Benjamin A Fisher

Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis

Summary:u2002 Rheumatoid arthritis (RA) is now clearly a true autoimmune disease with accumulating evidence of pathogenic disease‐specific autoimmunity to citrullinated proteins. Citrullination, also termed deimination, is a modification of arginine side chains catalyzed by peptidylarginine deiminase (PAD) enzymes. This post‐translational modification has the potential to alter the structure, antigenicity, and function of proteins. In RA, antibodies to cyclic citrullinated peptides are now well established for clinical diagnosis, though we argue that the identification of specific citrullinated antigens, as whole proteins, is necessary for exploring pathogenic mechanisms. Four citrullinated antigens, fibrinogen, vimentin, collagen type II, and α‐enolase, are now well established, with others awaiting further characterization. All four proteins are expressed in the joint, and there is evidence that antibodies to citrullinated fibrinogen and collagen type II mediate inflammation by the formation of immune complexes, both in humans and animal models. Antibodies to citrullinated proteins are associated with HLA ‘shared epitope’ alleles, and autoimmunity to at least one antigenic sequence, the CEP‐1 peptide from citrullinated α‐enolase (KIHAcitEIFDScitGNPTVE), shows a specific association with HLA‐DRB1*0401, *0404, 620W PTPN22, and smoking. Periodontitis, in which Porphyromonas gingivalis is a major pathogenic bacterium, has been linked to RA in epidemiological studies and also shares similar gene/environment associations. This is also the only bacterium identified that expresses endogenous citrullinated proteins and its own bacterial PAD enzyme, though the precise molecular mechanisms of bacterial citrullination have yet to be explored. Thus, both smoking and Porphyromonas gingivalis are attractive etiological agents for further investigation into the gene/environment/autoimmunity triad of RA.

Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis.

Gene-environment associations are important in rheumatoid arthritis (RA) susceptibility, with an association existing between smoking, HLA- DRB1 shared epitope alleles, PTPN22 and antibodies to cyclic citrullinated peptides(CCP). Here, we test the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated α-enolase, accounts for an important portion of these associations. In 1,497 individuals from three RA cohorts, antibodies to the immunodominant citrullinated α-enolase CEP-1 epitope were detected in 43–63% of the anti-CCP–positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 and smoking showed the strongest association with the anti-CEP-1–positive subset (odds ratio (OR) of 37, compared to an OR of 2 for the corresponding anti-CEP-1–negative, anti-CCP–positive subset). We conclude that citrullinated α-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of RA.

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

OBJECTIVEnTo map the antibody response to human citrullinated alpha-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross-reactivity with bacterial enolase.nnnMETHODSnSerum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated alpha-enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial enolase was investigated by immunoblotting.nnnRESULTSnAn immunodominant peptide, citrullinated alpha-enolase peptide 1, was identified. Antibodies to this epitope were observed in 37-62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated alpha-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2=0.803, P<0.0001). Affinity-purified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis enolase.nnnCONCLUSIONnWe have identified an immunodominant epitope in citrullinated alpha-enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.

Metabolic Profiling Predicts Response to Anti–Tumor Necrosis Factor α Therapy in Patients With Rheumatoid Arthritis

Objective Anti–tumor necrosis factor (anti-TNF) therapies are highly effective in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but a significant number of patients exhibit only a partial or no therapeutic response. Inflammation alters local and systemic metabolism, and TNF plays a role in this. We undertook this study to determine if the patients metabolic fingerprint prior to therapy could predict responses to anti-TNF agents. Methods Urine was collected from 16 RA patients and 20 PsA patients before and during therapy with infliximab or etanercept. Urine metabolic profiles were assessed using nuclear magnetic resonance spectroscopy. Discriminating metabolites were identified, and the relationship between metabolic profiles and clinical outcomes was assessed. Results Baseline urine metabolic profiles discriminated between RA patients who did or did not have a good response to anti-TNF therapy according to European League Against Rheumatism criteria, with a sensitivity of 88.9% and a specificity of 85.7%, with several metabolites contributing (in particular histamine, glutamine, xanthurenic acid, and ethanolamine). There was a correlation between baseline metabolic profiles and the magnitude of change in the Disease Activity Score in 28 joints from baseline to 12 months in RA patients (P = 0.04). In both RA and PsA, urinary metabolic profiles changed between baseline and 12 weeks of anti-TNF therapy. Within the responders, urinary metabolite changes distinguished between etanercept and infliximab treatment. Conclusion The clear relationship between urine metabolic profiles of RA patients at baseline and their response to anti-TNF therapy may allow development of novel approaches to the optimization of therapy. Differences in metabolic profiles during treatment with infliximab and etanercept in RA and PsA may reflect distinct mechanisms of action.

Gene-environment interaction influences the reactivity of autoantibodies to citrullinated antigens in rheumatoid arthritis

Gene-environment interaction influences the reactivity of autoantibodies to citrullinated antigens in rheumatoid arthritis

Antibodies to citrullinated α-enolase peptide 1 and clinical and radiological outcomes in rheumatoid arthritis

Introduction The anticyclic citrullinated peptide 2 (anti-CCP2) assay is a generic test for antibodies to citrullinated proteins, among which there is a subset of about 50% with antibodies to citrullinated enolase peptide 1 (CEP-1). The anti-CEP-1 positive subset is strongly associated with the HLA-DRB1 shared epitope and its interaction with smoking. Objective To investigate whether anti-CEP-1 antibodies may be helpful in predicting outcome. Methods Anti-CEP-1 and anti-CCP2 antibodies were measured in two prospective cohorts of patients (Karolinska n=272, Norfolk Arthritis Register (NOAR) n=408) with early rheumatoid arthritis (RA). Outcomes measured were C-reactive protein, erythrocyte sedimentation rate, visual analogue scales for pain and global assessment of disease activity, Health Assessment Questionnaire, physicians assessment, swollen and tender joint counts and radiological progression. Results Anti-CCP2 antibodies were present in 57% and 50%, and anti-CEP-1 in 27% and 24% of the Karolinska and NOAR cohorts, respectively. Importantly, no statistically significant differences in clinical outcomes were demonstrated between the anti-CEP-1−/CCP2+ and the anti-CEP-1+/CCP2+ subsets in either cohort, or in radiological outcomes in the Karolinska cohort. Conclusion Although antibodies to specific citrullinated proteins may have distinct genetic and environmental risk factors, the similarity in clinical phenotype suggests that they share common pathways in the pathogenesis of joint disease in RA.

Citrullination of autoantigens: Upstream of TNFα in the pathogenesis of rheumatoid arthritis

The discovery of autoimmunity to citrullinated protein/peptide antigens (ACPA) has led the concept that ACPA may be the essential link between disease susceptibility factors and the production of TNFα, which ultimately accounts for the disease phenotype. In this review we will consider (1) the mechanisms of citrullination, both physiological and pathological, (2) how known genetic and environmental factors could drive this peculiar form of autoimmunity and (3) how the immune response could lead to excessive production of TNFα by the synovial cells and ultimately to the disease phenotype (Fig. 1).

Quantitative power Doppler ultrasound measures of peripheral joint synovitis in poor prognosis early rheumatoid arthritis predict radiographic progression

OBJECTIVEnTo assess the value of quantitative vascular imaging by power Doppler US (PDUS) as a tool that can be used to stratify patient risk of joint damage in early seropositive RA while still biologic naive but on synthetic DMARD treatment.nnnMETHODSnEighty-five patients with seropositive RA of <3 years duration had clinical, laboratory and imaging assessments at 0 and 12 months. Imaging assessments consisted of radiographs of the hands and feet, two-dimensional (2D) high-frequency and PDUS imaging of 10 MCP joints that were scored for erosions and vascularity and three-dimensional (3D) PDUS of MCP joints and wrists that were scored for vascularity.nnnRESULTSnSevere deterioration on radiographs and ultrasonography was seen in 45 and 28% of patients, respectively. The 3D power Doppler volume and 2D vascularity scores were the most useful US predictors of deterioration. These variables were modelled in two equations that estimate structural damage over 12 months. The equations had a sensitivity of 63.2% and specificity of 80.9% for predicting radiographic structural damage and a sensitivity of 54.2% and specificity of 96.7% for predicting structural damage on ultrasonography.nnnCONCLUSIONnIn seropositive early RA, quantitative vascular imaging by PDUS has clinical utility in predicting which patients will derive benefit from early use of biologic therapy.

Prevalence of subjective voice impairment in rheumatoid arthritis.

Rheumatoid arthritis (RA) might lead to voice impairment through several mechanisms but its prevalence has been little investigated. RA patients attending a rheumatology outpatient clinic had joint assessments and completed the Voice Handicap Index-10 (VHI-10). A comparator group consisted of patients attending the department with other diseases. Seventy-three patients with RA and 73 comparators were recruited. Four patients with RA (5%) and one comparator (1%) had significantly abnormal VHI-10 scores. RA patients with a Disease Activity Score 28 >3.2, indicating more active disease, had significantly higher VHI-10 scores. A low prevalence of self-reported voice handicap occurs in RA and associates with more active disease.

Organ-specific autoantibodies but not anti-cyclic citrullinated peptides are a feature of autoimmunity in Down's syndrome

There is a well-recognised association of Downs syndrome with certain autoimmune diseases, in particular, thyroid autoimmunity, type 1 diabetes and coeliac disease. Recent publications have also reported an unexpectedly high prevalence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies.1 2 The recent identification of a potential susceptibility locus for rheumatoid arthritis (RA) at 21q22 in a genome-wide study3 further suggests the possibility of RA also being associated with trisomy 21.nnSera from 104 subjects with Downs syndrome, mean age 14.4 years (range 10–20), the Hester Adrian Research Centre population-based cohort, were obtained with informed consent and ethical …