The association of anti-CCP antibodies with disease activity in rheumatoid arthritis.
ABSTRACT: Antibodies to citrullinated proteins have been described in patients with rheumatoid arthritis (RA) and these appear to be the most specific markers of the disease. Our objective was to determine the frequency of antibodies to cyclic citrullinated peptides (CCPs) in patients with RA and the association of anti-CCP antibodies with disease activity, radiological erosions and HLA DR genotype. Forty patients with RA and 38 patients with fibromyalgia were included in this study. Serum samples were collected from both patient groups with RA and fibromyalgia. Anti-CCP was measured by the corresponding enzyme-linked immunosorbent assay. Additionally, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), disease activity score (DAS), visual analog scala (VAS), HLA genotype and radiographic information were determined in patients with RA. The rate of sensitivity and specificity of anti-CCP reactivity for the diagnosis RA were measured (sensitivity 50%, specificity 100%). There is no significant difference between anti-CCP (+) and anti-CCP (-) RA patients for DAS28, VAS, ESR, CRP, disease duration, HLA genotype, and radiological assessment of hand. However, there was a significant difference between anti-CCP (+) and anti-CCP (-) RA patients for RF and the radiological assessment of left and right wrists (respectively, P < 0.05, P = 0.04, P = 0.01). There was no significant correlation between anti-CCP antibody and ESR, CRP, VAS, DAS 28 or radiological assessment. A small but significant correlation was found between RF and anti-CCP antibody (P = 0.02, r = 0.35).
Project description:Antifibrillar collagen type II (anti-CII) antibody-positive patients with rheumatoid arthritis (RA) have early but not late signs of increased inflammation and joint erosions. We wanted to replicate this in a large RA cohort, and to relate to human leukocyte antigen (HLA)-DRB1* alleles.Anti-CII and anti-cyclic citrullinated peptide (CCP)2 were measured at baseline in 773 patients with RA from the Swedish Epidemiological Investigation in Rheumatoid Arthritis (EIRA) study with clinical follow-up data from the Swedish Rheumatology Quality Register (SRQ) registry, and 1476 with HLA-DRB1* information. Comparisons were done concerning C reactive protein (CRP), erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), Disease Activity Score encompassing 28 joints based on ESR (DAS28), DAS28CRP, pain-Visual Analogue Scale (VAS), global-VAS and Health Assessment Questionnaire Score (HAQ) at eight occasions during 5 years, and association with HLA-DRB1* alleles.Anti-CII associated with elevated CRP, ESR, SJC, DAS28 and DAS28CRP at diagnosis and up to 6 months, whereas anti-CCP2 associated with SJC and DAS28 from 6 months to 5 years, but not earlier. The anti-CII-associated phenotype was strong, and predominated in anti-CII/anti-CCP2 double-positive patients. Anti-CII was associated with improvements in CRP, ESR, SJC, TJC and DAS28, whereas anti-CCP2 was associated with deteriorations in SJC and DAS28 over time. Anti-CII-positive patients achieved European League Against Rheumatism good or moderate response more often than negative patients. Anti-CII was positively associated with HLA-DRB1*01 and HLA-DRB1*03, with significant interaction, and double-positive individuals had >14 times higher mean anti-CII levels than HLA double negatives. Whereas smoking was associated with elevated anti-CCP2 levels, smokers had lower anti-CII levels.Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse to the clinical, genetic and smoking associations described for anticitrullinated protein peptide autoantibodies. Although not diagnostically useful, early anti-CII determinations predict favourable inflammatory outcome in RA.
Project description:Objectives:Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We examined response to tofacitinib 5 or 10 mg two times a day in patients with seropositive vs seronegative RA. Methods:Data were pooled from five Phase III studies of conventional synthetic disease-modifying antirheumatic drug (csDMARD)- or biological DMARD-inadequate responders (ORAL Step [NCT00960440]; ORAL Scan [NCT00847613]; ORAL Solo [NCT00814307]; ORAL Sync [NCT00856544]; ORAL Standard [NCT00853385]). 'Serotype' subgroups were: anticyclic citrullinated peptide (CCP) and rheumatoid factor (RF) positive (anti-CCP+/RF+); anti-CCP+/RF negative (-); anti-CCP-/RF+; anti-CCP-/RF-. At month 3, ACR20/50/70 response rates, Disease Activity Score (DAS28-4[ESR])-defined remission (DAS28-4[ESR]<2.6) and low disease activity (LDA; DAS28-4[ESR]≤3.2), changes from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 Health Survey (SF-36) physical functioning and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Safety endpoints were compared. Results:Baseline demographics/characteristics were similar across subgroups. Tofacitinib significantly improved ACR20/50/70 response rates, DAS28-4(ESR) LDA rates and CFB in HAQ-DI and FACIT-F vs placebo across subgroups. More anti-CCP+/RF+ than anti-CCP-/RF- patients had ACR20/50/70 responses (ACR20/50: both tofacitinib doses; ACR70: 10 mg two times a day). SF-36 physical functioning improved in anti-CCP+/RF+, anti-CCP+/RF- and anti-CCP-/RF+ patients (both tofacitinib doses) and anti-CCP-/RF- patients (10 mg two times a day) vs placebo. More anti-CCP+/RF+ and anti-CCP+/RF- than anti-CCP-/RF- patients achieved DAS28-4(ESR) remission and LDA with tofacitinib 10 mg two times a day. Frequency of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across subgroups. Conclusion:Generally, tofacitinib efficacy (ACR20/50/70 responses) and safety were similar across subgroups. DAS28-4(ESR) remission rates and SF-36 physical functioning appeared lower in anti-CCP- patients.
Project description:Commensal bacteria and their pathogenic components in the gastrointestinal tract and oral cavity may play pathological roles in autoimmune diseases. To study the possible involvement of bacterial pathogens in autoimmune diseases, IgG and IgA antibodies against pathogenic components produced by three strains of commensal bacteria, Escherichia coli-lipopolysaccharide (E. coli-LPS), Porphyromonas gingivalis-LPS (Pg-LPS) and peptidoglycan polysaccharide (PG-PS) from Streptococcus pyogenes, were determined by an improved ELISA system for sera from two groups of patients with rheumatoid arthritis (RA), who met rapid radiographic progression (RRP) criteria and non-RRP, and compared to normal (NL) controls. Antibody responses to these bacterial pathogens are unique and consistent in individuals, and no fundamental difference was observed between RA and NL controls. Despite the similar antibody responses to pathogens, lower IgG or higher IgA and consequent higher IgA/IgG antibody ratio among the patients with RA related to disease marker levels and disease activity. Peculiarly, the IgA/IgG anti-Pg-LPS antibody ratio resulted from lower IgG and higher IgA antibody responses to Pg-LPS strongly correlated not only with rheumatoid factor (RF), but also correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and disease activity score of 28 joints with ESR (DAS28-ESR) in the RRP group. In contrast, the IgA/IgG anti-E. coli-LPS and anti-PG-PS antibody ratio correlated or tended to correlate with RF, ESR, CRP, and DAS28-ESR in the non-RRP group, whereas either the IgG or IgA anti-Pg-LPS antibody levels and consequent IgA/IgG anti-Pg-LPS antibody ratio did not correlate with any clinical marker levels in this group. Notably, anti-circular-citrullinated peptide (CCP) antibody levels, which did not correlate with either IgG or IgA antibody levels to any pathogens, did not correlate with severity of arthritis in both RRP and non-RRP. Taken together, we propose that multiple environmental pathogens, which overwhelm the host antibody defense function, contribute independently or concomitantly to evoking disease makers and aggravating disease activity, and affect disease outcomes.UMIN CTR UMIN000012200.
Project description:Objective:Integrated therapy of traditional Chinese medicine (TCM) and Western medicine (WM) has gradually been applied to the treatment of rheumatoid arthritis (RA). Recently published studies have provided a wealth of data and information about the effectiveness of combination treatments, but high-quality evidence-based meta-analysis on this issue is not available yet. This study was conducted to compare and evaluate the efficacy and safety of the integrated therapy for RA. Methods:PubMed, EMBASE, and the Cochrane Library were searched up to January 2020. Randomized controlled trials (RCTs) that compared the efficacy and safety of integrative TCM-WM with WM alone for RA were included. The outcome measures contained therapeutic effects (TEs), tender joint count (TJC), swollen joint count (SJC), duration of morning stiffness (DMS), grip strength (GS), disease activity score in 28 joints (DAS28), rheumatoid factor (RF), anti-cyclic peptide containing citrulline (anti-CCP), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and adverse events (AEs) to assess the efficacy and safety of different treatments. Results:A total of 20 RCTs with 2269 patients met the inclusion criteria. TCM used in these studies included Chinese herbal decoctions and tablets or capsules made from herbs and their extracts, while WM included disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids (GC). Compared with patients receiving WM treatment alone, patients with integrative TCM-WM treatment showed better TEs (OR?=?3.03, 95% CI [2.36, 3.88]). The integrative treatment group showed reductions in TJC (MD?=?-1.17, 95% CI [-2.12, -0.21]), SJC (MD?=?-0.87, 95% CI [-1.85, 0.10]), DMS (SMD?=?-0.69, 95% CI [-0.98, -0.41]), DAS28 (MD?=?-0.43, 95% CI [-0.57, -0.29]), RF (SMD?=?-0.59, 95% CI [-0.91, -0.27]), anti-CCP (SMD?=?-0.21, 95% CI [-0.36, -0.06]), ESR (MD?=?-8.36, 95% CI [-12.60, -4.12]), and CRP (MD?=?-6.73, 95% CI [-9.38, -4.08]), and increment in GS (SMD?=?0.12, 95% CI [-0.63, 0.87]). AEs, especially gastrointestinal disorders, abnormal liver function, leukopenia, skin allergies and rashes, headaches and dizziness, and alopecia, significantly decreased (OR?=?0.37, 95% CI [0.29, 0.47]) in the integrative treatment group. Conclusions:The findings of this meta-analysis indicate that integrative TCM-WM could obtain effective and safe results in the treatment of RA. Using TCM as an adjunctive therapy in RA has great prospects for further development.
Project description:The genetic association between human leukocyte antigen (HLA)-DRB1 alleles and the risk of development of autoantibodies has been investigated, but there are few studies from the Gulf region.To investigate the association between the HLA-DRB1 shared epitope and the risk for development of autoantibodies in rheumatoid arthritis (RA) patients in a Saudi population.Analytical cross-sectional study.Tertiary care hospital in Riyadh, Saudi Arabia.We enrolled consecutive Saudi RA patients attending the rheumatology clinic between January and April 2015. Previously published data on HLA typing on unmatched healthy controls were used for comparison. HLA typing was performed using sequence-specific oligonucleotide probes (SSOP). Rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, and antinuclear antibodies (ANA) were also measured. Logistic regression analysis was used to study the autoantibodies as possible explanatory variables for the presence of the HLA-DRB1 shared epitope.The association between the presence of the shared epitope and the risk of developing anti-CCP antibodies, ANA, and RF.In 76 patients with RA, carrying the shared epitope was associated with a significantly higher risk of having RA [OR=2.65, 95% CI (1.42-4.94), P=.0009]. However, only HLA-DRB1*04:05 was significantly as.sociated with RA [OR=3.73, 95% CI (1.61-8.96), Pc=.016]. In the logistic regression analysis, only anti-CCP was significantly associated with the shared epitope [OR=14.51, 95% CI (1.53-137.49), P=.02].Our analysis indicates that the presence of the HLA-DRB1 shared epitope is strongly associated with the development of anti-CCP antibodies in Saudi patients with RA.A larger sample size is needed to confirm our finding.
Project description:OBJECTIVE:To evaluate associations of HLA-DRB1 haplotypes and shared epitope (SE) with rheumatoid arthritis (RA) severity and all-cause mortality in RA. METHODS:Patients with RA from the Veterans Affairs Rheumatoid Arthritis (VARA) registry were followed from enrollment until death or December 31, 2013. Clinical characteristics, DNA, and serum were collected at enrollment. Radiographic damage, the presence or absence of subcutaneous nodules, disease activity measures, and functional status were assessed at enrollment and updated during followup. Sixteen HLA-DRB1 haplotypes and SE status were determined from banked DNA. Associations between HLA-DRB1 haplotypes, RA disease characteristics, and mortality were assessed in multivariable regression models. RESULTS:Within VARA, 1443 participants had genotyping and accrued 6150 patient-years of followup. Haplotypes VKA, VRA, LRA, SRA, SRE, SKR, and SEA, and SE alleles were significantly associated with seropositivity for rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP). Haplotypes VKA and SKR were associated with higher RF concentrations, while VRA, DRE, and GRQ were associated with lower RF concentrations. Haplotypes VKA, VRA, and LRA were associated with higher concentrations of anti-CCP antibody, while haplotypes SRA, SRE, LEA, SKR, and SEA were significantly associated with lower anti-CCP concentrations. Haplotype VKA (OR 1.39, 95% CI 1.08-1.80) was associated with increased frequency of radiographic damage at enrollment but none of the haplotypes were associated with the presence of subcutaneous nodules. Haplotypes SKA (HR 1.52, 95% CI 1.26-1.83) was associated with higher mortality. CONCLUSION:HLA-DRB1 haplotypes are independently and variably associated with seropositivity, autoantibody concentrations, and outcomes in RA.
Project description:HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA).We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis.A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions.In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA.In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.
Project description:BACKGROUND: Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years. OBJECTIVE: To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors. METHODS: 51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls. RESULTS: The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives. CONCLUSIONS: All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.
Project description:Rheumatoid arthritis (RA) is a chronic, systematic autoimmune disease that mainly affects joints and bones. Although the precise etiology is still unknown, Th17 cell is being recognized as an important mediator in pathogenesis of RA. VSTM1-v2 is a novel cytokine which has recently been reported to promote the differentiation of Th17 cells. This study is performed to study whether VSTM1-v2 can be recognized as a biomarker of RA, and is correlated to IL-17 expression. We obtained peripheral blood mononuclear cells (PBMCs) from 40 patients with RA and 40 age- and sex-matched healthy controls by standard Ficoll-Paque Plus density centrifugation. The mRNA expression levels of VSTM1-v2 and IL-17A in PBMCs were detected by real time-PCR. Disease activity parameters of RA were measured by routine methods. Our results showed that VSTM1-v2 mRNA expression in PBMCs from RA patients was significantly increased in comparison of that in healthy individuals. The VSTM1-v2 mRNA expression level was positively correlated with IL-17A mRNA expression level, DAS28, CRP and ESR, but was not correlated to RF, Anti-CCP or ANA. VSTM1-v2 might be a biomarker of RA and a novel factor in the pathogenesis of RA.
Project description:The main cause of death in rheumatoid arthritis (RA) is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP) antibody levels with increased carotid intima-media thickness (cIMT) in RA patients.Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC) were studied. All groups were assessed for atherogenic index of plasma (AIP) and cIMT. Anti-CCP, C-reactive protein (CRP), and levels of tumor necrosis factor alpha (TNF?) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA).The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P < 0.001). Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNF? and IL-6 (P < 0.01), and lower levels of high density lipoprotein cholesterol (HDL-c) (P = 0.02). The cIMT correlated with levels of anti-CCP (r = 0.513, P = 0.001), CRP (r = 0.799, P < 0.001), TNF? (r = 0.642, P = 0.001), and IL-6 (r = 0.751, P < 0.001). In multiple regression analysis, cIMT was associated with CRP (P < 0.001) and anti-CCP levels (P = 0.03).Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events.