Autoinflammatory diseases are genetically diverse, but clinically similar, conditions distinct from autoimmune illnesses, such as systemic lupus erythematosus or rheumatoid arthritis. Clinically, they are defined by recurrent episodes of inflammation that follow a characteristic pattern each time they occur. Some have a set length of time during which fever, peritonitis or arthritis manifest. Others are more sporadic and unpredictable, or may be triggered by exposure to cold.1
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Explore This IssueAugust 2019
At a cellular level, autoinflammatory diseases arise as a consequence of dysregulation of innate immunity, with no recruitment of adaptive immunity. Studies over the past decade or so have identified the inflammasome as a critical structure in the onset of classic autoinflammatory diseases. The inflammasome is a cytoplasmic protein complex assembled upon recognition of intracellular danger-associated molecular patterns by nucleotide-binding oligomerization domain (NOD) like receptors, especially NACHT, LRR and PYD domains containing protein 3 (NLRP3). The inflammasome plays a key role in the production and release of pro-inflammatory cytokines, specifically interleukin 1 (IL-1).1
Familial Mediterranean fever (FMF) is the most prevalent and best characterized autoinflammatory syndrome. It typically affects people of Mediterranean and Middle Eastern descent but may affect members of any ethnic group, include northern Europeans and those of Japanese descent.2 It is characterized by episodic, self-limiting attacks of fever along with abdominal pain, pleurisy, arthritis and a distinctive erysipelas-like rash.2 Attacks may last several hours to several days. Mutations in the MEFV (i.e., Mediterranean fever) gene, typically inherited in an autosomal recessive fashion, are responsible for FMF. To date, scores of disease-associated mutations have been associated with MEFV, the majority of which are missense changes found on exon 2 and 10.2 MEFV encodes a 781 amino acid protein pyrin (also known as marenostrin).2 Pyrin is expressed by polymorphonuclear cells, monocytes and synovial fibroblasts. It affects inflammation by regulating processing of IL-1β.
In classically affected populations with typical clinical findings, a family history suggestive of FMF and a well-established MEFV polymorphism (such as E148Q on exon 2 or M694I/M694V on exon 10), diagnosis of FMF is relatively straightforward. However, in other ethnic groups with atypical symptoms and no family history, diagnosing FMF can prove challenging. Additionally, it has been observed that up to 30% of people with FMF have only one MEFV gene mutation.2 These patients also respond well to colchicine, the treatment of choice for FMF.
We present the case of a patient with a seven-year history of paroxysmal bouts of a large-joint asymmetric arthritis who, after an extensive workup, was found to be heterozygous for the K695R mutation in pyrin.