An adult has recurring fever, an inflammatory rash, and repeatedly elevated inflammatory markers. Autoantibody testing is unrevealing. The next useful step is not automatically a larger panel. It is to ask which clinical features travel together, and what mechanism could connect them.
Autoinflammatory disease is not confined to childhood. An inherited condition may be recognized late, while acquired disorders can begin well into adult life. Absence of a family history does not close the door.
Describe the phenotype before naming the syndrome
Clarify age at first symptoms, episode duration, symptom-free intervals, triggers, organ involvement, and objective evidence of inflammation. Distinguish episodic disease from persistent inflammation. Review medications, infections, malignancy risk, and other inflammatory diagnoses rather than treating negative autoantibodies as a positive diagnostic test.
- Brief stereotyped attacks with serositis: consider FMF when the overall phenotype fits, including symptoms dating back to childhood that were never explained.
- Urticaria-like rash with systemic inflammation: consider CAPS and acquired conditions such as Schnitzler syndrome, while evaluating other dermatologic and systemic causes.
- Spiking fever, evanescent rash, sore throat, and arthritis: consider Still’s disease alongside its mimics.
- Inflammation with macrocytic anemia, chondritis, or neutrophilic skin disease: consider VEXAS, particularly in an older adult.
Order tests that can change the next decision
A useful initial assessment may include blood counts with differential, renal and liver testing, inflammatory markers, urinalysis, and protein assessment when indicated. Ferritin is especially relevant in a compatible Still’s/HLH/MAS presentation, but is nonspecific. Timing samples during and between episodes can be informative.
Skin biopsy may clarify the mechanism of an atypical rash. Serum protein electrophoresis and immunofixation are useful when the phenotype raises concern for Schnitzler syndrome; additional hematologic testing depends on the findings. Genetic testing should match the clinical question and the assay’s limitations.
Schnitzler syndrome: connect the rash to the blood findings
Schnitzler syndrome combines a chronic urticaria-like eruption with a monoclonal gammopathy, typically IgM, and other inflammatory features such as fever, bone pain, and elevated inflammatory markers. Neither hives nor a monoclonal protein alone establishes the diagnosis. Skin pathology and the overall diagnostic framework help distinguish mimics.
IL-1-targeted treatment can markedly improve inflammation in appropriate patients, but symptomatic response does not eliminate the monoclonal protein or the need for hematologic surveillance.
VEXAS changes the genetics conversation
VEXAS is caused by acquired, somatic changes in UBA1, usually in hematopoietic cells. It is not typically a disease passed through families. Although most recognized patients are older men, that demographic pattern is not an absolute exclusion rule.
Macrocytic anemia, cytopenias, inflammatory skin disease, pulmonary involvement, chondritis, and thrombosis can provide clues. Bone marrow vacuoles are not specific; molecular confirmation must be interpreted in the appropriate clinical setting. The ACR-endorsed guidance emphasizes coordinated hematologic and inflammatory assessment. Treatment is individualized, and evidence for competing approaches continues to evolve.
Interpret a negative panel as an assay result
A negative germline panel cannot exclude every autoinflammatory disorder. A relevant gene may not have been tested, a low-level somatic variant may be missed, or the disease may not have a single-gene cause. Conversely, a variant of uncertain significance should not replace clinical reasoning.
Ask whether further testing would change care. Specialist review may identify a need for different sequencing methods, pathology review, or reinterpretation of existing results rather than another untargeted panel.
The aim is not to attach the rarest label. It is to recognize treatable inflammation, identify organ and hematologic risks, and establish a plan that makes sense across specialties.
Keep reading
Sources and further reading
- ACR guidance for diagnosis and management of VEXAS (online 2025; journal issue 2026)
- Simon et al. Schnitzler’s syndrome: diagnosis, treatment, and follow-up (2013)
- EULAR/PReS Still’s disease recommendations (2024)
Adapted from Jonathan S. Hausmann’s presentation, “Autoinflammatory Diseases in Adults,” with references and terminology updated for this article. Individual patient cases and slide images have not been reproduced.
This article provides general education, not a diagnosis or an individual treatment plan. Discuss personal medical decisions with your care team.