ARTHRITIS & RHEUMATISM Vol. 56, No. 8, August 2007, pp 2784–2788 DOI 10.1002/art.22755 © 2007, American College of Rheumatology An Unexpectedly High Frequency of MEFV Mutations in Patients With Anti–Citrullinated Protein Antibody–Negative Palindromic Rheumatism Juan D. Can ˜ete, 1 Juan I. Arostegui, 2 Rube ´n Queiro ´, 3 Jordi Grataco ´s, 4 M. Victoria Herna ´ndez, 1 Marta Larrosa, 4 Mercedes Alperı ´, 3 Conchita Moll, 1 Josefa Rius, 2 Raimon Sanmartı ´, 1 and Jordi Yagu ¨e 2 Objective. To investigate whether the MEFV gene, which is involved in the regulation of the inflammatory response and has been associated with familial Medi- terranean fever (FMF) and intermittent hydrarthrosis, is implicated in the pathogenesis of palindromic rheu- matism (PR) and to examine its clinical presentation and its evolution in a Spanish cohort of PR patients. Methods. Family histories, demographic clinical data, and laboratory characteristics of 75 patients diag- nosed as having PR were collected from medical records and personal interviews. The healthy control group included 325 blood bank donors. The FMF control group was made up of 84 Spanish FMF patients. Genomic DNA was isolated, and MEFV gene mutation analysis was performed by polymerase chain reaction amplification and sequence analysis. Results. Sixty-five unrelated PR patients were finally included in the study. MEFV gene mutation analysis identified 8 of these 65 patients (12.3%) as carriers of at least 1 mutated MEFV allele. Patients with MEFV mutations had higher mean age and age at disease onset, but lower mean serum levels of anti– citrullinated protein antibodies (ACPAs). No other sig- nificant differences were observed between patients with and those without mutations. The frequency of MEFV mutations in ACPA-negative PR patients was 22.2%, compared with 5.3% in ACPA-positive PR patients (P  0.058). Conclusion. This study shows a previously unre- ported high prevalence of mutations of the MEFV gene in patients with ACPA-negative PR. This supports the hypothesis that it might be a susceptibility gene. Our findings also support the hypothesis that the MEFV gene might participate in the pathogenesis of other undifferentiated relapsing inflammatory rheumatic dis- orders. Palindromic rheumatism (PR), the most preva- lent idiopathic recurrent arthritis syndrome, is charac- terized by relapsing, short episodes of sudden-onset arthritis that have no recognizable triggering factors. These inflammatory episodes subside spontaneously with no residual clinical alterations or persistent radio- graphic changes. PR may precede the onset of chronic inflammatory conditions, especially rheumatoid arthritis (RA) (1). Autoantibodies such as rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPAs) (the most specific serologic marker of RA) are fre- quently seen in the sera of PR patients. It has been suggested that their presence increases the risk of devel- oping RA (2–4). However, ACPAs have been found in more than half of PR patients who have no other associated disease. This suggests that this entity could be Dr. Can ˜ete’s work was supported by research grants from the Fondo de Investigacio ´n Sanitaria (FIS 04/1023, FIS 04/1027, and FIS 05/0913) and by a research award from the Institut d’Investigacions Biome `diques August Pi i Sunyer. Dr. Yagu ¨e’s work was supported by a grant from Spain’s Ministerio de Sanidad y Consumo (FIS/PI 06/0241). 1 Juan D. Can ˜ete, MD, PhD, M. Victoria Herna ´ndez, MD, Conchita Moll, MD, Raimon Sanmartı ´, MD: Hospital Clı ´nic de Barcelona, and Institut d’Investigacions Biome `diques August Pi i Sunyer, Barcelona, Spain; 2 Juan I. Arostegui, MD, PhD, Josefa Rius, AS, Jordi Yagu ¨e, MD, PhD: Hospital Clı ´nic de Barcelona, Barcelona, Spain; 3 Rube ´n Queiro ´, MD, PhD, Mercedes Alperı ´, MD: Hospital Central de Asturias, Oviedo, Spain; 4 Jordi Grataco ´s, MD, Marta Larrosa, MD: Hospital Parc Taulı ´ de Sabadell, Sabadell (Barcelona), Spain. Drs. Can ˜ete and Arostegui contributed equally to this work. Address correspondence and reprint requests to Juan D. Can ˜ete, MD, PhD, Unitat d’Artritis, Servei de Reumatologia, Hospital Clı ´nic de Barcelona, Villarroel 170, 08036 Barcelona, Catalonia, Spain. E-mail: jcanete@clinic.ub.es. Submitted for publication December 27, 2006; accepted in revised form April 20, 2007. 2784