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• 6.1 – A patient is suspected to have an autoinflammatory (episodic fever) syndrome.
• 6.2 – It is first necessary to evaluate for other causes of recurrent or continual
inflammation, such as other PIDDs, autoimmune disease, or malignancy.
• 6.3 – If alternative (nonautoinflammatory) diagnoses are now suspected as a result
of further clinical study, then these should be pursued and ruled out before additional
investigation of autoinflammatory conditions is undertaken.
• Note that nonspecific autoantibodies (eg, anti-nuclear antibody, rheumatoid
factor, anti–double-stranded DNA, anti-phospholipid antibody, and anti-
neutrophil cytoplasmic antibody) can be persistently or transiently present at
mildly or moderately increased levels, especially in the noninflammasome defects.
• If the clinical presentation has features strongly suggestive of an autoinflammatory
component (eg, very early onset), such a diagnosis should still be entertained.
• 6.4 – Early-onset severe pustular skin disease is seen in patients with DIRA and
DITRA.
• DIRA is also associated with bone involvement with osteopenia and lytic bone
lesions.
• Sequence analysis for IL1RN and IL36RN, as well as chromosomal analysis for
deletions in the IL1 locus, should be investigated.
• 6.5 – If an evanescent nonurticarial rash is present with cold exposure, genetic testing
of CIAS1 should be done to test for FCAS, as well as NLRP13. If the rash is a cold-
induced urticarial rash, the patient should be tested for mutation of PLCG2 (PLAID).
• 6.6 – If fevers are associated with pyogenic arthritis and ulcerative skin lesions (ie,
pyoderma gangrenosum), cystic acne, or both, mutational analysis of the PSTPIP1
gene should be evaluated for PAPA syndrome.
• 6.7 – If granulomatous disease (rash, uveitis, or arthritis) is apparent, mutational
analysis of NOD2 should be considered for Blau syndrome.
• 6.8 – If febrile attacks are associated with abdominal or joint pains or rash, mutation
analysis of pyrin, TNF receptor I, and MVK should be undertaken.
• 6.9 – If bone lesions and dyserythropoietic anemia are associated with fevers,
analysis of LPIN2 for Majeed syndrome should be considered.
• 6.10 – If the presentation consists of purpura with 1 or more of lipodystrophy,
contractures, or muscle atrophy, a defect in PSMB8 should be investigated.
Figure 6. Diagnosis of Autoinflammatory Syndromes Notes
