, hormonal influences, microbiome perturbations, and innate/adaptive immune response alterations, which may further contribute to disease heterogeneity and therapeutic challenges [1]. Hormonal influences, particularly androgens, have been implicated in disease flares and gender-related differences in HS severity. Alterations in the skin and gut microbiome may also drive aberrant immune activation and chronic inflammation, contributing to lesion persistence and recurrence [1, 2], while epigenetic mechanisms are increasingly recognized as modulators of inflammatory gene expression, further adding to the complexity of the pathogenic landscape of HS [1, 2].

Despite these advances, a substantial proportion of patients exhibit a suboptimal response to current treatments, experience poor control of associated comorbidities (arthritis, psoriasis, systemic lupus erythematosus [SLE], and inflammatory bowel disease [IBD]) [2], or develop paradoxical inflammatory reactions [3]. These challenges complicate clinical management and may limit therapeutic options.

Current guidelines do not address the potential use of combined advanced targeted biological therapies [1, 2] or new small molecules [4], although selected patients may benefit from such an approach. Secukinumab 300 mg every 2 or 4 weeks has demonstrated robust short- and long-term efficacy and safety in the treatment of HS, supported by pivotal clinical trials [5] and real-world evidence. Upadacitinib, a selective JAK1 inhibitor with promising results [6, 7] for several immune-mediated inflammatory diseases (IMIDs), is currently under advanced investigation for HS [8]. Although the combination of adalimumab and upadacitinib [9] has been previously reported, to the best of our knowledge, there are no published cases on the concomitant use of secukinumab and upadacitinib for the management of HS and its associated comorbidities.

Clinical Cases

We report three female patients with moderate-to-severe HS and associated immune-mediated comorbidities (paradoxical palmoplantar psoriasis and SLE) who were successfully treated with this combination.

This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments, and also in compliance with national regulations and ethical principles governing biomedical research in Spain. According to national legislation (Law 14/2007 on Biomedical Research and the EU General Data Protection Regulation [GDPR] 2016/679), research involving anonymized data may be exempt from requiring institutional review board (IRB) approval. In this case, as a result of the full anonymization of the data and because this manuscript describes a retrospective case series of three patients, formal approval from a research ethics committee was not required, in accordance with current Spanish legislation and institutional policies. The patients in this manuscript have given informed consent to the publication of their case details and photographs.

Case 1

A 52-year-old woman with a history of poorly controlled SLE presented with Hurley stage III HS. She was previously receiving adalimumab for her acne inversa, which did not worsen her SLE. Although secukinumab was initiated following partial HS control with adalimumab, the patient continued to experience persistent lupus-associated arthralgias unresponsive to methotrexate, cyclosporine, or hydroxychloroquine. Given the good response to secukinumab in HS, upadacitinib 15 mg was subsequently introduced on the basis of the evidence of its potential efficacy in SLE, leading to improvement in both HS activity and lupus-related joint symptoms (week 4).

Case 2

A 22-year-old woman with Hurley stage II HS showed partial response to adalimumab. Six months after treatment initiation, she developed paradoxical scalp and palmoplantar psoriasis, refractory to topical corticosteroids, apremilast, methotrexate, and cyclosporine. Adalimumab was discontinued, and secukinumab was initiated, leading to improvement of HS, scalp and trunk psoriatic-plaques but with palmoplantar lesions persisting and even mildly worsening. Upadacitinib 15 mg was then added [10], leading to clearance of palmoplantar psoriasis (week 8) and further improvement in HS symptoms.

Case 3

A 25-year-old woman with poorly controlled Hurley stage II HS developed paradoxical scalp and palmoplantar psoriasis 8 months into adalimumab therapy. Adalimumab was discontinued, and secukinumab was initiated for both psoriasis and HS. However, palmoplantar lesions persisted and even worsened after 5 months despite concomitant treatment with roflumilast, methotrexate, cyclosporine, and topical corticosteroids. Given the inadequate response and severity of the psoriatic component, upadacitinib 30 mg was introduced, leading to marked improvement in both HS and psoriasis at week 6 (Fig. 1).

Fig. 1.

Palmoplantar psoriasis in patient 3 before (a) and 6 weeks after (b) upadacitinib initiation

In all three cases, upadacitinib was introduced 5–6 months after starting secukinumab and after primary failure to two or more classical immunosuppressors. Acitretin was not considered in cases 2 and 3 because of their reproductive age. The combination was well tolerated, with no adverse events or treatment discontinuations during a follow-up period of 3–6 months. Comorbidities were successfully managed in each case, and the combination also resulted in improved control of HS specially in nodular lesions. None of the patients developed acne as an adverse effect. The patients’ baseline characteristics are detailed in Table 1.

Table 1.

Baseline characteristics and treatment outcomes of patients with hidradenitis suppurativa treated with secukinumab and upadacitinib combination therapy

Patient number	Age/sex	Baseline comorbidities	Affected areas	Number of previous surgeries	Reason for upadacitinib	Secukinumab dose	IHS4 before secukinumab	IHS4 at week 24 with secukinumab	HISCr 75 at week 24 with secukinumab	Time to UPA onset	IHS4 16 weeks after UPA onset	Comorbidity controlled
1	52 years Female	BMI 28.2 Smoker, diabetes	Axillae, groin, perianal, submammary	4	Lupus arthropathy not controlled with hydroxychloroquine, methotrexate, belimumab	300 mg every 14 days	34	8	Yes	6 months 15 mg	2	Yes
2	22 years Female	BMI 32.1 Depression, smoker, asthma	Groin and perianal	2	Severe paradoxical palmoplantar psoriasis due to adalimumab not controlled with topicals, phototherapy, apremilast, cyclosporine, or methotrexate	300 mg every 14 days	18	7	No	5 months 15 mg	4	Yes
3	25 years Female	BMI 34.2 Smoker	Axillae, groin, submammary, trunk, perineum	3	Severe paradoxical palmoplantar psoriasis due to adalimumab not controlled with topicals, roflumilast, cyclosporine, or methotrexate	300 mg every 14 days	36	8	Yes	6 months 30 mg	3	Yes

IHS4 International Hidradenitis Suppurativa Severity Score System, HISCr Hidradenitis Suppurativa Clinical Response, UPA upadacitinib, BMI body mass index

Discussion

We present three cases successfully treated with a combination therapy of secukinumab 300 mg every 2 weeks plus upadacitinib 15–30 mg in patients with moderate-to-severe HS and associated IMIDs, namely SLE and severe palmoplantar psoriasis. In all three cases, the rationale for combining both agents was primarily driven by inadequate control of the comorbidities and the complex pathogenesis, despite previous failure of conventional systemic treatments. Given the lack of a standardized dosage in HS, the posology of upadacitinib was determined on the basis of the severity of the lesions.

Although current guidelines do not address the combined use of advanced therapies in HS, certain clinical scenarios may warrant dual inhibition [1, 2]. Combination treatment could be considered in patients with (1) inadequate response to multiple monotherapies, particularly when different disease pathways are suspected to be active; (2) coexistence of severe, uncontrolled comorbidities that require distinct therapeutic targets (e.g., HS with refractory SLE, arthritis, or IBD); or (3) paradoxical reactions to biologics limiting further use of standard agents. In these complex cases, after careful risk–benefit assessment and close monitoring, combination therapy may provide improved disease control and patient quality of life. However, this strategy should be reserved for experienced clinicians in selected patients, ideally within the context of multidisciplinary care.

Our cases add to the existing literature by providing the first clinical experience with the combination of secukinumab and upadacitinib in HS with systemic comorbidities. The novelty of this report lies in the complexity of the patients with HS, who failed multiple systemic agents and presented with difficult-to-treat conditions such as paradoxical psoriasis and SLE. These findings highlight that dual targeted therapy may represent a valuable therapeutic option in selected refractory cases and underline the need for prospective studies to further explore its safety, efficacy, and optimal positioning in HS.

In patients with coexisting paradoxical psoriasis, we did not consider switching to bimekizumab before exploring the combination approach, since secukinumab had already achieved an optimal response in HS and palmoplantar lesions had transiently worsened under that treatment, while scalp and trunk lesions improved. This clinical heterogeneity is consistent with reports that paradoxical psoriasis may present a heterogeneous immunological profile, distinct from classical Th17-driven psoriasis, which may explain the differential lesion behavior. Therefore, rather than moving to another IL-17A/F inhibitor, we opted to explore an alternative pathway by adding a JAK1 inhibitor.

The main limitation of our series is the relatively short follow-up period (3–6 months). Longer-term observation, ideally at least 1–2 years, will be necessary to confirm the durability of clinical responses and the long-term safety of dual targeted therapy in HS. In addition, this case series only represents a small number of patients and larger cohorts are needed for future investigations.

Nevertheless, clinicians should remain cautious and closely monitor for adverse effects, including infections, cytopenia, and metabolic or cardiovascular complications, which may be amplified with dual immunosuppression. Further studies are needed to compare the efficacy and safety of monotherapy versus combination approaches in this setting.

Conclusion

Dual targeted therapy with secukinumab plus upadacitinib achieved clinical improvement in HS and systemic comorbidities in three complex patients who had failed multiple systemic treatments. These cases highlight that combining biologics with JAK inhibitors may be a valuable therapeutic strategy in selected refractory patients, particularly when managing difficult comorbidities or paradoxical reactions. Although promising, this approach should be reserved for experienced clinicians and monitored closely. Larger studies are needed to confirm long-term safety, durability of response, and to define the optimal role of combination therapy in HS.

Author Contributions

Francisco Javier Melgosa Ramos, Esperanza Martínez Ruiz, Marta Galarreta Pascual, Virginia Sanz-Motilva, and Antonio Martorell have equally contributed to the conception, design, data collection, writing-draft preparation, and review of the present work. The final version to be published has been approved by all the authors.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Francisco Javier Melgosa Ramos has received honoraria and/or travel grants and/or has acted as an advisory board member for Novartis, Abbvie, Janssen Cilag, UCB, Lilly, LEO Pharma, L’Oreal, Sanofi, Almirall, and Amgen. Antonio Martorell has received honoraria and/or travel grants and/or has acted as an advisory board member or principal investigator in clinical trials for Incyte, Moonlake, MSD, Novartis, Abbvie, Johnson & Johnson, UCB, Lilly, LEO Pharma, Takeda, Sanofi, Almirall, and Amgen. Esperanza Martínez Ruiz, Marta Galarreta Pascual, and Virginia Sanz-Motilva have no conflicts of interest to declare.

Ethical Approval

This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments, and also in compliance with national regulations and ethical principles governing biomedical research in Spain. According to national legislation (Law 14/2007 on Biomedical Research and the EU General Data Protection Regulation [GDPR] 2016/679), research involving anonymized data may be exempt from requiring institutional review board (IRB) approval. In this case, as a result of the full anonymization of the data and because this manuscript describes a retrospective case series of three patients, formal approval from a research ethics committee was not required, in accordance with current Spanish legislation and institutional policies. The patients in this manuscript have given informed consent to the publication of their case details and photographs.