Time to Reclassify Autoinflammatory Syndromes Linked to Acne, Hidradenitis Suppurativa, and Arthritis?

Autoinflammatory syndromes combining acne, hidradenitis suppurativa (HS), and arthritis are poorly defined and inconsistently classified. Integrating detailed clinical phenotyping with genetic data could improve classification, guide therapy, and clarify underlying disease mechanisms. This is crucial to avoid mislabeling, ensure continuity of care, and align treatment with specific inflammatory pathways. In this context, the reply by Garcovich et al. to our previous article [1] highlights the possibility that patients presenting with HS, arthritis, and pyoderma gangrenosum may represent prototypical HS-associated autoinflammatory syndromes, providing a useful framework for discussion. Notably, among the seven reported cases with HS, arthritis, and pyoderma gangrenosum in our case–control study, only one was classified under a defined cutaneous-articular syndrome (PAPASH: pyogenic arthritis, pyoderma gangrenosum, acne, and HS), whereas the remaining cases were labeled as HS with arthritis and pyoderma gangrenosum according to individual clinical judgment. This heterogeneity in classification echoes Garcovich et al.'s [2] observations regarding the boundaries of these entities. The current landscape of autoinflammatory syndromes, includes a growing number of partially overlapping conditions, such as PAPA (pyoderma gangrenosum, acne, and pyogenic arthritis), PASH (pyoderma gangrenosum, acne, and HS), PAPASH, PASS (pyoderma gangrenosum, acne, and ankylosing spondylitis), PsAPASH (psoriatic arthritis, pyoderma gangrenosum, acne, and HS), PsAPSASH (pustular psoriasis, arthritis, pyoderma gangrenosum, synovitis, acne and HS) and SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) [3]. Rather than representing distinct entities, these acronyms mainly describe coexisting clinical features and lack pathophysiological or therapeutic grounding. Recent studies have moved beyond purely descriptive classifications, revealing shared innate immune mechanisms. Whole-exome sequencing has shown that PASH can arise from variants in different genes, including MEFV, NOD2, OTULIN, and GJB2, while the same gene or even identical variants (e.g., in PSTPIP1 or NCSTN) may be associated with different clinical syndromes, including PAPASH or overlapping PASH/SAPHO phenotypes [4]. This demonstrates both genetic heterogeneity and pleiotropy, emphasizing the importance of incorporating genetic data into HS-associated autoinflammatory syndrome classification. Among these syndromes, SAPHO is the most extensively characterized, with diagnostic and radiologic criteria widely applied in clinical practice. However, it also lacks a consistent genetic signature, and therapeutic approaches vary. Additional limitations include poorly defined arthritis in many other syndromes: although PsAPASH clearly defines the type of arthritis involved (psoriatic arthritis), PAPA and PAPASH include “pyogenic arthritis,” and PASS describes “ankylosing spondylitis”, both of which are now largely considered outdated terms. Moreover, PsAPSASH includes the term “arthritis” without specifying whether it refers to acute forms like palindromic rheumatism or chronic forms, or whether the arthritis is inflammatory or crystal induced. Moreover, a second closely related source of ambiguity concerns the distinction between acne and HS. As highlighted by Kemény et al. [5], biologics are ineffective in moderate-to-severe acne vulgaris, whereas tumor necrosis factor-alpha (TNF-α), interleukin (IL)-17, and IL-1 inhibitors are effective in lesions overlapping with HS or autoinflammatory disease, suggesting that many “acne” lesions may represent follicular HS. In summary, historical classification of HS-associated autoinflammatory syndromes was adequate for its time, but the era of targeted biologics demands precise characterization of cutaneous and articular manifestations, as treatment response depends on underlying inflammatory pathways. Integrating genetic and clinical data is essential to improve understanding, avoid misdiagnosis, and guide therapy. This approach should form the basis for a new classification of autoinflammatory syndromes linked to acne, HS, and arthritis, reflecting both biology and clinical practice. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.