Effect of Colchicine on Recurrent Serositis in Familial Mediterranean Fever

A 78-year-old man was admitted with a 2-year history of periodic fever of unknown etiology, with frequent remissions and exacerbations of pericardial and pleural effusions. He had a history of tuberculosis at 22 years of age and had no relevant family history. Chest radiography demonstrated cardiomegaly and left-sided pleural effusion (Figure A). Chest computed tomography revealed extensive pericardial effusion and left encapsulated pleural effusion (Figure B). Oxygen saturation was 92% on 2 L/min of oxygen. Based on the available clinical and radiological findings, the differential diagnosis encompassed malignant lymphoma, tuberculosis pleuropericarditis, collagen diseases, and autoinflammatory disorders such as familial Mediterranean fever. Blood test showed normal white blood cells of 6300/µL, elevated levels of C-reactive protein of 12.1 mg/dL, and soluble interleukin-2 receptor of 1260 U/mL (normal range <466 U/mL). Interferon-γ release assay for tuberculosis and autoantibodies detecting collagen diseases were all negative. We could not perform pericardial or pleural punctures because of the patient's poor general condition. Several antibiotics were firstly administered to rule out infectious disorders and were found to be ineffective. Pericardial and pleural effusions aggravated after a week of admission, as was shown by chest radiography (Figure C). Detailed examinations and clinical course indicated that the autoinflammatory disorder, familial Mediterranean fever was likely. Therefore, Mediterranean fever gene mutation analysis was performed, and heterozygous A165A mutation in exon 2 and homozygous R314R mutation in exon 3 were found (Figure D). From the abnormality of familial Mediterranean fever related genes in addition to periodic fever, and recurrent and refractory pleuropericarditis, we finally diagnosed the patient as having familial Mediterranean fever. Treatment solely with colchicine of 1 mg/day was started. Three days after starting treatment, his fever went down dramatically. Thereafter, pericardial and bilateral pleural effusions were dramatically improved without any side effects (Figure E and F). Familial Mediterranean fever is an autoinflammatory disorder caused by a mutation of a Mediterranean fever gene that codes for a protein called pyrin. The mutated pyrin in familial Mediterranean fever activates the inflammasome.1Özen S Batu ED Demir S Familial Mediterranean fever: recent developments in pathogenesis and new recommendations for management.Front Immunol. 2017; 8: 253Crossref PubMed Scopus (101) Google Scholar Although the reported incidence of pericarditis is less than 1%,2Kees S Langevitz P Zemer D Padeh S Pras M Livneh A Attacks of pericarditis as a manifestation of familial Mediterranean fever (FMF).QJM. 1997; 90: 643-647Crossref PubMed Scopus (109) Google Scholar other serosites, including pleuritis and peritonitis, are not so rare in late-onset familial Mediterranean fever.3Kishida D Yazaki M Nakamura A Tsuchiya-Suzuki A Shimojima Y Sekijima Y Late-onset familial Mediterranean fever in Japan.Mod Rheumatol. 2020; 30: 564-567Crossref PubMed Scopus (4) Google Scholar A recent review noted that in Japan, the onset of familial Mediterranean fever is late in onset of around 15% of patients.3Kishida D Yazaki M Nakamura A Tsuchiya-Suzuki A Shimojima Y Sekijima Y Late-onset familial Mediterranean fever in Japan.Mod Rheumatol. 2020; 30: 564-567Crossref PubMed Scopus (4) Google Scholar Clinical manifestation and prevalence may be associated with regions, ethnicities, and environmental factors, in addition to the zygosity of Mediterranean fever gene mutations in elderly patients.1Özen S Batu ED Demir S Familial Mediterranean fever: recent developments in pathogenesis and new recommendations for management.Front Immunol. 2017; 8: 253Crossref PubMed Scopus (101) Google Scholar However, based on the above-mentioned reports, clinicians should consider familial Mediterranean fever for elderly patients with recurrent serositis and periodic fever. The administration of colchicine dramatically suppressed its disease activity in the present case. The efficacy of colchicine was recently established in patients with any cause of acute pericarditis, recurrent pericarditis, or both,4Imazio M Gaita F LeWinter M Evaluation and treatment of pericarditis: a systematic review.JAMA. 2015; 314: 1498-1506Crossref PubMed Scopus (219) Google Scholar including autoinflammatory disorders such as familial Mediterranean fever.5Wright DG Wolff SM Fauci AS Alling DW Efficacy of intermittent colchicine therapy in familial Mediterranean fever.Ann Intern Med. 1977; 86: 162-165Crossref PubMed Scopus (55) Google Scholar However, some patients with familial Mediterranean fever do not respond to colchicine. The M694V mutation has been reported to cause resistance to colchicine.6Talaat HS Sheba MF Mohammed RH et al.Genotype mutations in Egyptian children with familial Mediterranean fever: clinical profile, and response to colchicine.Mediterr J Rheumatol. 2020; 31: 206-213Crossref PubMed Scopus (7) Google Scholar Whether other mutations are associated with the colchicine resistance remains unclear. Interestingly, silent mutations, which are variations of the coding sequence without any amino acid sequence changes, but not typical mutations, were identified in the current familial Mediterranean fever case. Although further accumulation of cases is necessary, silent mutations could be predictive of good response to colchicine. In conclusion, when treating any patient with recurrent serositis, familial Mediterranean fever and colchicine treatment should be considered.