Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itching and eczematous lesions. It affects 15% to 25% of children and 4% to 7% of adults and usually appears within the first 5 years of childhood (1). Hidradenitis suppurativa (HS) is a chronic inflammatory disease with recurrent course affecting skin-bearing apocrine glands, typically in the axillae, breasts, groin, and perineum. HS affects approximately 1% of the general population and typically begins post puberty, with the highest incidence observed among young women aged 20 to 29 (2).

The coexistence of HS and AD has already been reported in the literature (3, 4). Epidemiological studies have shown the presence of systemic comorbidities common to both pathologies (e.g. hypertension, obesity and psychiatric disorders) (2, 5). Common risk factors between AD and HS include smoking, female sex, and African-American race (4).

Both diseases have a pathogenesis that involves the complex interaction between immune dysregulation, environmental triggers, genetic factors and dysbiosis (6). It was previously believed that AD and HS are driven by different immunologic pathways. However, the recent awareness of a broader Th1, Th2 and Th17 dysregulation in AD, which goes beyond the T helper (Th2) cell-driven disease, has highlighted common immunological pathways with HS, driven by Th1/Th17 cells (5). Furthermore, similar deficient notch signaling (that plays a key role in the regulation of epidermis and pilosebaceous unit differentiation) and antimicrobial peptide (AMP) dysregulation were seen in both conditions (4). While in HS the role of Notch signaling dysregulation is unclear, in AD it can cause epidermal barrier defects and an increase in pro-inflammatory cytokines, such as thymic stromal lymphopoietin (TSLP) (7). Although the role of AMP dysregulation remains to be fully elucidated, in both AD and HS it acts by promoting an inflammatory response in the context of altered skin flora (8). Moreover, the role of other shared biomarkers, such as interleukin-13 or periostin, which promote fibrosis in the pathogenesis of both AD and HS, remains to be clarified (5). A better understanding of these shared immune pathways could guide the appropriate use of immunomodulatory drugs to avoid exacerbating one disease to the benefit of the other.

Upadacitinib, a JAK-1 inhibitor (JAKi), has demonstrated remarkable efficacy in the treatment of moderate to severe AD (9) and is increasingly being used and studied across a broad spectrum of dermatological disorders including HS. However, published clinical data on the specific use of upadacitinib for HS are very limited and several clinical trials are currently ongoing. The potential therapeutic targets for this JAKi are proinflammatory cytokine such as IL-6, IL-23, and interferons which have been shown to be upregulated in sites affected by HS (10).

The aim of this multicentric Italian retrospective study is to assess therapeutic effects of upadacitinib on concomitant HS in AD patients.

Although AD and HS are significantly different clinically (onset, pathogenesis, and treatment), they share common systemic comorbidities and some immunological pathways. Additionally, both diseases are associated with a deep impact on quality of life and an increased burden of health care use (14). Sherman et al. in a large epidemiological study showed a statistically significant bidirectional association between AD and HS (1). Specifically, patients with HS and comorbid AD were more likely to be younger, female and non-smokers and have a lower BMI than patients with HS alone.

Upadacitinib represents an effective and safe option for the treatment of moderate to severe AD as shown in clinical trials and real-world clinical practice on large cohorts of patients. In an Italian observational study on one hundred and forty-six patients followed for 48 weeks, the achievement of EASI 75, EASI 90 and EASI 100 was observed in 87.6%, 69.1% and 44.3% of the sample, respectively (15). Studies on Japanese patients showed similar results both on AD clinical signs and symptoms even though with lower percentages of EASI 75, EASI 90 and EASI 100 improvement (16). Ibba et al., in a recent systematic review including 17 real-world studies, reported high efficacy of upadacitinib across diverse patient phenotypes, with no significant new safety concerns (17). In AD patients with an insufficient response to 15 mg, a dose increase of upadacitinib up to 30 mg increase significantly eczematous rash and pruritus. The treatment responsiveness to upadacitinib 30 mg appeared lower on the head and neck compared with other body sites, particularly the trunk, but remain a valid option for patients with a limited response to 15 mg treatment (18).

The broad-spectrum inhibition of many pro-inflammatory cytokines has led to the evaluation of upadacitinib in other pathological conditions, including HS. In a phase 2 study, patients with moderate-to-severe HS treated with upadacitinib 30 mg have experienced clinical improvement with a greater HiSCR50 at week 12 when compared with the placebo group (38.3% vs 23.8%) (19). A phase 3 study (NCT05889182) is still ongoing.

In our cohort, AD clinical outcomes improved from baseline to week 52, in line with data reported in clinical trials and real-life experience. In the AD+HS subgroup, improvements were observed in both AD and HS outcomes. In this subset, 4/7 patients received upadacitinib 15 mg/day and 3/7 received 30 mg/day. Mean IHS4 score decreased from 6.9 ± 4.3 at baseline to 3.1 ± 2.3 at week 4, with further decreases over time (2.2 ± 1.8 at week 16 and 0.2 ± 0.5 at week 32), with HiSCR and IHS4–55 responses observed at each visit among patients with available assessments (Figure 2; Table 4); denominators decreased over time (n=7, 6, and 4). Accordingly, HiSCR was achieved by 4/7 (57.1%) at week 4 and by 4/4 (100%) at week 32 among patients assessed at those visits. Our observations are consistent with the phase 2 study on the efficacy of upadacitinib in HS where 34% of patients achieved HiSCR50 at 4 weeks and 38.3% at week 12 (19). Such early clinical improvements confirm the rapidity of action of upadacitinib in immune-mediated diseases, such as rapid pain relief in psoriatic arthritis and ankylosing spondylitis (20). In a retrospective cohort study on 20 HS patients treated with Upadacitinib, HiSCR50 was achieved in 75% of subjects at week 4 and in 100% at week 12 with maintenance of clinical response at week 24. DLQI scores and pain rating scores improved as well (21). A proteomic analysis on this cohort showed a significant reduction in the expression of inflammatory cytokines such as IL-12, IL-23 and IL-10 by week 4 of treatment. In clinical responder patients, a rapid attenuation of B-Cell and IFN-γ associated chemokines was observed (22). This broad-spectrum inhibition could be an extremely useful therapeutic weapon in HS, whose pathogenesis is linked to the simultaneous activation of innate and adaptive immune mechanisms, in part driven by JAK-STAT signaling-dependent cytokines (23, 24). Studies published to date suggest that upadacitinib is one of the most promising small molecules for the treatment of HS (25, 26).

In our study the favorable trajectories observed may be related to the predominance of moderate HS forms, with fewer lesions and fewer drainage tunnels, potentially reflecting a lower inflammatory burden compared with clinical trials. Nevertheless, given that HS is characterized by the formation of drainage tunnels and scarring, timely treatment may be relevant even in moderate forms, as delayed diagnosis and management can compromise the response to biologics (27). Furthermore, the presence of patients who had not previously received HS-targeted biologics (TNFalpha or IL-17 inhibitors), but only antibiotic therapies, may have contributed to the observed clinical outcome. HS is a condition with an increased risk of infections regardless of the treatment used to manage it. Meta-analysis studies showed an incidence of 24.2% with a greater presence of respiratory and skin infections. However severe infections were rare (28). In the phase 2 randomized, placebo-controlled study, at 48 weeks no severe infections were observed in HS patients treated with upadacitinib 15 mg, while among patients who received 30 mg, only 2 out of 47 had severe infections. Anyway, the only adverse event potentially related to the underlying disease and treatment was a case of severe inguinal cellulitis (19). On the other hand, atopic dermatitis also presents an increased intrinsic risk of infections related to barrier defects and a reduction in antimicrobial peptides (29). However, the use of upadacitinib, as highlighted by clinical studies, did not lead to an increased risk of severe infections (30). Obviously, the risk of infection in patients with AD and concomitant HS must always be considered. The possible appearance of signs and symptoms of infection must be adequately treated with specific antibiotic therapy, temporarily suspending or otherwise adjusting upadacitinib until the infection has resolved. No rescue strategies were used in our patients, probably due to the presence of moderate clinical manifestations of HS and the rapid resolution of the lesions.

This study has some limitations, including the small size of the AD+HS subgroup and the retrospective design. HS identification and severity assessments were based on routine medical records (not systematic screening), and follow-up completeness varied across visits. In such a small subgroup, decreasing denominators may influence the interpretation of observed patterns over time and limit the generalizability of responders patterns. Additionally, no adjustment for potential confounders (e.g., baseline HS severity, BMI, smoking status, prior HS treatments, and dose changes) was performed. Further studies with standardized HS assessment and prospective designs are needed to better characterize outcomes in patients with concomitant AD and HS.

Our data, although preliminary, suggest that upadacitinib could be a valid therapeutic choice in the treatment of patients with AD and concomitant HS. It is essential that dermatologists be aware of this association and perform skin examinations with particular attention to the sites typical of both conditions. Awareness of the potential co-occurrence of HS and AD is crucial for therapeutic choice and patient-centered management.