Background: CAPS result from NLRP3 variants causing IL-1 inflammation. Somatic mosaicism causes atypical presentations and diagnostic delays. Lifelong inflammation with negative serology poses challenges.

Objectives: To present a case of mosaic CAPS diagnosed after 44 years of unexplained inflammation and demonstrate the diagnostic and therapeutic impact of genetic testing and IL-1 blockade.

Case Description: A 43-year-old female born in South Africa in 1981 experienced inflammatory symptoms from birth. Clinical manifestations included recurrent pruritic erythematous rashes, episodic polyarthritis predominantly affecting knees and ankles requiring bilateral patellectomies (ages 18 and 21), and congenital splenomegaly documented on ultrasound. Despite extensive investigations throughout childhood and adulthood in South Africa, no definitive diagnosis was established. Serial skin biopsies demonstrated urticarial vasculitis, chronic discoid lupus features, and neutrophilic dermatosis patterns. Between 2012-2022, treatment with prednisolone (5-20 mg/day), dapsone (100 mg/day), and azathioprine (150 mg/day) provided partial but unsustained benefit. Autoimmune serology remained consistently negative (ANA, ENA, dsDNA, ANCA, RF, CCP). Following relocation to the UK in 2024, she presented with persistent multisystem inflammation including malar rash with nasolabial sparing, widespread maculopapular eruptions, digital clubbing, sicca symptoms, and weekly polyarticular flares. Constitutional symptoms comprised recurrent fevers (38-39°C), drenching night sweats, and profound fatigue.

Results: Laboratory investigation revealed persistent inflammation: ESR 72 mm/h, CRP 88 mg/L, SAA 260 mg/L. CT imaging demonstrated multiple enlarged lymph nodes (axillary up to 2.5 cm, retroperitoneal 1.8 cm, inguinal 2.2 cm) with splenomegaly (16.5 cm), raising concerns for lymphoproliferative disease. Excisional lymph node biopsy showed reactive follicular hyperplasia without malignancy. Given 44 years of unexplained multisystem inflammation with negative autoimmune workup, autoinflammatory gene panel testing was performed via next-generation sequencing. A pathogenic somatic NLRP3 p.G307S variant was identified with 9% variant allele fraction (exon 3a), establishing mosaic CAPS diagnosis. Anakinra 100 mg daily was initiated with dramatic response. CRP normalized from 88 to 3 mg/L by day 7, SAA from 260 to 3 mg/L by day 13. Clinically, joint swelling resolved, rash markedly improved, and systemic symptoms abated completely. No adverse effects were reported, confirming IL-1β-driven pathophysiology.

• Mosaic CAPS: lifelong inflammation, negative serology.

• Neutrophilic dermatoses + arthropathy + organomegaly from birth.

• Reactive lymphadenopathy needs genetics, not biopsies.

• Test somatic NLRP3 despite no family history.

• Anakinra normalizes markers in days, confirms IL-1β disease.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.