Table 2

Points to consider for the diagnosis of CAPS, TRAPS, MKD and DIRA

		LoE	GoR	LoA (0–10) mean±SD
1	Patients with clinical symptoms of CAPS, TRAPS, MKD and DIRA who do not carry any of the disease-causing mutations described here should be referred to specialty/research centres to guide further workup and treatment.	5	D	9.4±1
Genetic workup
2	Genetic testing using an NGS platform, if available, should be used to make a genetic diagnosis. Sanger sequencing of targeted genes known to cause CAPS (NLRP3), TRAPS (TNFRSF1A), MKD (MVK) and DIRA (IL1RN) can be used if the clinical suspicion is strong or to validate NGS.	4	D	9.4±1.1
3	Deep sequencing in patients with CAPS and TRAPS may be needed to detect some somatic mutations that may not be identified by standard NGS or Sanger sequencing.	5	D	9.5±1.1
CAPS specific
4	Patients with low penetrance variants in NLRP3 may present with clinical manifestations different from CAPS; their treatment response and prognosis may differ from ‘canonical’ CAPS.	2	B	9.4±1.2
TRAPS specific
5	Patients with low penetrance variants in TNFRSF1A (ie, R121Q (previously referred to: R92Q) may present with clinical manifestations different from TRAPS and their treatment response and prognosis may differ from ‘canonical’ TRAPS.	2	B	9.5±1.2
DIRA specific
6	In patients with DIRA, Sanger sequencing, WES or WGS may not detect large deletions in IL1RN, thus complicating a genetic diagnosis. In cases with a high clinical suspicion of DIRA and negative Sanger sequencing or WES/WGS, chromosomal microarray analysis (CMA) is recommended to detect large deletions. The use of deletion-specific primers, in countries with founder variants that include large deletions, is recommended.	3	B	9.3±1.2
Clinical workup
7	The clinical workup of systemic inflammation should include CRP, ESR and CBC with differential; if available SAA and S100 proteins may be assessed. Patients with longstanding untreated systemic inflammation need to be screened for the presence of amyloidosis.	5	D	9.7±0.6
CAPS specific
8	The following clinical features in the presence or absence of autosomal dominant inheritance should prompt consideration of a diagnostic workup of CAPS: urticaria-like rash cold/stress-triggered episodes sensorineural hearing loss chronic aseptic meningitis skeletal abnormalities	2	B	9.8±0.5
9	The initial diagnostic workup should include an audiogram and an ophthalmologic examination. Lumbar puncture and a head MRI should be performed if clinically indicated.	5	D	9.8±0.5
TRAPS specific
10	The following clinical features should prompt consideration of a diagnostic workup of TRAPS: long-lasting fever episodes migratory rash periorbital oedema myalgia a positive family history	2	B	9.8±0.5
MKD specific
11	The following clinical features should prompt consideration of a diagnostic workup of MKD: age at onset <1 year gastrointestinal symptoms painful lymph nodes aphthous stomatitis a history of triggers of the periodic fever attack (ie, postvaccination) a maculopapular rash	2	B	9.8±0.5
12	In patients with unexplained/undifferentiated inflammatory diseases, the presence of mevalonic acid in urine should prompt further diagnostic workup for MKD.	4	C	9.5±0.7
DIRA specific
13	The following clinical features particularly if occurring sporadically, should prompt consideration of a diagnostic workup of DIRA: pustular psoriasis-like rashes osteomyelitis (ie, CRMO-like disease, rib flaring and cloaking of the femoral head, odontoid lesions/osteomyelitis) absence of bacterial osteomyelitis nail changes (ie, onychomadesis)	5	D	9.6±0.8
14	For patients with suspected DIRA, X-ray examinations of the chest and upper and lower limbs and/or MRI/CT to assess the spine, including odontoid, should be included in the diagnostic workup to assess the extent of the inflammatory bone involvement. A dermatology consultation and skin biopsy should be considered as the presence of neutrophilic dermatosis with exocytosis of neutrophils and subcorneal pustules is highly suggestive of DIRA.	5	D	9.7±0.8

Level of evidence (LoE): 1a: systematic review of randomised controlled trials (RCTs); 1b: individual RCT; 2a: systematic review of cohort studies; 2b: individual cohort study (including low-quality RCT); 3a: systematic review of case–control studies; 3b: individual case-–control study; 4: case-series (and poor-quality cohort and case-–control studies); 5: expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’; Grade of recommendation (GoR): A: based on consistent level 1 studies; B: based on consistent level 2 or 3 studies or extrapolations from level 1 studies; C: based on level 4 studies or extrapolations from level 2 or 3 studies; D: based on level 5 studies or on troublingly inconsistent or inconclusive studies of any level.
CAPS, cryopyrin-associated periodic syndromes; CBC, complete blood count; CRMO, chronic recurrent multifocal osteomyelitis; CRP, C-reactive protein; CT, computed tomography; DIRA, deficiency of the interleukin-1 receptor antagonist; ESR, erythrocyte sedimentation rate; LoA, level of agreement; MKD, mevalonate kinase deficiency; MRI, magnetic resonance imaging; NGS, next-generation sequencing; SAA, serum amyloid A; TRAPS, tumour necrosis factor receptor associated periodic syndrome; WES, whole exome sequencing; WGS, whole genome sequencing.