Table 3.

Recommendations for the diagnosis of MKD.

Diagnosis:	LoE	LoA (1–9) mean ± SD
Laboratory investigations:
1. Prioritize MVK gene testing for its crucial role in establishing a definitive diagnosis of MKD, as it significantly contributes to confirming the condition.	B	8,2 ± 1,6
2. However, other laboratory findings should also be considered together with clinical observations, especially in patients with negative results of genetic tests due to potentially yet unrecognised mutations.	B	7,7 ± 2,2
3. Verify inflammation through laboratory tests, for example total WCC, ESR, CRP, SAA during attacks. These are not diagnostic of MKD but will confirm systemic inflammation; note that these usually vary (and may normalize) between flares.	A	8,13 ± 1,4
4. IgD-level testing is not recommended due to its negligible diagnostic value.	B	8,67 ± 0,6
5. Urinary mevalonic acid levels are usually the highest during flares. Nevertheless, normal urinary mevalonic acid level alone has a low negative predictive value and does not negate the possibility of MKD and, therefore, is not mandatory before advancing to genetic testing.	B	7,47 ± 2,1
6. It is recommended that enzyme activity assays be reserved for cases involving patients with particularly severe phenotypes, where the results may significantly influence the clinical decision, particularly in evaluating the need for bone marrow transplantation. This assay is conducted only in a limited number of specialised laboratories, thus limiting its availability as a routine diagnostic test.	B	7,53 ± 1,5
Clinical classification and guiding genetic investigations (clinical parameters as predictors):	LoE	LoA (1-9) mean ± SD
1. Clinical diagnostic scores and classification criteria can be used as supportive tools to evaluate patients with suspected hereditary autoinflammatory syndromes, such as MKD.	A	7,9 ± 1,1
2. However, genetic tests are now much more widely available and should be performed if the clinical diagnosis is suspected, regardless of a clinical predictive score/classification result.	B	8,4 ± 1,3
2a. Consider genetic testing regardless of scores: even if diagnostic scores are negative, consider genetic testing when clinical suspicion persists.	A	7,4 ± 2,1
2b. Maintain a holistic approach to patient evaluation. Consider all clinical presentations and history fully, as these syndromes often present with a range of symptoms that may not be fully captured by diagnostic scores.	A	8,4 ± 1,3
Genetic testing	LoE	LoA (1-9) mean ± SD
1. Conduct genetic testing for all suspected cases of MKD to confirm/refute the diagnosis.	B	7,9 ± 1,4
2. Consult “The Registry of Hereditary Auto-inflammatory Disorder Mutations” database to assess the pathogenicity of identified genetic variants (https://infevers.umai-montpellier.fr/web/).	A	8,3 ± 0,7
3. Ensure that genetic results are interpreted in the context of patient inflammatory symptoms, engaging an auto-inflammatory expert for an accurate assessment.	B	8,6 ± 0,5
4. Provide genetic counselling to patients and their families.	A	8,5 ± 1,1
5. For patients with clinical signs of MKD but with negative or inconclusive genetic testing, consider additional genetic tests, including searches for deletions or duplications in the MVK gene.	B	7,8 ± 1,9
6. Patients with negative results of genetic tests should be classified as having an undifferentiated or unclassified autoinflammatory disorder (uAID), and their treatment should follow the best practices established for uAID.	A	7,6 ± 1,9
7. For patients with negative genetic results, consider consulting other specialist centres to ensure the most informed approach to further investigation and treatment.	A	7,7 ± 1,7

Level of evidence (LoE): A: Level I evidence or consistent findings from multiple studies of levels II, III, or IV; B: Levels II, III, or IV evidence and findings are generally consistent; C: Levels II, III, or IV evidence, but findings are inconsistent; D: Level V evidence: little or no systematic empirical evidence; Level of agreement (LoA).