Henri A. Ménard

Insights into rheumatoid arthritis derived from the Sa immune system

The Sa system is a recently described immune system that has a specificity and positive predictive value of nearly 100% for rheumatoid arthritis (RA) in Asia, Europe and the Americas. Its sensitivity of 30-40% suggests that it identifies a subset of RA patients. Anti-Sa antibodies are present from disease onset and are predictive of disease severity. The immune reactants are plentiful in the target tissue: antigen is present in the synovium, IgG antibody in the fluid. Immunologically, Sa is a hapten-carrier antigen in which vimentin is the carrier and citrulline is the hapten. The citrullination of vimentin is closely related to apoptosis, and citrullinated vimentin is extremely sensitive to digestion by the ubiquitous calpains. Nevertheless, Sa is found in only a few cell lines. Calpastatin, the natural specific inhibitor of calpains, is also a RA-associated, albeit non-specific, autoimmune system. Is it possible that calpain-related apoptotic pathways could be prominent in cells containing Sa? The task is to reconcile the specificity of Sa/citrullinated proteins in a multifactorial and polygenic disease such as RA.

Stiffness of the rib cage in a subset of rheumatoid patients.

In a previous investigation of lung function in patients with rheumatoid arthritis (RA), we observed that some patients had significant dysfunction of their chest wall mechanics without pleural disease that could contribute to their respiratory symptoms. To investigate further the chest wall functions of patients with RA, we selected 10 female lifetime nonsmoking patients with RA and compared them to 10 paid normal volunteers in detailed functional evaluations of lung and chest wall. Patients with significant airflow limitation were excluded from this study. We found a significant 7% reduction in total lung capacity in the RA patients without significant change in lung compliance. However, we found a significant reduction in rib cage compliance in patients with RA (0.044 ± 0.006 L/cmH2O vs 0.064 ± 0.012 in controls), which was associated with a significant 38% reduction in expansion of the rib cage volume during various breathing maneuvers. These changes occurred in the absence of lung or pleural disease. This study documents that patients with RA have limited expansion of rib cage relative to abdomen, thus rib cage restriction and stiffness, which may contribute to reduced lung volume. The shift of thoracoabdominal breathing configuration observed in patients with RA will likely reduce the effectiveness of breathing muscles and thus could contribute to the dyspnea sensation experienced by patients with RA.

Naproxen: Long‐Term Study in Rheumatoid Arthritis and “Placebo Pulse”

Naproxen is by now a relatively well-known antirheumatic drug, and many short-term studies have shown its efficacy and relatively good tolerance. We have observed 64 patients with definite or classical rheumatoid disease, 27 of whom have been followed for well over two years on daily doses of naproxen to ascertain the persistence of drug efficacy and safety. In this part of our study, patients were subjected to complete clinical and biochemical evaluations at two-monthly intervals. Naproxen was well tolerated, and the few side effects reported were transient and mild in nature. Sequential laboratory studies revealed no significant anomaly. Clinical evaluation showed no pattern suggestive of decreasing antirheumatic activity. A question frequently encountered in the treatment of certain diseases such as rheumatoid arthritis is whether long-term improvement is due to efficacious suppressive therapy or spontaneous abatement of disease activity. We devised a double-blind placebo pulse phase in which 19 of our 28 long-term patients participated in a study within a study lasting four weeks. They were divided into two groups. The first group took their usual dose of naproxen during the first two weeks and a corresponding number of placebo tablets in the next two weeks. The procedure was reversed in the other group. We conclude that naproxen remains efficacious.

Immunogenetic factors as determinants of asbestosis

To evaluate the possible role of immunogenetic factors as predisposing determinants of the development of asbestosis in exposed workers, we obtained 53 phenotypes of the human leucocyte antigen (HLA)-A, B, C, and DR antigens in 72 long-term workers of the mines and mills of Quebec and in a reference population of 150 residents. Among the asbestos workers, 32 did not have any abnormality and 40 had asbestosis. The 2 groups did not differ in term of age, exposure, or cigarette smoking habits. In agreement with previous reports, we found no significant change in frequency of the HLA-A, B, or C phenotypes. Furthermore, we did not find any significant change in the frequency of 10 phenotypes of the HLA-DR loci. We conclude that immunogenetic factors are not major predisposing determinants of asbestosis.

Assessing process of care in rheumatoid arthritis at McGill University hospitals.

ObjectiveIn rheumatoid arthritis (RA), quality indicators (QIs) are tools used to measure process of care. This study aimed to assess performance of selected QIs from the 2004 Arthritis Foundation’s QI Set at 2 major sites of a university network of teaching hospitals. MethodsThe charts and electronic hospital records of 76 RA patients were audited to determine adherence to QIs. Logistic multivariate regression analyses were performed to investigate potential determinants of nonadherence and propose measures to facilitate better QI compliance, as a potential strategy towards RA care improvement. ResultsWe identified consistent observance of QIs mandating prescription of disease-modifying antirheumatic drug therapy for all patients, drug adjustment with disease activity, prednisone tapering, and bisphosphonate therapy if indicated for patients on glucocorticoids. However, there was either lack of documentation or true inconsistent adherence to QIs dealing with radiograph performance, functional capacity assessment, and screening for hepatitis and tuberculosis before commencement of methotrexate and biologic agents, respectively. For the specific QIs analyzed, we did not find any definite independent associations with the studied variables. ConclusionsOur findings indicate that while there is frequent evidence for adherence to certain RA quality care standards at our centers, there is less compliance to others. Strategies to optimize the performance or documentation of those found most lacking, namely, functional capacity and screening for specific drug contraindications, could improve patient care. Radiographic disease monitoring, while lacking, may represent a move toward other more sensitive methods of RA progression detection, such as joint ultrasound. The inclusion of patient- and physician-derived information could help elucidate the reasons underlying nonadherence.

Anti-cyclic citrullinated peptide in preclinical rheumatoid arthritis. Food for thought.

Citrullinated (cit-) epitope detection is an evolving science with different substrates being proposed continuously1–4. Given all the published enthusiasm with anti-cyclic citrullinated peptide (CCP), why does the test need to be improved? It is assumed that the cit-epitopes targeted in cit-peptides/proteins are all detected by anti-CCP and are invariable in the various individuals during the phases of disease. That premise may be incorrect. Recent objective critical evaluation of anti-CCP is severe. Its added value in rheumatoid arthritis (RA) diagnostics, over and above previously existing clinical and laboratory tools, is deemed marginal5. The huge anti-CCP literature contains recurring inconsistencies suggesting that authors are using the same test to measure different things in a very heterogeneous disease. Moreover, it is difficult to understand how a test can be associated with more severe evolution in early RA6 and also be positive without arthritis for 10 to 15 years before people get sick7–10. How does one reconcile that? The solution of Chibnik, et al in this issue of The Journal 7 is to pay more attention to titers of anti-CCP to explain the transition from pre-RA to RA. Just having anti-CCP is not sufficient; also important is how much one has. The higher the titer, the shorter the interval to disease onset! Titers rise steadily until disease onset and then stabilize, as is … Address reprint requests to Dr. H.A. Menard, Division of Rheumatology, McGill University Health Center, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada; E-mail: henri.a.menard{at}muhc.mcgill.ca

Heterogeneity of ANCA Sera Showing Atypical, Peripheral and Classical Cytoplasmic Immunofluorescence Patterns

Atypical (A) ANCA immunofluorescence (IF) patterns have been described in several disease groups. We have previously reported a distinct cytoplasmic A-ANCA in 7-10% of patients with SLE and/or RA. Here, we show that these rheumatic disease associated A-ANCAs are best identified using U937 cells as substrate and that they do not target either a serine proteinase or a peroxidase. Furthermore, these sera immunoprecipitate a 40 kDa or a 42 kDa band using in vivo 35S-amino acid labelled HL60 or U937 cell extracts, respectively. Although these bands are the only one seen with pure A-ANCA sera, they can also be found in addition to the expected bands of PR3 or MPO in up to 30% of bona fide C- or P-ANCA sera. These data confirm and extend our previous observations. They also suggest that target heterogeneity of ANCA antibodies is frequent. Care should thus be taken in interpreting in a cause and effect relationship, an IF pattern or a biological effect produced by a serum with ill documented monospecificity. The exact nature and significance of this (these) new antigen(s) have yet to be clarified.