Palindromic Rheumatism Patients Research Articles

Identification of Distinct Genetic Profiles of Palindromic Rheumatism Using Whole-Exome Sequencing.

Previous studies have underlined the genetic susceptibility in the pathogenesis of palindromic rheumatism (PR), but the known PR loci only partially explain the disease's genetic background. We aimed to genetically identify PR by whole-exome sequencing (WES). This multicenter prospective study was conducted in 10 Chinese specialized rheumatology centers between September 2015 and January 2020. WES was performed in 185 patients with PR and in 272 healthy controls. PR patients were divided into PR subgroups who were negative for anti-citrullinated protein antibody (ACPA-) and positive for ACPA (ACPA+) according to ACPA titer (cutoff value 20 IU/liter). We conducted whole-exome association analysis for the WES data. We used HLA imputation to type HLA genes. In addition, we used the polygenic risk score to measure the genetic correlations between PR and rheumatoid arthritis (RA) and the genetic correlations between ACPA- PR and ACPA+ PR. Among 185 patients with PR enrolled in our study, 50 patients (27.02%) were ACPA+ and 135 PR patients (72.98%) were ACPA-. We identified 8 novel loci (in the ACPA- PR group: ZNF503, RPS6KL1, HOMER3, HLA-DRA; in the ACPA+ PR group: RPS6KL1, TNPO2, WASH2P, FANK1) and 3 HLA alleles (in the ACPA- PR group: HLA-DRB1*0803 and HLA-DQB1; in the ACPA+ PR group: HLA-DPA1*0401) that were associated with PR and that surpassed genome-wide significance (P < 5 × 10-8 ). Furthermore, polygenic risk score analysis showed that PR and RA were not similar (R2 < 0.025), whereas ACPA+ PR and ACPA- PR showed a moderate genetic correlation (0.38 < R2 < 0.8). This study demonstrated the distinct genetic background between ACPA- and ACPA+ PR patients. Additionally, our findings strengthened that PR and RA were not genetically similar.

Assessing the Immune Cell Subset and Genetic Mutations in Patients With Palindromic Rheumatism Seronegative for Rheumatoid Factor and Anti-Cyclic Citrullinated Peptide.

The etiology underlying cases of palindromic rheumatism (PR) not associated with other rheumatic diseases in patients who are seronegative for rheumatoid factor and anti-cyclic citrullinated peptide (seronegative PR) is unclear. We aimed to investigate the immune cells and genes involved. This was a single-center comparative study of 48 patients with seronegative PR and 48 healthy controls. Mass cytometry and RNA sequencing were used to identify distinct immune cell subsets in blood. Among the 48 seronegative PR patients, plasma samples from 40 patients were evaluated by enzyme-linked immunosorbent assay for cytokine levels, and peripheral blood samples from 25 patients were evaluated by flow cytometry for mononuclear cell subsets. Plasma samples from 21 patients were evaluated by real-time polymerase chain reaction for differential gene and protein expression, and samples from 3 patients were analyzed with whole-exome sequencing for gene mutations. Immunophenotyping revealed a markedly increased frequency of CD14+CD11b+CD36+ and CD4+CD25-CD69+ cells in seronegative PR patients with active flares compared with healthy controls (P < 0.0001 for both cell subset comparisons). Gene enrichment analyses of RNA-sequencing data from sorted CD14+CD11b+CD36+ and CD4+CD25-CD69+ cells showed involvement of the inflammatory/stress response, phagocytosis, and regulation of apoptosis functional pathways. Up-regulated expression of CXCL16 and IL10RA was observed in monocytes from PR patients. Up-regulation of PFKFB3, DDIT4, and TGFB1, and down-regulation of PDIA6 were found in monocytes and lymphocytes from PR patients with active flares and PR patients in intercritical periods. Plasma levels of S100A8/A9 and interleukin-1β were elevated in PR patients. Whole-exome sequencing revealed novel polygenic mutations in HACL1, KDM5A, RASAL1, HAVCR2, PRDM9, MBOAT4, and JRKL. In seronegative PR patients, we identified a distinct CD14+CD11b+CD36+ cell subset that can induce an inflammatory response under stress and exert antiinflammatory effects after phagocytosis of apoptotic cells, and a CD4+CD25-CD69+ T cell subset with pro- and antiinflammatory properties. Individuals with genetic mutations involving epigenetic modification, potentiation and resolution of stress-induced inflammation/apoptosis, and a dysregulated endoplasmic reticulum stress response could be predisposed to seronegative PR.

Cigarette smoking and risk of palindromic rheumatism: A propensity score matching analysis

Present study was conducted to investigate smoking status in palindromic rheumatism (PR) patients compared to healthy individuals as well as to assess the effect of smoking on clinical features and outcomes of PR. One hundred and forty-six patients with diagnosis of PR and 346 healthy controls were included in this study. Demographic, clinical, and laboratory characteristics and the smoking history of PR patients at the cohort entry were obtained from patients’ records. Demographic and smoking history of the control group were obtained by direct interview. In order to reduce heterogeneity between the studied groups, propensity score matching (PSM) analyses was performed. Matching was achieved by considering age, gender, educational status, and marital status. After PSM, we carried out a multivariate analysis with PR as the main outcome variable, ever smoking as the main predictor variable and age, gender, educational status, and marital status as covariates. PSM resulted in 123 PR patients and 246 matched controls. Multivariate analysis did not show a significant increase in the risk of PR in ever smokers. Seventy-six patients were anti-citrullinated protein/peptide antibody positive (ACPA-positive). Multivariate logistic regression showed a significant increase in the risk of PR in ACPA-positive ever smokers. Except lower sustained remission rate in ever smokers, no significant differences were observed in clinical manifestations and outcomes of PR between ever and never smokers. In conclusion, smoking is a risk factor for ACPA-positive PR.

Early and advanced stages in palindromic rheumatism patients: Test characteristics of three classification criteria and discrimination potential

Aim of the workIt is to identify the classification characteristics of diagnostic criteria in the early (≤3 year) and advanced stage (>3 year) of palindromic rheumatism (PR). Patients and methods269 patients of PR were selected out of those with recurrent intermittent arthritis and were divided into two groups with ≤3 year (n = 99) and >3 year (n = 170) disease duration. The clinical characteristics and the positive incidence according to 3 classification criteria: Pasero and Barbieri (1986); Hannonen et al. (1987) and Guerne and Weisman (1992) were compared. Furthermore, the positive incidences of each criterion were calculated. ResultsThe mean age of the patients was 39.2 ± 10.8 years and M:F 1.2:1. The agreement of the Hannonen et al. (1987) and Guerne and Weisman (1992) criteria was the highest with 0.63 of κ value. When the positive incidences by each criteria were compared between groups of the ≤3 year and >3 year, both Hannonen et al criteria (76.8% and 91.2%) and Guerne and Weisman (62.6% and 85.8%) were significantly different (p = 0.001). The criterion that showed the obvious difference between early and advanced stages were as follow: (Pasero and Barbieri) >5 attacks in the last 2 years and ≥3 joints involved in different attacks; (Hannonen et al.) subsequent attacks in at least three different joints and for (Guerne and Weisman) six-month history of brief-sudden-onset and recurrent episodes of monoarthritis and ≥3 joints involved in different attacks. ConclusionsThe individual PR criteria showed different classification characteristics in ≤3 year and >3 year.

The evaluation of gene polymorphisms associated with autoinflammatory syndrome in patients with palindromic rheumatism complicated by intermittent hydrarthrosis.

Palindromic rheumatism (PR) is a type of acute arthritis or periarthritis characterized by recurrence, paroxysmal, or intermittent disease attacks and occasionally progresses to other types of rheumatic disease. PR patients who are anti-citrullinated protein antibodies (ACPA)-negative have a high prevalence of MEFV gene polymorphisms, and intermittent hydrarthrosis (IH) is also associated with MEFV polymorphisms. The purpose of this study was to evaluate the clinical characteristics of and autoinflammatory syndrome-associated gene polymorphisms in patients with PR and IH and to identify predictive factors for developing other rheumatic diseases. Six PR patients (four females; median age at disease onset, 20.0years; median age at evaluation, 47.0years) were retrospectively evaluated for clinical features and polymorphisms in genes responsible for autoinflammatory diseases. All six patients fulfilled the diagnostic criteria for PR and showed clinical feature of IH. Two presented with recurrent fever. All six patients were negative for rheumatoid factor and ACPA and had normal articular X-ray findings. Among the six patients, MEFV gene polymorphisms known to cause FMF were identified in four, CIAS1 mutation was observed in one, and TNFRSFIA mutation was observed in one. Colchicine was effective in three patients with MEFV polymorphisms. The other five patients continued to experience PR, although three patients achieved remission with medication. PR presenting with IH might be associated with gene polymorphisms responsible for autoinflammatory diseases; colchicine appears to be effective in these patients.Key Point• Palindromic rheumatism with intermittent hydrarthrosis might be associated with gene polymorphisms responsible for autoinflammatory diseases.

Anti-carbamylated protein antibody isotype pattern differs between palindromic rheumatism and rheumatoid arthritis.

Background:A restricted response against citrullinated peptides/proteins, with less isotype usage, has been found in palindromic rheumatism (PR) in comparison with rheumatoid arthritis (RA). We hypothesized that this different antibody response may be observed for other post-translational modified proteins. We compared the prevalence and isotype usage of two specificities of anti-carbamylated peptide/protein antibodies (Anti-CarP) in patients with PR and RA.Methods:Cross-sectional study including 54 patients with pure PR and 53 patients with RA, matched by sex, age, disease duration and ACPA. Anti-CarP specificities were determined by home-made enzyme-linked immunosorbent assay tests using a synthetic chimeric fibrin/filaggrin homocitrullinated peptide (CFFHP) and fetal calf serum (FCS) homocitrullinated protein as antigens. IgG, IgA and IgM isotypes were measured.Results:Anti-CarP were positive (CFFHP or FCS) in 24% and 64% of patients with PR and RA, respectively (p < 0.005). All Anti-CarP isotype proportions were significantly lower in PR than in RA: Anti-CarP-IgG (24% versus 51%), Anti-CarP-IgA (7% versus 34%) and Anti-CarP-IgM (7% versus 36%). Mean titers of Anti-CarP isotypes were also lower in PR. In Anti-CarP positive patients, the isotype distribution differed between PR and RA: IgG Anti-CarP was used in all PR patients and in 79% of RA patients. By contrast, a significantly lower isotype usage of both IgA (31% versus 53%) and IgM (31% versus 56%) was observed in PR patients. No significant differences in clinical or demographic characteristics were observed according to Anti-CarP status in PR patients, except for a higher prevalence of ACPA and higher mean titers of ACPA and rheumatoid factor in Anti-CarP positive patients.Conclusion:Anti-CarP are found in patients with PR but in a lower proportion and with a different isotype usage from in RA, suggesting a distinct B cell response to homocitrullinated antigens in PR.

Relapsing periodic arthritis, palindromic rheumatism and MEFV gene-related variants alleles in children

BackgroundRelapsing periodic arthritis is a general term used for a group of diseases with recurring and periodic nature, in which the joints are intermittently involved. The aim of this study is to evaluation of the possible relationship between MEFV gene mutations in intermittent arthritis of children which has recurring and periodic nature.MethodsIn this cross-sectional study we reviewed medical records of all patients with recurrent and periodic arthritis referred to pediatric rheumatology clinic from 2003 to 2019.We excluded all patients with suspicious anamnesis and/or positive history of FMF, JIA, gout, psoriasis, IBD and SLE. The peripheral blood of these patients was screened for the 12 common pathogenic MEFV gene variants (FMF Strip Assay, Vienna lab, Vienna, Austria) according to manufacturer’s instructions.ResultsAmong 195 recorded files, 11 patients were identified with idiopathic recurrent and periodic feature. 3 patients suffering from recurrent transient synovitis hip (RSH) and 8 patients were fully compatible with the Pasero and Barbieri modified criteria of palindromic rheumatism (PR). Their mean age at diagnosis was 6.5 and 4.6 years and the average follow-up was 2.6 and 6.6 years in PR and RSH patients, respectively. The most frequently involved joints were knees and ankles in PR patients. The mean duration of attacks was 3.3 days in RSH patients and with various courses in PR. The median number of attacks was 4.75 in PR and 3 in RSH patients per year. In PR group 7 patients showed no mutations and all patients of RSH had these mutations; V726A, R761H, A744S as in heterozygote pattern.ConclusionAn idiopathic relapsing periodic arthritis in children with exclusively hip involvement is a MEFV gene related arthropathy; whereas with various joint attacks it could be considered as childhood PR.

Efficacy of rituximab in resistant palindromic rheumatism: first report in literature.

Rituximab (RTX) provides significant clinical benefits in active rheumatoid arthritis (RA) patients with inadequate response to DMARDs and anti-TNF. There is no data regarding efficacy of RTX in seropositive Palindromic Rheumatism (PR), a forerunner of RA. To determine the efficacy and safety of RTX treatment in active PR patients exhibiting inadequate response to conventional synthetic DMARDs (csDMARDs). The retrospective study, over a period of 3years, included seropositive (RF ± antiCCP) PR patients with inadequate control of PR (> 4 attacks per months) despite combination csDMARDs and were treated with RTX. All the patientswere treated with an initial dose of 500mg RTX and later with a second infusion after 2 weeks' period in those who did not achieve adequate/ complete disease control. Patients were continued on csDMARDS and retreated with RTX on relapse of symptoms. Thirty-three seropositive PR patients with a mean age of 48.15 ± 14.2years, mean disease duration of 68.4 ± 68.2 months, mean follow up period of 24.3 ± 10.8months, were treated with RTX. 88% patients were on combination DMARDS and 79% patients were females.All patient achieved rapid and complete control of palindromic attacks with RTX. Fifteen patients had a relapse after a mean duration of 10.4 ± 5.5months and needed repeat RTX infusions following which remission was achieved. None of the patients progressed to RA till the end of the follow-up. No serious adverse effects were recorded. RTX treatment could be effective in achieving disease control in active palindromic rheumatism not responding to csDMARDs. • PR is thought to be a forerunner of RA and rituximab (RTX) has been found to be effective in RA. • Our study supports the hypothesis that B cells play an important role in the pathophysiology of PR and that the combination (RTX+ conventional drugs) can prevent the disease evolution into RA. • This 3-year retrospective study showed that rituximab was found to be effective in those who responded poorly to conventional drugs and remission was achieved in all patients. • Although it is a rare disease, we see palindromic rheumatism patients in India more often. As the symptoms are very debilitating in these patients, in those patients, not controlled on conventional drugs, rituximab offers newer promise in controlling the attacks and prevents further progression to RA.

Risk of autoimmune rheumatic diseases in patients with palindromic rheumatism: A nationwide, population-based, cohort study.

ObjectiveTo estimate the relative risk of autoimmune rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren’s syndrome (SS), dermatomyositis (DM) and polymyositis (PM), among patients with palindromic rheumatism (PR) compared with non-PR individuals.MethodsThe study utilized 2003–2013 claims data from the Taiwanese National Health Insurance Research Database. We identified 4,421 cases of PR from 2007 to 2012 and randomly chose 44,210 non-PR individuals who matched (1:10) for age, sex and the year of index date without prior history of RA, SLE, SSc, SS, DM, or PM. After adjusting for age, sex, and the Charlson comorbidity index, we calculated the hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard model to quantify the risk of RA, SLE, SS, DM and PM in PR patients compared with that in matched non-PR individuals.ResultsAmong the 4,421 patients with PR, 569 (12.87%) developed RA, 269 (6.08%) developed SS, 113 (2.56%) developed SLE, 5 (0.11%) developed SSc, 8 (0.18%) developed PM, and 1 (0.02%) developed DM. After adjusting for potential confounders, the patients with PR had an increased risk of RA (HR, 118.76; 95% CI, 89.81–157.04), SS (HR, 59.57; 95% CI, 43.87–80.88), SLE (HR, 51.56; 95% CI, 32.96–80.66) PM (HR, 57.38; 95% CI, 6.90–476.83), and SSc (HR, 13.42; 95% CI, 3.79–47.55) but not of DM (HR, 3.44; 95% CI, 0.34–34.59).ConclusionPatients with PR had an increased risk of developing RA, SS, SLE, PM, and SSc.

Association between periodontitis and the risk of palindromic rheumatism: A nationwide, population-based, case-control study.

ObjectiveTo estimate the association between a history of periodontitis (PD) and the risk of incident palindromic rheumatism (PR).MethodsUsing a nationwide, administrative database, this study identified 4,421 newly-diagnosed PR cases from 2007 to 2012 and randomly selected 44,210 non-PR controls matched (1:10) for sex, age and the year of the index date. After adjusting for comorbid diabetes mellitus, we estimated the odds ratios (ORs) with 95% confidence intervals (CIs) using conditional logistic regression analysis to quantify the association between a history of PD and the risk of PR. The influences of the lag time and severity of PD were examined by calculating ORs for subgroups of patients based on the time interval between the last PD-related visit and the index date and PD-related cumulative cost and number of visit.ResultsThis study showed an association between a history of PD and incident PR (OR, 1.51; 95% CI, 1.41–1.61). The association remained significant after variation of PD definitions. The magnitude of the association was greater in those with shorter lag time between the latest date of PD diagnosis and PR index date and those who had a higher number of visits for PD or a greater cumulative cost for PD-related visits. After excluding 569 PR patients who developed rheumatoid arthritis after the index date, we found a consistent time- and dose-dependent association between PD and PR risk.ConclusionThis study demonstrated a time- and dose-dependent association between PD exposure and PR risk.

Differing specificities and isotypes of anti-citrullinated peptide/protein antibodies in palindromic rheumatism and rheumatoid arthritis

BackgroundTo analyze differences in the recognition of anti-citrullinated peptide/protein antibody (ACPA) citrullinated epitopes and isotypes in patients with palindromic rheumatism (PR) and rheumatoid arthritis (RA).MethodsACPA fine specificities (citrullinated peptides of enolase, fibrin, and vimentin) and isotypes (IgG, IgM, and IgA) were analyzed in 54 patients with longstanding PR and 54 patients with established RA.ResultsCCP2 tested positive in 66.7% of patients with PR and RA. The ACPA distribution of fine specificities and isotypes differed between PR and RA patients. PR patients had a lower frequency of fine ACPA specificities than RA patients, which was significant in the case of a peptide derived from vimentin (PR 24.1% vs. 59.3% RA; p < 0.001). The mean number of ACPA specificities was lower in PR than in RA patients, and only 25.9% of PR patients recognized ≥2 additional specificities compared with 46.3% of RA patients. Significantly less isotype usage, especially IgA, was observed in PR patients.ConclusionThe ACPA immune response differed in patients with PR and RA, with fewer fine specificities and isotype usage in patients with PR. Some patients with PR may have impaired maturation of the B-cell response against citrullinated peptides with no progression to RA.

What can palindromic rheumatism tell us?

Palindromic rheumatism (PR) is a syndrome characterised by recurrent, self-resolving inflammatory attacks in and around the joints. An association between PR and rheumatoid arthritis (RA) has long been postulated; a significant proportion of PR patients eventually develop RA and the majority also have anti-CCP antibodies. Therefore, PR is often considered a prodrome of RA. However, the clinical and imaging phenotype of PR has several important distinctions from RA. This suggests that despite the similarities, distinct disease mechanisms are at play. Given the paucity of evidence-based therapy in PR, a better understanding of these mechanisms will be important for refined and targeted therapeutic approaches for this important condition.

Palindromic rheumatism: a reappraisal

Palindromic rheumatism (PR) is characterized by acute, usually monoarticular, arthritis occurring intermittently and lasting for a few days. A significant number of patients with PR develop chronic rheumatic disease, especially rheumatoid arthritis (RA). There remains controversy as to whether PR is a disease entity in itself, or just a preclinical or abortive form of RA. Recently, a high frequency of anticitrullinated peptide/protein antibodies, the most specific biomarkers of RA, have been found in serum from PR patients, further strengthening the link with RA. However, although rheumatoid factor and anticitrullinated peptide/protein antibodies positivity are predictors of progression to RA in PR, a significant number of patients with these autoantibodies do not develop RA after a long follow-up. No controlled clinical trials have been carried out in PR and the treatment and management is still empirical. This review exhaustively analyzes and updates the epidemiological, clinical, diagnostic, prognostic...

Clinical features analysis of 22 palindromic rheumatism patients

Objective To analyze clinical features in palindromic rheumatism(PR).Methods To collect clinical data of 22 PR cases with more complete information,and analyze their clinical characteristics.Results In 22 enrolled patients aged 21 ～47 years old,13 patients were male and 9 patients were female.All patients mainly had localized red,swollen,hot,and with painful in the involved joints or periarticular soft tissues.The symptoms could be self relieved after 2 ～ 7 days or relieved after taking non-steroidal anti-inflammatory drugs(NSAIDs),but appeared repeatedly.73%(16/22)of the patients showed that the interval time between attacks was gradually decreasing.General performance was rare.Most laboratory tests were normal,but appeared low titer of antinuclear antibody(ANA) and rheumatoid factor(RF) positive occasionally.Conclusion If the inflammation in or around the joint appearing repeatedly,the symptoms being self improved in short-term or sensitive to NSAIDs,appearing repeatedly without joint deformity nor bone destruction,and autoantibodies being negative in laboratory tests,it should be first considered the diagnosis of PR. Key words: Palindromic Rheumatism; Arthritis; Diagnosis

Contribution of anti-CCP antibodies, proximal interphalangeal joint involvement, HLA-DRB1 shared epitope, and PADI4 as risk factors for the development of rheumatoid arthritis in palindromic rheumatism

Objectives: To determine which variables at baseline are predictive for the development of rheumatoid arthritis (RA) from palindromic rheumatism (PR) in a Japanese population.Methods: Anti-cyclic citrullinated peptide (anti-CCP) antibodies, joint involvement pattern, genotypes of HLA-DRB1, peptidylarginine deiminase (PADI4), and protein tyrosine phosphatase (PTPN22) were examined in 28 patients with PR at baseline, and their clinical outcome was prospectively evaluated. The same variables were also investigated in 38 healthy controls.Results: Eleven out of 28 patients with PR developed RA. The prevalence of anti-CCP antibodies in the PR patients who developed RA was significantly higher compared to the patients who did not. Proximal interphalangeal (PIP) joint involvement at baseline was also predictive towards the development of RA. Compared with the controls, differences in the frequency of single-nucleotide polymorphism (SNP) on padi4_104 [T(RA susceptible)→C(RA non-susceptible)] and the presence of an RA susceptible homozygote of the PADI4 haplotype were detected in patients with PR whereas we could not find any further difference in PR patients who developed RA compared to PR patients who do not develop RA in PADI4. None of the subjects possessed the PTPN22 SNP (1858C→T). Cox regression analysis revealed that anti-CCP antibodies as well as PIP involvement are the most relevant variables for the development of RA from PR. None of the PR patients with either HLA-DRB1*SE alleles (or the HLA-DRB1*0405 allele) or anti-CCP antibodies developed RA.Conclusions: Anti-CCP antibodies, in relation to HLA-DRB1*SE carriership, and PIP involvement are predictive for the development of RA from PR in the Japanese population.

Predicting the Progression of Palindromic Rheumatism to Rheumatoid Arthritis: The Role of Ultrasonography and Anti-cyclic Citrullinated Peptide Antibodies

We investigated whether sonography and anti-cyclic citrullinated peptide (anti-CCP) antibodies in Chinese patients with palindromic rheumatism (PR) during active episodes are of predictive value for development of rheumatoid arthritis (RA). Clinically involved regions of 84 PR patients during active episodes were examined with ultrasonography using a 6–13 MHz linear transducer. Serum levels of anti-CCP antibodies were determined by enzyme-linked immunosorbent assay. All patients were followed up monthly for 3 years after investigation. Thirteen (15%) of the PR patients had progressed to RA after a mean of 1.4 years (range, 0.4–3.0 years). Of these 13 patients, 11 patients (85%) had sonographic features of synovitis and 8 patients (62%) had a positive anti-CCP antibody test. The absence of sonographic features of synovitis during active episodes provided a very high 3-year predictive value in excluding the possibility of progression to RA for PR patients with a negative anti-CCP antibody test. Both the sonographic findings of synovitis and a positive anti-CCP antibody test were significant predictors for progression of PR to RA within 3 years by backward stepwise logistic regression analysis. Sonographic examination together with an anti-CCP antibody test during active episodes is useful for predicting the progression of PR to RA.

An unexpectedly high frequency of MEFV mutations in patients with anti–citrullinated protein antibody–negative palindromic rheumatism

To investigate whether the MEFV gene, which is involved in the regulation of the inflammatory response and has been associated with familial Mediterranean fever (FMF) and intermittent hydrarthrosis, is implicated in the pathogenesis of palindromic rheumatism (PR) and to examine its clinical presentation and its evolution in a Spanish cohort of PR patients. Family histories, demographic clinical data, and laboratory characteristics of 75 patients diagnosed 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. 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 significant 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). This study shows a previously unreported 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 disorders.

Prevalence and clinical significance of anti-cyclic citrullinated peptide and antikeratin antibodies in palindromic rheumatism. An abortive form of rheumatoid arthritis?

To analyse the prevalence and clinical significance of anti-cyclic citrullinated peptide antibodies (anti-CCP) and antikeratin antibodies (AKA) in patients with palindromic rheumatism (PR). Sixty-three patients with PR were included: 33 were defined as pure or persistent PR at the time of serum test measurement, and 30 as associated PR, defined as patients with past history of PR who had developed persistent arthritis at the time of serum test: [21 with rheumatoid arthritis (RA)]. Sixty patients with early RA, and 80 with seronegative spondyloarthropathy were included as control groups. Anti-CCP were determined by a standardized ELISA test and AKA by indirect immunofluorescence in rat oesophagus. Clinical characteristics of these pure PR patients were compared according to the presence or absence of anti-CCP antibodies. A follow-up study was also performed. Anti-CCP were detected in 18 out of 32 (56.3%) patients with pure PR and 10 out of 30 (33.3%) with associated PR (38.1% in RA-associated PR patients). AKA were detected in 12 patients out of 33, with pure PR (36.4%), and in 9 out of 30 with associated PR (30%) (33.3% in RA-associated PR patients). The prevalence of anti-CCP and AKA in the RA control group was 55% (not significantly different from the pure PR group) and 61.7% (with respect to pure PR patients, P=0.02), respectively. In the spondyloarthropathy group, the prevalence of anti-CCP and AKA was 2.5 and 3.8%, respectively (P<0.001 compared with pure PR patients). No significant clinical differences were observed between pure PR patients with and without CCP antibodies. Anti-CCP and, to a lesser extent, AKA, were found in a high proportion of patients with PR, suggesting that this syndrome is an abortive form of RA. The predictive value of these antibodies in PR, as markers of progression to an established RA, remains uncertain.