Elizabeth Perry

Bronchiectasis Is a Model for Chronic Bacterial Infection Inducing Autoimmunity in Rheumatoid Arthritis

To examine the potential of chronic severe bacterial infection to generate rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPAs), by studying patients with bronchiectasis (BR) alone and BR patients with rheumatoid arthritis (BR/RA).

RA autoantibodies as predictors of rheumatoid arthritis in non-cystic fibrosis bronchiectasis patients

To the Editor: The mechanisms underlying the strong association between rheumatoid arthritis (RA) and bronchiectasis were recently reviewed [1]. A literature review highlighted 289 reports of bronchiectasis associated with RA, with the respiratory symptoms preceding joint symptoms in 90% of the reports [2], strongly suggesting that the processes in bronchiectasis predispose to RA. Rheumatoid factor (RF) and anti-cyclic citrullinated antibody (anti-CCP) are integral in the initiation of RA. A Danish study (n=9712) observed that the baseline IgM RF was predictive of a significant, six-fold increased risk of RA development if the RF was two- to four-fold above the normal range [3]. Likewise, a strongly positive anti-CCP test significantly increases the risk of RA (OR 25) [4]. Two studies have investigated RF in bronchiectasis [5, 6] with no studies to date investigating anti-CCP. In our BRAC RA (Bronchiectasis, Asthma, Control, Rheumatoid Arthritis) study, a prospective, multicentre, case–control, observational study was conducted to determine the relationship between bronchiectasis and RF and anti-CCP. Recruitment was completed over 12 months using identical methodology and reviewed by the same researcher (E. Perry) with full ethical approval (Integrated Research Application System approval number 12324; Health Research Authority, London, UK). All recruited bronchiectasis patients were under respiratory specialist care, and had high-resolution computed tomography (HRCT) evidence of bronchiectasis and a history of two or more respiratory infections per year. Key exclusion criteria included inflammatory arthritis, tuberculosis or other forms of lung disease. Cystic fibrosis was excluded using genotyping and sweat testing following British Thoracic Society guidelines. Asthma patients were identified from a database where the diagnosis had been confirmed by expert review. Healthy controls were matched with the asthma patients, where possible, for smoking history, age and sex. Anti-CCP measurement was undertaken by ELISA assays including …

Increased disease activity, severity and autoantibody positivity in rheumatoid arthritis patients with co‐existent bronchiectasis

Patients with rheumatoid arthritis (RA) and co‐existent bronchiectasis (BRRA) have a five‐fold increased mortality compared to rheumatoid arthritis alone. Yet previous studies have found no difference in clinical and serological markers of RA disease severity between BRRA patients and RA alone. However, RA disease activity measures such as Disease Activity Score of 28 joints – C‐reactive protein (DAS28‐CRP) and anti‐cyclic citrullinated peptide antibodies (anti‐CCP) have not been studied, so we assessed these parameters in patients with BRRA and RA alone.

Autoantibodies against C1q as a Diagnostic Measure of Lupus Nephritis: Systematic Review and Meta-analysis.

Objectives To evaluate the diagnostic accuracy of C1q autoantibodies in identifying lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE). Data sources and methods Citation indexes were searched and 370 articles published from 1977 to 2013 were evaluated. The 31 selected studies included in the meta-analysis were cross-sectional in design. Among the 31 studies, 28 compared anti-C1q antibodies in 2769 SLE patients with (n=1442) and without a history of LN (n=1327). Nine studies examined anti-C1q in 517 SLE patients with active (n=249) and inactive LN (n=268). Hierarchical summary receiver operating characteristic (HSROC) random effects models were fitted to pool estimates of accuracy across the studies. Results Anti-C1q antibodies discriminated between patients with and without a history of LN, with a median specificity of 73.5%. The HSROC model estimated the corresponding sensitivity to be 70.4%. A hypothetical patient with a 55% prior probability of having a history of LN as opposed to no history (the median prevalence across 28 eligible studies) would have a post-test probability of 76.4% following a positive test result (positive predictive value) or 33.0% following a negative test result (negative predictive value). For discriminating active from inactive LN the median specificity of anti-C1q antibodies was 80%, with a corresponding estimated sensitivity value 75.7% based on the HSROC model. A hypothetical patient with a 56% prior probability of active as opposed to inactive LN (the median prevalence across the 9 eligible studies) would have a post-test probability of 82.8% following a positive test result or 27.9% following a negative test result. Conclusions Although C1q antibodies are associated with lupus nephritis the post-test probabilities are not sufficiently convincing to provide reasonable certainty of the presence or absence of history of disease/active disease.

Heightened autoantibody immune response to citrullinated calreticulin in bronchiectasis: implications for rheumatoid arthritis

Calreticulin (CRT) and citrullinated (citCRT) are implicated in rheumatoid arthritis (RA) pathology. citCRT binds to RA shared epitopes (SE) on HLA-DR molecules with high affinity and triggers pro-inflammatory events in adjacent cells. The aim of the study was to detect the presence of citCRT prior to developing RA and evaluate if citCT is a target for autoantibodies in RA cohorts with and without lung disease. Antibodies were assessed by ELISA against native CRT, citCRT and general protein citrullination, in sera from 50 RA patients without lung disease, 122 bronchiectasis (BR) patients, 52 bronchiectasis patients with RA (BRRA), 87 asthma patients and 77 healthy controls (HC). Serum citCRT was detected by immunoblotting and mass spectrometry. Genomic DNA was genotyped for HLA-DRB1 alleles. Patients were assessed for DAS28, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies. Extracellular citCRT was detected in BR patients sera prior to them developing RA. A citCRT SE binding peptide GEWKPR261citQIDNPDYK was identified. Anti-CRT antibodies were observed in 18% of BR patients with or without RA. Anti-citCRT antibodies were observed in ∼35% of BR or RA patients, increasing to 58% in BRRA patients. In the RA alone patients 7/20 (35%) who were negative for RF and anti-CCP were anti-CRT antibody positive and had higher DAS28 scores than triple negative RA alone patients. Three of the four BR patients who developed RA over 18 months were anti-citCRT+ve SE+ve. The detection of citCRT in BR and development of anti-citCRT in BR patients suggests citCRT antigens are early targets of antigenicity in these patients, especially in SE+ve patients prior to the onset of RA.

A6.3 Patients with bronchiectasis, with or without rheumatoid arthritis, have an elevated anti-citrullinated peptide antibodies (ACPA) response.

Background and Objectives ACPA, particularly antibodies to citrullinated enolase and vimentin, are associated with smoking in patients with rheumatoid arthritis (RA). There is increasing evidence that these links are due to expression of citrullinated proteins in the lungs of smokers. Whether this is a direct effect of smoking or inflammation is presently poorly understood. Bronchiectasis, a strong risk factor for RA, tends to occur in non-smokers, and can therefore be used to examine the role of inflammation in generating an ACPA response independent of smoking. Materials and Methods This multi-centre study included 53 patients with HRCT proven bronchiectasis and RA, 50 patients with RA without lung disease, 124 bronchiectasis without RA and 87 asthma patients as controls. Serum samples were analysed for ACPAs using anti-CCP (2nd generation assay) and in-house ELISA’s were used to measure fine specificities to citrullinated α-enolase (CEP-1), citrullinated vimentin (cVim) and fibrinogen (cFib) together with their arginine-containing control peptides. Smoking history was detailed for all patients. Results Comparing the RA/bronchiectasis and the RA patients without lung disease, anti-CCP antibodies were more frequently positive (87% vs 48%) and titre significantly greater (p<0.0001) in the RA/bronchiectasis group, despite a lower frequency of smoking (42% vs 58%). The frequency and titre were also increased in the RA/bronchiectasis group for anti CEP-1 (60% vs 24%; p < 0.001), cVim (34% vs 11%; p < 0.001) and anti-cFib (38% vs 18%; p = 012). Comparing the bronchiectasis with asthma groups, none of who had RA, 5% vs 2% had anti-CCP, 9% vs 2% had anti CEP-1 and none were anti-cVim or anti-cFib positive. However, the increased ACPA response in bronchiectasis vs asthma was significant for anti-CEP-1 (p < 0.001). Testing with REP-1, the arginine-containing control peptide for enolase, showed that the response in the bronchiectasis patients was not citrulline-specific. Conclusions We have demonstrated that despite a low prevalence of smokers, RA/bronchiectasis patients have increased anti-CCP antibodies and an ACPA fine specificity profile similar to that previously shown in RA and smoking (anti-CEP-1 and anti-cVIM). Additionally we identified significantly elevated levels of anti-CEP-1 in the bronchiectatis patients, though unlike in the RA patients, the response was not citrulline-specific, similar to that previously reported for periodontitis. This indicates that the lung may be an initiating site for immunity to RA autoantigens due to inflammation independent of smoking.

AB0440 What effect does the presence of bronchiectasis have on CCP antibody levels in patients with rheumatoid arthritis

Background It is well established that anti cyclic citrullinated peptide (CCP) antibodies are a marker of rheumatoid arthritis (RA) and are associated with greater articular damage [1]. There is increasing evidence to suggest that they may also be related to systemic complications of RA, especially those affecting the lung [2]. Recently, CCP antibodies have been reported in the presence of chronic infection. We wondered if the presence of bronchiectasis might affect the levels of CCP antibody in RA patients? Objectives To measure the levels of anti CCP antibody in patients with RA and compare those found in patients with and without bronchiectasis in order to assess the possible influence of chronic pulmonary infection on CCP antibody production. Methods We identified 23 patients with RA and bronchiectasis from our hospital database. All these index patients met the recent EULAR guidelines for RA and had the presence of bronchiectasis confirmed on high resolution computed tomography. We then identified 23 case controls with RA on EULAR criteria who were matched for age and gender with each index case. We recorded smoking status and history for each patient. We then measured anti CCP antibody levels in all patients (normal range 0-7 U/ml), and compared the results between the two groups using Chi squared statistics and Students paired t testing after ensuring uniform distribution. Results Patients with RA and bronchiectasis had a mean age of 66 (54 - 79 years), with a male to female ratio of 11:12. The RA patients with bronchiectasis were positive for the presence of CCP antibodies in 83% of cases, and mean levels were 158.6 U/ml (SE 29.9). By contrast, RA patients without bronchiectasis had a positivity rate of 54% [p=0.013], with a mean value of 57.9 U/ml (SE 24.1) [p=0.003]. However, the groups also showed a difference in smoking history with just 33% of bronchiectasis patients having never smoked, as opposed to 72% of RA controls, although none of the index cases were still smokers at the time of the study. Cumulative smoking in pack years was not significantly different between the groups. Conclusions These data show an association between chronic lung infection in the form of bronchiectasis and anti CCP antibody status in RA patients. This may be partly explained by smoking. Further studies in non smokers and in patients with chronic lung infection without RA are required to define the potential relevance of this. However, these data add weight to the growing suspicion that the lungs may be an important portal for the acquisition of antigens triggering autoimmune responses in RA [3]. References Jansen LM, van Schaardenburg D, van der Horst-Bruinsma I, van der Stadt RJ, de Koning MH, Dijkmans BA, The predictive value of anti-cyclic citrillunated peptide antibodies in early arthritis. J Rheumatol 2003;30: 1691-5 Alexiou I, Germenis A, Koutroumpas A et al. Anti-cylcic citrullinated peptide (CCP) antibodies and extra articular manifestations in Greek patients with rheumatoid arthritis. Clin Rheumatology 2008; 27: 511-3 Demoruelle M, Weisman M, Derber L et al. Lung abnormalities in subjects with elevations of Rheumatoid Arthritis-related autoantibodies without arthritis by examination and imaging suggest the lung is an early and perhaps initiating site of inflammation in rheumatoid arthritis ACR 2011 Abs. 769 Disclosure of Interest None Declared