Lillian Barra

Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian α‐enolase and arthritis in DR4‐IE–transgenic mice

OBJECTIVE To examine the hypothesis that the subset of rheumatoid arthritis (RA) characterized by antibodies to citrullinated α-enolase is mediated by Porphyromonas gingivalis enolase in the context of DR4 alleles. METHODS Recombinant human α-enolase and P gingivalis enolase, either citrullinated or uncitrullinated, were used to immunize DR4-IE-transgenic mice and control mice (class II major histocompatibility complex-deficient [class II MHC(-/-)] and C57BL/6 wild-type mice). Arthritis was quantified by measurement of ankle swelling in the hind paws and histologic examination. Serum IgG reactivity with α-enolase and citrullinated α-enolase was assayed by Western blotting and enzyme-linked immunosorbent assay (ELISA). Antibodies to peptide 1 of citrullinated α-enolase (CEP-1) and its arginine-bearing control peptide, REP-1, were also assessed by ELISA. RESULTS Significant hind-ankle swelling (≥0.3 mm) occurred in DR4-IE-transgenic mice immunized with citrullinated human α-enolase (9 of 12 mice), uncitrullinated human α-enolase (9 of 12 mice), citrullinated P gingivalis enolase (6 of 6 mice), and uncitrullinated P gingivalis enolase (6 of 6 mice). Swelling peaked on day 24. None of the control groups developed arthritis. The arthritic joints showed synovial hyperplasia and erosions, but there was a paucity of leukocyte infiltration. Antibodies to human α-enolase, both citrullinated and unmodified, and to CEP-1 and REP-1 were detectable in all immunized mice except the class II MHC(-/-) control mice. CONCLUSION This is the first animal model that links an immune response to P gingivalis enolase to an important subset of RA, defined by antibodies to citrullinated α-enolase in the context of DR4. The fact that arthritis and anti-CEP-1 antibodies were induced independent of citrullination of the immunizing antigen suggests that the unmodified form of α-enolase may be important in initiating the corresponding subset of human RA.

Antihomocitrullinated Fibrinogen Antibodies are Specific to Rheumatoid Arthritis and Frequently Bind Citrullinated Proteins/peptides

Objective. Anticitrullinated protein/peptide antibodies (ACPA) are implicated in rheumatoid arthritis (RA) pathogenesis and linked to the shared epitope (SE). Citrulline modification is very similar to a different modified amino acid, homocitrulline. We investigated antihomocitrullinated protein/ peptide antibody (AHCPA) specificity for RA, whether ACPA were also able to bind homocitrullinated targets, and whether the SE could accommodate homocitrullinated peptide. Methods. Homocitrullinated fibrinogen was used to screen sera from patients with RA, psoriatic arthritis, and systemic lupus erythematosus, and healthy subjects for AHCPA using ELISA. Homocitrullination sites on fibrinogen were identified by mass spectrometry. ACPA were affinity-purified using a synthetic citrullinated peptide and tested for binding to homocitrullinated protein/peptide. Inhibition of antihomocitrullinated fibrinogen antibody binding was examined. Homocitrullinated peptide interaction with the SE was studied using computer modeling. Results. IgG antihomocitrullinated fibrinogen antibodies were found specifically in 49% of patients with RA. Enrichment of ACPA by affinity purification from 5 patients with RA also enriched AHCPA. Serum AHCPA was inhibited by citrullinated fibrinogen and more significantly by homocitrullinated fibrinogen. Computer modeling indicated that the SE could accommodate a homocitrullinated peptide without steric hindrance. Mass spectrometry identified that 89/103 lysines of fibrinogen could be homocitrullinated, and 5 peptides that could be both citrullinated and homocitrullinated and are predicted to bind the SE. Conclusion. Antihomocitrullinated fibrinogen antibodies are specific to RA. The presence of AHCPA coincides with ACPA, and AHCPA copurifies with ACPA in affinity purification and is inhibited by citrullinated and homocitrullinated antigens. Thus AHCPA and ACPA are frequently cross-reactive and homocitrullinated proteins/peptides may bind the SE.

Anti-citrullinated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients.

OBJECTIVE First-degree relatives (FDRs) of rheumatoid arthritis (RA) patients sharing genetic and environmental risk factors for RA may represent a pre-RA state. Since anti-cyclic citrullinated protein/peptide antibodies (ACPAs) appear years before the onset of RA, the purpose of this study was to determine the prevalence of various ACPAs in FDRs of RA patients. METHODS We evaluated 88 RA patients, 50 unaffected FDRs, and 20 healthy control subjects. Six different types of ACPAs were determined by enzyme-linked immunosorbent assay. Joint and periodontal disease symptoms were self-reported. Patients and FDRs were HLA typed for the shared epitope (SE) and the RA-protective alleles HLA-DRB*1301/1302. RESULTS FDRs had a high prevalence of ACPAs (48%) as compared to controls (10%). Prevalence of the SE and smoking in FDRs was also high (62% and 49%, respectively). Of all of the ACPAs in the FDRs, 13 of 32 (41%) were of the IgA isotype. The most commonly expressed IgG ACPA targeted citrullinated vimentin, occurring in 20% of FDRs. The FDRs had an average of 1 type of ACPA, whereas the RA patients expressed a median of 5 different ACPAs. The only FDR to later develop RA expressed 4 different ACPAs. Joint and periodontal disease symptoms in the FDRs were significantly associated with smoking (OR 5.714 [95% confidence interval (95% CI) 1.151-28.3] and OR 12.25 [95% CI 2.544-58.99], respectively), but not with ACPAs. CONCLUSION The rate of ACPA positivity in unaffected FDRs of RA patients with a high prevalence of the SE and smoking was 48%, whereas ACPAs were rare in the healthy controls. ACPAs in the FDRs of RA patients was most commonly of the IgA isotype, but IgG ACPA targeting citrullinated vimentin was also frequently found.

Lack of seroconversion of rheumatoid factor and anti-cyclic citrullinated peptide in patients with early inflammatory arthritis: a systematic literature review

OBJECTIVE Serological markers are thought to be useful in predicting which patients with early inflammatory arthritis (EIA) will progress to RA. The objective of this study is to determine the per cent RF and anti-CCP seroconversion in EIA patients at 1-5 years of follow-up: 80% of established RA is RF or CCP positive. METHODS We conducted a systematic literature review of all English publications and recent abstracts from ACR and EULAR. Patients ≥16 years of age with at least one swollen joint and symptoms < 2 years were included. RESULTS Twelve publications met the criteria: 10 studies included data on RF, while only 5 addressed anti-CCP. Sample sizes ranged from 15 to 395 and follow-up was 6-60 months. There was marked heterogeneity between studies; therefore, results could not be pooled for a meta-analysis. Baseline RF and anti-CCP positivity was also highly variable: 8-55 and 4-45%, respectively. Seroconversion rates for EIA were 1.9-5.0% at up to 30 months follow-up for RF and 1.3-8.9% at up to 60 months follow-up for anti-CCP. CONCLUSION There is minimal change in RF or anti-CCP positivity up to 5 years of follow-up. Prevalence data for RF in established RA is significantly higher than the baseline values reported here. The low rates of seroconversion would suggest a lower prevalence in EIA and the reason for this difference remains unknown. It is unclear whether antibody-negative patients are more likely to remit and be lost to follow-up in established RA populations.

Real-world anti-tumor necrosis factor treatment in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: cost-effectiveness based on number needed to treat to improve health assessment questionnaire

Objective. To determine the effectiveness and cost-effectiveness of anti-tumor necrosis factor (anti-TNF) medications in a real-world environment for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) using the Health Assessment Questionnaire (HAQ). Methods. We created a database of patients with RA, PsA, or AS treated with anti-TNF agents (etanercept, infliximab, or adalimumab) at a large outpatient rheumatology clinic. Patient characteristics, baseline HAQ prior to treatment, subsequent yearly HAQ, and reasons for termination were collected. The cost based on percentage of patients achieving ≥ 0.2 improvement in HAQ (minimal clinically important difference, MCID) was calculated using the 2008 direct cost (Cdn) of the medication. Results. Data were available on 297 patients (206 with RA, 57 PsA, 34 AS). The mean age was 55 years, with 12 years of disease, and the mean baseline HAQ (standard error, SE) was 1.37 (0.04). The changes in HAQ (SE) at Years 1, 2, and 3 were −0.31 (0.04), −0.24 (0.06), and −0.27 (0.07) for annual cost to achieve MCID of

Vasculitis in patients with inflammatory bowel diseases: A study of 32 patients and systematic review of the literature

41,636,

Prognosis of Seronegative Patients in a Large Prospective Cohort of Patients with Early Inflammatory Arthritis

42,077, and

Anticitrullinated protein antibodies and rheumatoid factor fluctuate in early inflammatory arthritis and do not predict clinical outcomes.

42,147, respectively. The number needed to treat (NNT) was 1.94 (RA), 1.88 (PsA), and 2.30 (AS). There were no statistical differences between the diseases studied. Conclusion. We obtained data on the effectiveness and cost-effectiveness of anti-TNF drugs using the HAQ score, which is known to be an excellent predictor of work disability, morbidity, and mortality. HAQ scores decreased with treatment and were sustained throughout the 3–5 years of followup. The NNT of approximately 2 seems favorable and was similar between diseases.

CanVasc Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitides

BACKGROUND Published small case series suggest that inflammatory bowel disease [IBD; Crohns disease (CD) or ulcerative colitis (UC)] and vasculitis co-occur more frequently than would be expected by chance. OBJECTIVES To describe this association by an analysis of a large cohort of carefully studied patients and through a systematic literature review. METHODS Patients with both IBD and vasculitis enrolled in the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Studies, followed in Canadian Vasculitis research network (CanVasc) centers and/or in the University of Torontos IBD clinic were included in this case series. A systematic literature review of patients with IBD and vasculitis involved a PubMed search through February 2014. The main characteristics of patients with Takayasu arteritis (TAK) and IBD were compared to those in patients with TAK without IBD followed in the VCRC. RESULTS The study identified 32 patients with IBD and vasculitis: 13 with large-vessel vasculitis [LVV; 12 with TAK, 1 with giant cell arteritis (GCA); 8 with CD, 5 with UC]; 8 with ANCA-associated vasculitis [AAV; 6 granulomatosis with polyangiitis (GPA), 2 with eosinophilic granulomatosis with polyangiitis (EGPA)]; 5 with isolated cutaneous vasculitis; and 6 with other vasculitides. Patients with LVV and AAV were mostly female (18/21). The diagnosis of IBD preceded that of vasculitis in 12/13 patients with LVV and 8/8 patients with AAV. The review of the literature identified 306 patients with IBD and vasculitis: 144 with LVV (133 TAK; 87 with IBD preceding LVV), 19 with AAV [14 GPA, 1 EGPA, 4 microscopic polyangiitis (MPA)], 66 with isolated cutaneous vasculitis, and 77 with other vasculitides. Patients with IBD and TAK were younger and had more frequent headaches, constitutional symptoms, or gastrointestinal symptoms compared to those patients in the VCRC who had TAK without IBD. CONCLUSIONS These findings highlight the risk of vasculitis, especially TAK, in patients with IBD (both CD and UC).

Imaging modalities for the diagnosis and disease activity assessment of Takayasu's arteritis: A systematic review and meta-analysis

Objective. Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are believed to be associated with more severe rheumatoid arthritis; however, studies in early inflammatory arthritis (EIA) have yielded conflicting results. Our study determined the prognosis of baseline ACPA-negative and RF-negative patients. Methods. Patients enrolled in the Canadian Early Arthritis Cohort had IgM RF and IgG anticyclic citrullinated peptide antibodies 2 (anti-CCP2) measured at baseline. Remission was defined as a Disease Activity Score of 28 joints (DAS28) < 2.6 using logistic regression accounting for confounders at 12-month and 24-month followup. Results. Of the 841 patients, 216 (26%) were negative for both RF and anti-CCP2. Compared to seropositive subjects, seronegative subjects were older (57 ± 15 vs 51 ± 14 yrs), more males proportionately (31% vs 23%), and had shorter length of symptoms (166 ± 87 vs 192 ± 98 days), and at baseline had higher mean swollen joint count (SJC; 8.8 ± 6.8 vs 6.5 ± 5.6), DAS28 (5.0 ± 1.6 vs 4.8 ± 1.5), and erosive disease (32% vs 24%, p < 0.05). Treatment was similar between the 2 groups. At 24-month followup, seronegative compared to seropositive subjects had greater mean change (Δ ± SD) in disease activity measures: ΔSJC counts (−6.9 ± 7.0 vs −5.1 ± 5.9), ΔDAS28 (−2.4 ± 2.0 vs −1.8 ± 1.8), and ΔC-reactive protein (−11.0 ± 17.9 vs −6.4 ± 17.5, p < 0.05). Accounting for confounders, antibody status was not significantly associated with remission. However, at 12-month followup, ACPA-positive subjects were independently more likely to have new erosive disease (OR 2.94, 95% CI 1.45–5.94). Conclusion. Although seronegative subjects with EIA have higher baseline DAS28 compared to seropositive subjects, they have a good response to treatment and are less likely to develop erosive disease during followup.