Brief Report: Anti–Carbamylated Protein Antibodies Are Present in Arthralgia Patients and Predict the Development of Rheumatoid Arthritis

Objective

Recently, we discovered a new autoantibody system in rheumatoid arthritis (RA): anti–carbamylated protein (anti‐CarP) antibodies. These antibodies have value in predicting joint destruction; however, it is not clear whether they are present before the diagnosis of RA and whether they have value as predictors of RA development. Therefore, we studied whether anti‐CarP antibodies are present in patients with arthralgia and whether their presence is associated with the development of RA.

Methods

Sera from 340 arthralgia patients who did not have clinical signs of arthritis but who were positive for IgM rheumatoid factor (IgM‐RF) and/or anti–cyclic citrullinated peptide 2 (anti–CCP‐2) and 32 healthy controls were tested for anti‐CarP IgG antibodies. Of the patients with arthralgia, 111 were IgM‐RF positive/anti–CCP‐2 antibody negative and 229 were anti–CCP‐2 antibody positive. Patients were observed for the development of RA (based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria) during a median followup period of 36 months. Cox proportional hazards regression analysis was performed to compare the risk of developing RA between arthralgia patients who were positive for anti‐CarP antibodies and those who were negative for anti‐CarP antibodies during followup.

Results

Anti‐CarP antibodies were present in the sera of 39% of the patients. One hundred twenty patients developed RA, after a median of 12 months (interquartile range [IQR] 6–24). The presence of anti‐CarP antibodies was associated with the development of RA in the entire arthralgia cohort after correction for RF and anti–CCP‐2 antibody status (hazard ratio 1.56 [95% confidence interval 1.06–2.29], P = 0.023), as well as in the anti–CCP‐2 antibody–positive subgroup (odds ratio 2.231 [95% confidence interval 1.31–3.79], P = 0.003).

Conclusion

Anti‐CarP antibodies are present in patients with arthralgia, and their presence predicts the development of RA independent of anti–CCP‐2 antibodies.

     

Association between positivity of serum autoantibodies and liver disease severity in patients with biopsy-proven NAFLD

Background and aimsSome previous studies reported serum autoantibody positivity in patients with nonalcoholic fatty liver disease (NAFLD). The clinical significance of these findings remains uncertain. We aimed to investigate the association between the presence of serum autoantibodies and liver disease severity in NAFLD.Methods and resultsA total of 388 consecutive patients with biopsy-proven NAFLD were included in the study. Various serum autoantibodies (including also anti-nuclear antibodies [ANA]) were detected by indirect immunofluorescent or immunoblotting assays. Overall, 84 (21.6%) patients with biopsy-confirmed NAFLD had positivity for at least one of the measured serum autoantibodies. ANA positivity was present in 50 (12.9%) patients, whereas anti-U1RNP or pANCA antibodies were detectable in 9 (2.3%) and 6 (1.5%) patients, respectively. Multivariate logistic regression analysis showed that ANA positivity (adjusted-odds ratio: 4.51, 95%CI: 1.77–11.5; P = 0.002) or positivity of any serum autoantibodies (adjusted-odds ratio: 3.14, 95%CI: 1.30–7.62; P = 0.01) were independently associated with advanced liver fibrosis (stages F3–F4). In serum autoantibody/ANA-positive patients, the proportion of those with advanced fibrosis was also greater among carriers of PNPLA3 rs738409 GG or CG than among those carrying PNPLA3 rs738409 CC genotype.ConclusionsSerum autoantibody positivity was independently associated with advanced liver fibrosis in patients with biopsy-proven NAFLD. The presence of serum autoantibodies in patients with advanced fibrosis occurred more frequently amongst those carrying PNPLA3 rs738409 GG or CG genotypes.     

Serum antibodies to periodontal pathogens prior to rheumatoid arthritis diagnosis: A case-control study

Objectives1) To quantify the association between anti-Porphyromonas gingivalis serum antibody concentrations and the risk of developing rheumatoid arthritis (RA), and 2) to quantify the associations among RA cases between anti-P. gingivalis serum antibody concentrations and RA-specific autoantibodies. Additional anti-bacterial antibodies evaluated included anti-Fusobacterium nucleatum and anti-Prevotella intermedia.MethodsSerum samples were acquired pre- and post- RA diagnosis from the U.S. Department of Defense Serum Repository (n = 214 cases, 210 matched controls). Using separate mixed-models, the timing of elevations of anti-P. gingivalis, anti-P. intermedia, and anti-F. nucleatum antibody concentrations relative to RA diagnosis were compared in RA cases versus controls. Associations were determined between serum anti-CCP2, ACPA fine specificities (vimentin, histone, and alpha-enolase), and IgA, IgG, and IgM RF in pre-RA diagnosis samples and anti-bacterial antibodies using mixed-effects linear regression models.ResultsNo compelling evidence of case-control divergence in serum anti-P. gingivalis, anti-F. nucleatum, and anti-P. intermedia was observed. Among RA cases, including all pre-diagnosis serum samples, anti-P. intermedia was significantly positively associated with anti-CCP2, ACPA fine specificities targeting vimentin, histone, alpha-enolase, and IgA RF (p<0.001), IgG RF (p = 0.049), and IgM RF (p = 0.004), while anti-P. gingivalis and anti-F. nucleatum were not.ConclusionsNo longitudinal elevations of anti-bacterial serum antibody concentrations were observed in RA patients prior to RA diagnosis compared to controls. However, anti-P. intermedia displayed significant associations with RA autoantibody concentrations prior to RA diagnosis, suggesting a potential role of this organism in progression towards clinically-detectable RA.     

Glutamic acid decarboxylase (GAD) autoantibodies are additional predictive markers of Type 1 (insulin-dependent) diabetes mellitus in high risk individuals

Summary The prevalence of glutamic acid decarboxylase autoantibodies was determined with an immunotrapping enzyme activity assay in newly-diagnosed Type 1 (insulin-dependent) diabetic patients as well as in first-degree relatives using rat brain homogenate as a source of glutamate decarboxylase. Twenty-six out of 86 islet-cell cytoplasmic autoantibody positive and one out of 24 islet cell autoantibody negative patients of recent onset, had autoantibodies to glutamate decarboxylase above the upper 99% confidence limit obtained from 89 control sera. Among 27 islet cell autoantibody positive relatives including 19 siblings and 8 parents, antibodies to glutamate decarboxylase were found in 8 of 9 (89%) relatives and 7 of 8 (87.5%) siblings with islet cell autoantibody titres above 20 JDF units, in 1 of 19 (5.2%) relatives with islet cell autoantibody titres between 2 and 5 JDF units, in 2 of 263 (0.7%) siblings and 1 of 139 parents without islet cell autoantibodies. In first-degree relatives, high titre islet cell autoantibodies and autoantibodies to glutamate decarboxylase were tightly associated (X²=182, p=0.0001). None of the relatives with low genetic risk (n=64), i.e. HLA-different to the diabetic proband, was found to be antibody positive. Antibodies to glutamate decarboxylase were present only in those relatives sharing at least one haplotype with the diabetic proband, including two islet cell autoantibody negative but HLA-identical siblings. Autoantibodies to glutamate decarboxylase were present in 7 of 9 (77%) relatives who developed the disease, including one islet cell autoantibody negative sibling. Altogether, the simultaneous presence of autoantibodies to glutamate decarboxylase and high titre islet cell autoantibody increases the positive predictive value for the disease from 66% to 75%. This study indicates therefore that autoantibodies to glutamate decarboxylase detected by an immunotrapping enzyme activity assay are additional predictive markers for future development of Type 1 diabetes and should be now prospectively studied in high risk individuals as well as other autoantibodies to Beta-cell autoantigens.     

Impact of Right Atrial Remodeling in Heart Failure With Preserved Ejection Fraction

BackgroundFew studies have investigated right atrial (RA) remodeling in heart failure (HF) with preserved ejection fraction (HFpEF). This study sought to characterize the RA remodeling in HFpEF and to determine its prognostic significance.Methods and ResultsPatients with HFpEF were classified based on the presence of RA enlargement (RA volume index >39 mL/m² in men and >33 mL/m² in women). Compared with patients with normal RA size (n = 234), patients with RA dilation (n = 67) showed a higher prevalence of atrial fibrillation (AF), worse right ventricular systolic function, more severe pulmonary hypertension, and a greater prevalence of mild tricuspid regurgitation, as well as impaired RA reservoir function, with increased hepatobiliary enzyme levels. AF was strongly associated with the presence of RA dilation (odds ratio [OR] 10.2, 95% confidence interval [CI] 4.00–26.1 in current AF vs no AF and odds ratio 3.38, 95% CI 1.26–9.07, earlier AF vs no AF). Patients with RA dilation had more than a two-fold increased risk of composite outcomes of all-cause mortality or HF hospitalization (adjusted hazard ratio 2.01, 95% CI 1.09–3.70, P = .02). The presence of RA dilation also displayed an additive prognostic value over left atrial dilation alone.ConclusionsThese data demonstrate that HFpEF with RA remodeling is associated with distinct echocardiographic features characterizing advanced right heart dysfunction with an increased risk of adverse outcomes.     

Associations of autoantibodies,autoimmune risk alleles,and clinical diagnoses from the electronic medical records in rheumatoid arthritis cases and non–rheumatoid arthritis controls

Objective

The significance of non–rheumatoid arthritis (RA) autoantibodies in patients with RA is unclear. The aim of this study was to assess associations of autoantibodies with autoimmune risk alleles and with clinical diagnoses from the electronic medical records (EMRs) among RA cases and non‐RA controls.

Methods

Data on 1,290 RA cases and 1,236 non‐RA controls of European genetic ancestry were obtained from the EMRs of 2 large academic centers. The levels of anti–citrullinated protein antibodies (ACPAs), antinuclear antibodies (ANAs), anti–tissue transglutaminase antibodies (AGTAs), and anti–thyroid peroxidase (anti‐TPO) antibodies were measured. All subjects were genotyped for autoimmune risk alleles, and the association between number of autoimmune risk alleles present and number of types of autoantibodies present was studied. A phenome‐wide association study (PheWAS) was conducted to study potential associations between autoantibodies and clinical diagnoses among RA cases and non‐RA controls.

Results

The mean ages were 60.7 years in RA cases and 64.6 years in non‐RA controls. The proportion of female subjects was 79% in each group. The prevalence of ACPAs and ANAs was higher in RA cases compared to controls (each P < 0.0001); there were no differences in the prevalence of anti‐TPO antibodies and AGTAs. Carriage of higher numbers of autoimmune risk alleles was associated with increasing numbers of autoantibody types in RA cases (P = 2.1 × 10⁻⁵) and non‐RA controls (P = 5.0 × 10⁻³). From the PheWAS, the presence of ANAs was significantly associated with a diagnosis of Sjögren's/sicca syndrome in RA cases.

Conclusion

The increased frequency of autoantibodies in RA cases and non‐RA controls was associated with the number of autoimmune risk alleles carried by an individual. PheWAS of EMR data, with linkage to laboratory data obtained from blood samples, provide a novel method to test for the clinical significance of biomarkers in disease.

     

Factors Associated with Pneumocystis jirovecii Pneumonia in Patients with Rheumatoid Arthritis Receiving Methotrexate: A Single-center Retrospective Study

Objective To investigate the risk factors for the development of Pneumocystis jirovecii pneumonia (PCP) in patients with rheumatoid arthritis (RA) undergoing methotrexate (MTX) therapy. Methods This single-center retrospective cohort study included consecutive patients with RA who received MTX for at least one year. The study population was divided into PCP and non-PCP groups, depending on the development of PCP, and their characteristics were compared. We excluded patients who received biologic disease-modifying anti-rheumatic drugs (DMARDs), Janus kinase inhibitors, and anti-PCP drugs for prophylaxis. Results Thirteen patients developed PCP, and 333 did not develop PCP. At the initiation of MTX therapy, the PCP group had lower serum albumin levels, a higher frequency of pulmonary disease and administration of DMARDs, and received a higher dosage of prednisolone (PSL) than the non-PCP group. A multivariate Cox regression analysis revealed that the concomitant use of PSL [hazard ratio (HR) 5.50, p=0.003], other DMARDs (HR 5.98, p=0.002), and serum albumin <3.5 mg/dL (HR 4.30, p=0.01) were risk factors for the development of PCP during MTX therapy. Patients with these risk factors had a significantly higher cumulative probability of developing PCP than patients who lacked these risk factors. Conclusion Clinicians should pay close attention to patients with RA who possess risk factors for the development of PCP during MTX therapy.     

Interleukin-13 in autoimmune rheumatic diseases: relationship with the autoantibody profile

OBJECTIVE: Several cytokines play a role in the production of autoantibodies such as RF and ANA by B-lymphocytes; the role of IL-13 in this process has not been previously studied. We investigated the relationship between the serum concentration of this cytokine and circulating autoantibodies. METHODS: IL-13 serum levels, as well as RF and ANA, were evaluated in 282 patients with autoimmune rheumatic diseases including RA (n=84), SLE (n= 114), SS (n=52) and Scl (n=32). RESULTS: Serum levels of IL-13 (pg/ml) were significantly higher in patients with RA (p < 0.00003), SLE (p < 0.03), SS (p < 0.0007), or Scl (p < 0.025) compared to controls. IL-13 serum levels correlated with those of RF in RA (p < 0.00001), SLE (p < 0.003) and Scl (p < 0.03). IL-13 levels were higher in RA (p<0.0003), SLE (p<0.005) and Scl (p<0.05) patients with RF than in patients without RF. SS patients with antiSSA/Ro antibodies had significantly higher IL-13 levels than SS patients without this autoantibody (p < 0.04). No statistically significant correlation was found between IL-13 levels and any other antinuclear autoantibody, total immunoglobulin levels or the main clinicalfeatures of each disease. CONCLUSION: The evidence of higher IL-13 levels in our RA, SLE, SS and Scl patients confirms that this cytokine is involved in the pathogenesis of autoimmune rheumatic diseases. The relationship of this cytokine with RF in RA, SLE and Scl, as well as with antiSSA/ Ro antibody in SS, strengthens the hypothesis that it plays a role in autoantibody production. However, the different autoantibody synthesis by B-cells recognises different pathways depending on the underlying autoimmune disease.     

Serum interleukin-6 and survivin levels predict clinical response to etanercept treatment in patients with established rheumatoid arthritis

Objectives: To investigate the correlation of nine potential biomarkers with clinical response to etanercept (ETN) therapy in establish rheumatoid arthritis (RA) patients.

Methods: Seventy-three patients with established RA were enrolled in the prospective cohort study. Sixty-nine of 73 cases were included into final analysis for response after 24-week ETN therapy. Serum expression of nine studied proteins was measured by enzyme-linked immunosorbent assay (ELISA). Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17A, IL-21, IL-34, RANKL, survivin, and COMP were selected as candidate biomarkers.

Results: Serum IL-6 level was increased in responders than in nonresponders at baseline, p?=?.034; to the contrary, serum survivin level was decreased in responders, p?=?.009. Receiver operating characteristic (ROC) curve illuminated the combination of IL-6 and survivin expressions could predict clinical response with a high AUC 0.875, 95% CI: 0.771–0.976. Furthermore, we found the combination of IL-6 high expression and survivin low expression increased the responding possibility to nearly 20-fold (OR 19.687, 95% CI: 4.087–94.839, p?<?.001) compared to IL-6 low or survivin high expression by univariate analysis. However, only survivin low expression (p?=?.002) and CRP (p?=?.014) high expression were independent predictive factors for achieving clinical response, while IL-6 lack independent predictive value (p?=?.267).

Conclusions: Comprehensive measurement of IL-6 and survivin in serum could be served as a convincing biomarker for clinical response in ETN-treated patients with established RA.     

Study of PTPN22 1858C/T polymorphism in rheumatoid arthritis patients from Western India

BackgroundRheumatoid arthritis (RA) is an inflammatory autoimmune disorder with etiologies including genetic and environmental factors. Protein tyrosine phosphatase non-receptor type22 (PTPN22) 1858C/T polymorphism is widely suspected to be a susceptibility gene for RA in the non-HLA genes group.AimThis study aimed at determining whether PTPN22 1858C/T polymorphism is associated with RA patients from Western India and to evaluate its possible association with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies.MethodsA total of 130 Indian RA patients and 100 age and sex matched normal controls were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP) for the PTPN22 1858C/T polymorphism.ResultsRF positivity was seen among 73.8% RA patients studied and the overall incidence of anti-CCP antibodies was 86.2%. The homozygous genotype (T/T) was absent in both groups. Among RF positives, C/C homozygosity was 90.6% whereas 9.4% patients were C/T heterozygous. Among anti-CCP positives, 89.1% had C/C genotype while the remaining 10.9% have the C/T genotype. Statistically significant association was obtained between the polymorphism and anti-CCP positivity in RA patients (OR: 2.939, ‘p’ value = 0.0595).ConclusionOur study suggested that a positive autoantibody status may predispose an individual to RA. PTPN22 may act as a susceptibility gene only in certain ethnic groups and there is no direct association between PTPN22 C1858 polymorphism and RA patients from Western India. Still a larger study is needed to understand whether this polymorphism predisposes individual to disease-associated antibodies among Indian RA patients.     

Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: A European retrospective multicohort analysis

ObjectivesTo evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients.MethodsThe study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme‐linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data.ResultsADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2–20.2) and 0% (0–5.9) at 3 months, 17.6% (11.4–26.4) and 0% (0–25.9) at 6 months, 17.7% (12.6–37.5) and 34.1% (11.4–46.3) at 12 months, 50.0% (25.9–87.5) and 37.5% (25.9–77.4) at 15 months and 50.0% (25.9–87.5) and 66.7% (37.7–100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1–3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0–8.7; infliximab: HR 2.7, 95% CI 1.1–6.8), moderate disease activity (DAS28 3.2–5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3–33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2–6.3).ConclusionsThe current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.     

Anti-TNFα treatment decreases the previously increased serum Indian Hedgehog levels in patients with ankylosing spondylitis and affects the expression of functional Hedgehog pathway target genes

ObjectiveIndian Hedgehog (Ihh) is the ligand that activates the Hedgehog pathway (HH) in the skeleton—the main controller of endochondral ossification. We aimed at assessing serum levels of Ihh in patients with ankylosing spondylitis (AS) and the effect of serum from patients with AS on HH pathway activation.MethodsSerum Ihh levels were measured in 59 patients with AS, 70 patients with rheumatoid arthritis (RA), and 53 healthy subjects. The effect of serum from patients with AS on HH pathway activation was evaluated using an osteoblast-like cell line model.ResultsPatients with AS not on anti-TNFα treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFα treatment (mean ± SEM of OD: 0.370 ± 0.025 vs. 0.279 ± 0.026 for patients with AS and RA, respectively, p = 0.027) and healthy subjects (p = 0.031). Patients with AS on anti-TNFα treatment had significantly lower Ihh levels compared to patients with AS not on such treatment (p = 0.028). Patients with RA on anti-TNF treatment had higher levels of Ihh compared to patients not on such treatment (p = 0.013). PTHrP levels were similar in patients with RA, AS, and healthy subjects and were not affected by anti-TNFα treatment. We next assessed HH pathway activation in Saos2 cells following incubation with serum from AS patients prior to and following anti-TNF treatment. The HH pathway was downregulated following treatment.ConclusionsIhh levels are increased in patients with AS and decrease following anti-TNFα treatment; this finding may have pathogenic and clinical implications.     

Dipeptidyl peptidase-4 inhibitors and risk of arthralgia: A systematic review and meta-analysis

BackgroundThe US Food and Drug Administration has warned that treatment with dipeptidyl peptidase (DPP)-4 inhibitors may promote serious arthralgia. However, the clinical evidence for this is relatively lacking.ObjectiveFor this reason, a systematic review and meta-analysis of randomized controlled trials (RCTs) were carried out to determine the relationship between DPP-4 inhibitors and risk of arthralgia, and also to investigate any potential risk factors.MethodsAn extensive electronic search for RCTs comparing DPP-4 inhibitors with any comparators was performed up to July 2016. Outcomes of interest were overall and serious arthralgia. Summary risk ratios (RRs) with 95% confidence intervals (CIs) were calculated.ResultsA total of 67 RCTs (involving 79,110 patients) was ultimately included. Pooled results showed that DPP-4 inhibitors were associated with a slightly but significantly increased risk of overall arthralgia (RR: 1.13, 95% CI: 1.04–1.22; P = 0.003) and a non-significant increased risk of serious arthralgia (RR: 1.44, 95% CI: 0.83–2.51; P = 0.20). Also, subgroup analyses showed that add-on/combination therapy and longer diabetes duration (> 5 years) were possible factors associated with the increased risk of overall arthralgia.ConclusionThese findings suggest that DPP-4 inhibitors can increase the risk of arthralgia. Thus, the benefits of glycaemic control must be weighed against the risk of arthralgia when prescribing DPP-4 inhibitors. Further studies are now needed to identify and confirm these risk factors.     

Rheumatoid arthritis patients have higher prevalence and burden of asymptomatic coronary artery disease assessed by coronary computed tomography: A systematic literature review and meta-analysis

BackgroundRheumatoid arthritis (RA) is associated with increased risk of coronary artery disease (CAD) and studies with coronary computed tomography have suggested increased rates of asymptomatic CAD determined by the coronary calcium score (CCS) in these patients. To synthesize the evidence on this topic, we conducted a systematic review and meta-analysis of the literature.MethodsA systematic review was performed of data comparing the prevalence and burden of asymptomatic CAD in RA and controls using CCS with or without coronary computed tomographic angiography (CCTA). For the meta-analysis, pooled data provided the estimated risk ratio (RR) of CAD and weighted mean differences of CCS in patients with RA compared to controls.ResultsThe search revealed 1841 results of which 1083 were screened and 26 full text papers were evaluated. Eight studies were included with data on 788 patients with RA and 1641 controls. Patients with RA had significantly increased risk of CAD (RR = 1.26 [95% CI 1.04–1.52]; p = .021) and increased weighted mean differences for CCS (48.25 [95% CI 26.97–69.53]; p < .001) compared to controls. Limited evidence suggested that patients with RA had a higher prevalence of moderate-severe (CCS > 100) CAD and more multivessel CAD, and RA duration and disease activity were associated with higher CCS, RA disease activity was linked with presence of high risk (non-calcified or mixed) coronary plaques, and treatment with methotrexate was tied to absence of CAD, respectively.ConclusionsIn patients with RA, asymptomatic CAD is more prevalent, with higher mean CCS, more multivessel disease, and more high-risk plaques compared to controls.     

A Pilot Study on the Role of Autoantibody Targeting the β1-Adrenergic Receptor in the Response to β-blocker Therapy for Congestive Heart Failure

BackgroundAutoantibodies directed against the β1-adrenergic receptor exert agonistlike actions by inducing receptor uncoupling and cause myocardial damage as well as fatal ventricular arrhythmias. Previous studies have shown that β-blockers can modulate these actions of the autoantibodies. We investigated the influence of such autoantibodies in patients with congestive heart failure (CHF) receiving β-blocker therapy.Methods and ResultsEighty-two CHF patients were randomly assigned to treatment with metoprolol or carvedilol for 16 weeks. Autoantibodies were detected in 20 patients (24%) by enzyme-linked immunosorbent assay. Left ventricular function in response to β-blocker therapy did not differ significantly by the presence of the autoantibody in global analysis. However, changes of the left ventricular end-diastolic dimension (P = .04), end-systolic dimension (P < .01), and ejection fraction on radionuclide ventriculography (P = .02) were significantly larger in autoantibody-positive patients than antibody-negative patients. Changes in the plasma level of brain natriuretic peptide tended to be larger in autoantibody-positive patients (P = .09). The increase of heart rate normalized by the increase of plasma norepinephrine during exercise (an index of adrenergic responsiveness) showed a greater decrease in autoantibody-positive patients than autoantibody-negative patients (P = .035).ConclusionOur data suggest that β-blocker therapy might be more effective in CHF patients with autoantibodies targeting the β1-adrenergic receptor.     

Gene expression profiling in autoantibody‐positive patients with arthralgia predicts development of arthritis

Objective

To identify molecular features associated with the development of rheumatoid arthritis (RA), to understand the pathophysiology of preclinical development of RA, and to assign predictive biomarkers.

Methods

The study group comprised 109 anti–citrullinated protein antibody (ACPA)– and/or rheumatoid factor–positive patients with arthralgia who did not have arthritis but were at risk of RA, and 25 patients with RA. The gene expression profiles of blood samples obtained from these patients were determined by DNA microarray analysis and quantitative polymerase chain reaction.

Results

In 20 of the 109 patients with arthralgia who were at risk of RA, arthritis developed after a median of 7 months. Gene expression profiling of blood cells revealed heterogeneity among the at‐risk patients, based on differential expression of immune‐related genes. This report is the first to describe gene signatures relevant to the development of arthritis. Signatures significantly associated with arthritis development were involved in interferon (IFN)–mediated immunity, hematopoiesis, and chemokine/cytokine activity. Logistic regression analysis revealed that the odds ratio (OR) for developing arthritis within 12 months was 21.0 (95% confidence interval [95% CI] 2.8–156.1 [P = 0.003]) for the subgroup characterized by increased expression of genes involved in IFN‐mediated immunity and/or cytokine/chemokine‐activity. Genes involved in B cell immunology were associated with protection against progression to arthritis (OR 0.38, 95% CI 0.21–0.70 [P = 0.002]). These processes were reminiscent of those in patients with RA, implying that the preclinical phase of disease is associated with features of established disease.

Conclusion

The results of this study indicate that IFN‐mediated immunity, hematopoiesis, and cell trafficking specify processes relevant to the progression of arthritis independent of ACPA positivity. These findings strongly suggest that certain gene signatures have value for predicting the progression to arthritis, which will pave the way to preventive medicine.

     

Cardiovascular morbidity and associated risk factors in Spanish patients with chronic inflammatory rheumatic diseases attending rheumatology clinics: Baseline data of the CARMA Project

ObjectiveTo establish the cardiovascular (CV) morbidity and associated risk factors for CV disease (CVD) in Spanish patients with chronic inflammatory rheumatic diseases (CIRD) and unexposed individuals attending rheumatology clinics.MethodsAnalysis of data from the baseline visit of a 10-year prospective study [CARdiovascular in rheuMAtology (CARMA) project] that includes a cohort of patients with CIRD [rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA)] and another cohort of matched individuals without CIRD attending outpatient rheumatology clinics from 67 hospitals in Spain. Prevalence of CV morbidity, CV risk factors, and systematic coronary risk evaluation (SCORE) assessment were analyzed.ResultsA total of 2234 patients (775 RA, 738 AS, and 721 PsA) and 677 unexposed subjects were included. Patients had low disease activity at the time of recruitment. PsA patients had more commonly classic CV risk factors and metabolic syndrome features than did the remaining individuals. The prevalence of CVD was higher in RA (10.5%) than in AS (7.6%), PsA (7.2%), and unexposed individuals (6.4%). A multivariate analysis adjusted for the presence of classic CV risk factors and disease duration revealed a positive trend for CVD in RA (OR = 1.58; 95% CI: 0.90–2.76; p = 0.10) and AS (OR = 1.77; 95% CI: 0.96–3.27; p = 0.07). Disease duration in all CIRD groups and functional capacity (HAQ) in RA were associated with an increased risk of CVD (OR = 2.15; 95% CI: 1.29–3.56; p = 0.003). Most patients had a moderate CV risk according to the SCORE charts.ConclusionsDespite recent advances in the management of CIRD, incidence of CVD remains increased in Spanish subjects with CIRD attending outpatient rheumatology clinics.     

Association between protein tyrosine phosphatase 22 variant R620W in conjunction with the HLA–DRB1 shared epitope and humoral autoimmunity to an immunodominant epitope of cartilage‐specific type II collagen in early rheumatoid arthritis

Objective

To analyze the genetic impact of allelic variants of the protein tyrosine phosphatase N22 (PTPN22) and HLA–DRB1 alleles on IgG autoantibody formation directed toward an immunodominant conformational epitope (C1^III; amino acid residues 359–369) of type II collagen (CII) in early rheumatoid arthritis (RA).

Methods

Sera obtained at study inclusion from an inception cohort of RA patients (n = 221; mean symptom duration 6 months) were analyzed for circulating anti–C1^III IgG autoantibodies. An enzyme‐linked immunosorbent assay based on solid‐phase–coupled synthetic triple‐helical collagen peptides was used to quantify humoral autoimmune responses. HLA–DRB1 genotypes were determined by allele‐specific polymerase chain reaction amplification of genomic DNA and sequence‐specific hybridization. PTPN22*620W genotyping was performed using an allelic discrimination TaqMan assay.

Results

Anti–C1^III IgG autoantibody titers were significantly elevated in patients with early RA as compared with those in healthy controls (n = 70). The increased titers were more pronounced in RA patients harboring alleles of the RA‐associated HLA–DRB1 shared epitope (SE) consensus sequence than in those lacking the SE. In addition, the PTPN22*620W variant was strongly associated with a vigorous humoral autoimmune response to the cartilage‐specific CII determinant C1^III.

Conclusion

Allelic variants encoding the binding pocket for peptide presentation (SE) to T cells and a functional domain of a negative regulator of T cell receptor signaling (PTPN22*620W), respectively, synergize in early RA to break self tolerance toward C1^III, an evolutionarily conserved cartilage determinant that is also frequently targeted in arthritogenic humoral autoimmunity in mice.

     

Porphyromonas gingivalis and disease‐related autoantibodies in individuals at increased risk of rheumatoid arthritis

Objective

To examine the relationship of Porphyromonas gingivalis to the presence of autoantibodies in individuals at risk of rheumatoid arthritis (RA).

Methods

Study participants included the following: 1) a cohort enriched in subjects with HLA–DR4 and 2) subjects at risk of RA by virtue of having a first‐degree relative with RA. None of the study subjects satisfied the American College of Rheumatology 1987 classification criteria for RA. Autoantibodies measured included anti–citrullinated protein antibody (ACPA; by second‐generation anti–cyclic citrullinated peptide antibody enzyme‐linked immunosorbent assay [ELISA]) and rheumatoid factor (RF; by nephelometry or ELISA for IgA, IgM, or IgG isotype). Individuals were considered autoantibody positive (n = 113) if they had ≥1 RA‐related autoantibody; individuals were further categorized as high risk (n = 38) if they had ACPA or positive findings ≥2 assays for RF. Autoantibody‐negative individuals (n = 171) served as a comparator group. Antibody to P gingivalis, P intermedia, and F nucleatum were measured. Associations of bacterial antibodies with group status were examined using logistic regression.

Results

Anti–P gingivalis concentrations were higher in high‐risk (P = 0.011) and autoantibody positive group (P = 0.010) than in the autoantibody negative group. There were no group differences in anti–P intermedia or anti–F nucleatum concentrations. After multivariable adjustment, anti–P gingivalis concentrations (but not anti–P intermedia or anti–F nucleatum) were significantly associated with autoantibody‐positive and high‐risk status (P < 0.05).

Conclusion

Immunity to P gingivalis, but not P intermedia or F nucleatum, is significantly associated with the presence of RA‐related autoantibodies in individuals at risk of RA. These results support the hypothesis that infection with P gingivalis may play a central role in the early loss of tolerance to self antigens that occurs in the pathogenesis of RA.