化膿性無菌性関節炎・壊疽性膿皮症・アクネ症候群

INTRODUCTION: Hidradenitis suppurativa (HS)-related autoinflammatory syndromes, simply termed as syndromic HS (sHS), represent a group of rare immune-mediated inflammatory disorders in which HS coexists with systemic or cutaneous autoinflammatory features like PASH (pyoderma gangrenosum-PG-, acne and HS), PAPASH (PASH, pyogenic arthritis), PASS (PG, acne, HS, and ankylosing spondylitis), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). In recent years, genetic studies identified several novel pathogenic variants underlying sHS; however, most investigations rely exclusively on affected individuals sequencing and the absence of parental genomic information limits the possibility to determine inheritance patterns. METHODS: To address these gaps, we performed trio-based whole-exome sequencing (WES) on five individuals diagnosed with sHS and their unaffected parents. RESULTS: The pathway related to epidermal adhesion and desmosome organization was the most represented across our cohort, encompassing seven genes: DSC3, DSG1, FAT1, LAMA3, MICALL2, PLEC and TJP2. Integrin-extracellular matrix (ECM) adhesion signaling pathway, represented by ten genes (CSPG4, FERMT3, ITGA3, LAMA3, LAMA5, LIMS2, LTBP3, PLEC, TGM2, TNC) was also retrieved. Also, variants affecting innate immune pathways, including cytokine signalling and antigen presentation, have been observed. CONCLUSION: Our exploratory findings suggest that genetically heterogeneous variants in syndromic HS converge on biological processes involving epithelial junction organisation, extracellular matrix interactions and innate immune regulation. Although not establishing a unique pathogenic mechanism, these observations identify epithelial barrier biology as a candidate pathway warranting validation in larger cohorts and functional studies.

PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) is a rare autosomal dominant autoinflammatory disorder caused by mutations in the PSTPIP1 gene. In pediatric patients, arthritis often precedes cutaneous manifestations by several years, leading to frequent misdiagnosis as septic arthritis. Treatment is challenging, with IL-1 inhibitors being the most pathophysiology-based first-line therapy, but their accessibility is limited by high costs. We reported an 11-year-old Chinese boy with a 7-year history of recurrent, migratory arthritis. Trio whole-exome sequencing identified a heterozygous PSTPIP1 c.770A>G (p.Glu257Gly) variant, classified as likely pathogenic. The father carried the same variant; he had experienced arthralgias in early childhood but became asymptomatic after age 10 without any treatment, demonstrating incomplete penetrance. This variant is extremely rare, reported in only one of 16 patients in the Eurofever registry, all of European descent, making this the first Asian case. Due to financial constraints, IL-1 inhibitors were inaccessible. Tofacitinib (3.5 mg twice daily, adjusted from adult dose based on body surface area) was initiated in February 2026. After 2 months, joint swelling and pain decreased significantly. As of July 10, 2026, no recurrence of joint swelling and pain had been observed during follow-up. However, radiography revealed irreversible structural damage (bone demineralization, joint space narrowing, osteophyte formation), and the patient still had limited mobility. Rehabilitation specialists advised against aggressive range-of-motion exercises and recommended home-based ultrasound and electrical stimulation to prevent muscle atrophy. Long-term follow-up is ongoing. PAPA syndrome should be considered in children with culture-negative, antibiotic-unresponsive recurrent arthritis, even without skin findings. Early genetic diagnosis can prevent unnecessary procedures. For patients who cannot access IL-1 inhibitors, tofacitinib may reduce inflammation, but it cannot reverse established joint damage. Given the relatively short follow-up duration, the long-term durability of response, safety, and impact of tofacitinib on disease progression remain to be determined. This report provides early, preliminary evidence of JAK inhibitor use in this population, contributing initial data to the limited Asian literature.

PURPOSE OF REVIEW: To summarize and critically evaluate recent literature on autoinflammatory syndromes of hidradenitis suppurativa (HS). RECENT FINDINGS: HS-associated autoinflammatory syndromes traditionally encompass pyoderma gangrenosum (PG), acne, and HS (PASH); pyogenic arthritis, PG, acne, and HS (PAPASH); psoriatic arthritis, PG acne, and HS (PsAPASH); and PG, acne, HS and ankylosing spondylitis (PASS). However, this spectrum continues to expand, with recent literature considering the inclusion of additional autoinflammatory diseases such as HS associated with SAPHO, including synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO); and Hyperimmunoglobulin D Syndrome (HIDS). HS-associated autoinflammatory syndromes are thought to be driven by dysregulation of the innate immune system and the subsequent overexpression of key inflammatory cytokines such as IL-1, and targeted IL-1 therapies have demonstrated particularly brisk and efficacious response. Multiple genes related to follicular keratinization or inflammatory regulation have been implicated, and sequencing methods such as whole-exome sequencing and variant enrichment analysis continue to identify novel genetic variants and are being used to further elucidate genotype-phenotype correlations. HS-associated autoinflammatory syndromes are an evolving spectrum of rare, severe, diseases in which HS coexists with other autoinflammatory conditions, most commonly PASH and related syndromes. They are driven by innate immune dysregulation and pathogenic genetic variants, with whole-exome sequencing aiding diagnosis and genotype-phenotype correlation. Management is often challenging and highly individualized, with targeted biologic therapies such as IL-1 inhibitors showing the most consistent and rapid clinical benefit.

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant hereditary autoinflammatory disease caused by PSTPIP1 gene variants and belongs to the PSTPIP1-associated inflammatory diseases (PAIDs). Its core clinical manifestations include recurrent pyogenic arthritis, pyoderma gangrenosum, and severe acne with onset in childhood or adolescence. Some patients may also present with multisystem involvement, such as inflammatory bowel disease and scleritis. Inflammation markers, such as CRP and ESR, are often significantly elevated. Treatment mainly involves targeted inhibition of inflammatory pathways, such as IL-1 inhibitors and TNF-α inhibitors. In this article, we report a Chinese patient with PAPA syndrome with disease onset at 13 years of age, whose main manifestations were pyoderma gangrenosum and acne. Genetic testing revealed a de novo PSTPIP1 gene variant (c.748G>A, p.Glu250Lys). We also reviewed recent literature on PAPA syndrome, summarizing its clinical manifestations, diagnosis, and treatment to enhance physicians' understanding of the condition.

Mutations in the gene PSTPIP1 may cause several different autoinflammatory syndromes, but the mechanisms by which distinct PSTPIP1 mutations lead to these differing phenotypes are not fully understood. The two best characterized autoinflammatory conditions resulting from PSTPIP1 mutation are pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome. Here, we report a novel gain-of-function PSTPIP1 mutation (p.N236K) causing PAMI syndrome in a patient with systemic autoinflammation and severe neutropenia. This mutant form of PSTPIP1 shows increased binding to pyrin and leads to heightened inflammasome formation, relative to WT PSTPIP1. We also identify a transcriptional signature in blood from PAMI patients suggestive of enhanced T cell activation and altered neutrophil survival and/or function. Further research on PSTPIP1-related autoinflammatory conditions is needed to more deeply understand the genetic and immunological drivers of disease and contribute to improving patient outcomes.