Post-traumatic stress disorder and serum cytokine and chemokine concentrations in patients with rheumatoid arthritis✰.

OBJECTIVE: Although post-traumatic stress disorder (PTSD) is identified as a risk factor in the development of rheumatoid arthritis (RA), associations of PTSD with disease progression are less clear. To explore whether PTSD might influence disease-related measures of systemic inflammation in RA, we compared serum cytokine/chemokine (cytokine) concentrations in RA patients with and without PTSD. METHODS: Participants were U.S. Veterans with RA and were categorized as having PTSD, other forms of depression/anxiety, or neither based on administrative diagnostic codes. Multiplex cytokines were measured using banked serum. Associations of PTSD with cytokine parameters (including a weighted cytokine score) were assessed using multivariable regression, stratified by anti-CCP status and adjusted for age, sex, race, and smoking status. RESULTS: Among 1,460 RA subjects with mean (SD) age of 64 (11) years and disease duration of 11 (11) years, 91% were male, 77% anti-CCP positive, and 80% ever smokers. Of these, 11.6% had PTSD, 23.7% other depression/anxiety, and 64.7% had neither. PTSD, but not depression/anxiety, was associated with a higher cytokine score and number of high-concentration analytes in adjusted models, though this was limited to anti-CCP positive subjects. PTSD was associated with heightened expression of several individual cytokines including IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-17, IFN-γ, GM-CSF, MCP-1, and TNF-α. CONCLUSION: Anti-CCP positive RA patients with PTSD have higher serum cytokine concentrations than those without PTSD, demonstrating that systemic inflammation characteristic of RA is heightened in the context of this relatively common psychiatric comorbidity.

Role of Anti-Carbamylated Protein Antibodies Compared to Anti-Citrullinated Protein Antibodies in Indigenous North Americans With Rheumatoid Arthritis, Their First-Degree Relatives, and Healthy Controls.

OBJECTIVE: Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies, including seropositivity for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). In addition, antibodies to carbamylated proteins (anti-CarP) are present in patients with RA and are associated with joint damage. This study was undertaken to assess the presence of anti-CarP antibodies in indigenous North Americans (First Nations [FN] populations) with RA compared to their at-risk first-degree relatives (FDRs) and healthy controls. METHODS: Anti-CarP IgG and ACPAs (specifically, anti-cyclic citrullinated peptide [anti-CCP] antibodies) were measured by enzyme-linked immunosorbent assay in the sera of FN patients with RA (n = 95), their unaffected FDRs (n = 109), and healthy FN controls (n = 85). Antibodies to additional citrullinated peptides were measured using a multiplex ACPA array, and the number of peptides recognized was reported as an ACPA score. Groups were compared using the chi-square test and Mann-Whitney U test. Associations between RA and seropositivity for RF, ACPAs, and anti-CarP antibodies were determined by logistic regression. RESULTS: Anti-CarP antibodies were more frequent in FN patients with RA (44.3%) compared to FDRs (18.3%) and FN controls (4.7%) (both P < 0.0001 versus RA). Moreover, anti-CarP antibodies were more frequent in FDRs than in FN controls (P = 0.008). The ACPA score was higher in anti-CCP-positive FN patients with RA than in anti-CCP-positive FN FDRs (median score 7 [interquartile range (IQR) 7] versus median score 1 [IQR 4]; P = 0.04). The association with RA was strongest when all 3 autoantibodies (RF, anti-CCP, and anti-CarP) were present in the patients' serum (odds ratio 194, 95% confidence interval 23-1,609, P < 0.0001). CONCLUSION: Anti-CarP antibodies are prevalent in FN patients with RA and also more common in their at-risk FDRs compared to healthy controls. The results indicate an association of RF, ACPAs, and anti-CarP with RA that is strongest when all 3 autoantibodies are present. These findings may provide new insights into the evolution of autoimmunity in preclinical RA.

Polymorphisms in the TNF-α, TNFR1 gene and risk of rheumatoid arthritis in Chinese Han population.

Recent advances have highlighted a major genetic contribution to the pathogenesis of rheumatoid arthritis (RA).The aim of this study was to investigate whether polymorphisms of TNF-α (rs1800630, rs1800629) and TNFR1 (rs767455) were associated with susceptibility to and clinical outcome of RA in Chinese Han population. The target gene polymorphisms were genotyped in 256 patients with RA and 331 healthy controls using a high resolution melting (HRM) method. ESR, CRP, RF anti-CCP and anti-GPI level were also assayed and compared in genotypes of each polymorphism. Significant difference was observed in the genotype distributions and allele frequencies of TNF-α rs1800629 (P = 0.001, P < 0.001, respectively) between patients with RA and controls. There is no evidence to suggest an association between genotypes of the 3 SNPs according to age, gender, disease duration, DAS28 and serum level of autoantibodies. This study identifies a potentially important role for TNF-α rs1800629 polymorphisms in the susceptibility to RA.However, further studies in larger cohorts are required.

Oral and topical boswellic acid attenuates mouse osteoarthritis.

OBJECTIVE: Boswellic acid is a plant-derived molecule with putative anti-inflammatory effects. This study was performed to determine whether oral or topical administration of boswellic acid can attenuate joint damage in a mouse model of osteoarthritis (OA). METHODS: Levels of boswellic acid were measured in the blood and synovium of mice treated with oral or topical boswellic acid. OA was generated by surgical destabilization of the medial meniscus (DMM). Therapy with oral or topical boswellic acid was initiated one day after surgery and continued for 12 weeks, when knees were harvested and scored histologically for degree of cartilage loss, osteophyte formation, and synovitis. Microdissected OA synovium was stimulated with IL-1ß or lipopolysaccharide (LPS) in the presence or absence of boswellic acid and cytokine production by quantitative polymerase chain reaction (PCR) or multiplex enzyme linked immunoabsorbant assay (ELISA). RESULTS: Topical treatment resulted in synovial concentrations of boswellic acid 2-6-fold higher than that measured in plasma. Cartilage loss was significantly reduced in mice treated with oral or topical boswellic acid compared with vehicle control (P < 0.01 for both oral and topical therapies). Likewise, treatment with either oral boswellic acid or boswellic acid ointment reduced of synovitis (P = 0.006 and 0.025, respectively) and osteophyte formation (P = 0.009 and 0.030, respectively). In vitro, boswellic acid was able to inhibit IL-1ß and TLR4 mediated induction of several inflammatory mediators from OA synovial explant tissue. CONCLUSIONS: Significant synovial concentration and therapeutic efficacy can be achieved with topical boswellic acid treatment. These findings suggest that boswellic acid has potential as a disease-modifying agent in OA.

Trapeziometacarpal subluxation predisposes to incident trapeziometacarpal osteoarthritis (OA): the Framingham Study.

OBJECTIVE: Osteoarthritis (OA) of the thumb carpo-metacarpal joint is a common condition that can lead to substantial pain, instability, deformity, and loss of motion. It has been hypothesized that instability of the trapeziometacarpal joint combined with strenuous use can potentially lead to OA. However, as yet there have been no longitudinal evaluations to determine if this hypothesis is true. We examined the relation of radial subluxation to the risk of radiographic OA at trapeziometacarpal joint. METHODS: We conducted a nested case-control study. We restricted our evaluation of cases to subjects with no radiographic trapeziometacarpal OA at baseline (1967). We defined incident trapeziometacarpal OA as the development of a modified Kellgren and Lawrence grade>or=2 in that joint at a later examination (1992-1993). Radial subluxation of the base of the first metacarpal off the trapezium and the amount of the base of the first metacarpal covering the articulating surface of the trapezium were measured using a digital calculation caliper. We examined the relation of gender-specific quartile groups of radial subluxation to the risk of trapeziometacarpal OA using a conditional logistic regression model. RESULTS: We assessed 203 men and 431 women. After adjusting for age, handedness, number of other joints with OA, and grip strength, the odds ratios for the risk of trapeziometacarpal OA in men were 1.0, 1.8, 2.7, and 3.1 from the lowest quartile of radial subluxation to the highest quartile, respectively (P for trend=0.015). There was no significant relationship between radial subluxation quartiles and incident trapeziometacarpal OA in women. CONCLUSION: This study provides evidence that radial subluxation predisposes to subsequent OA of the trapeziometacarpal joint in men.