Rheumatoid Arthritis: Schur PH

Rosenau BJ, Schur PH. · Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · J Rheumatol. · Pubmed #19435971 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis; while the cause is unknown, it has been speculated that an infectious agent could be the trigger for the disease. Numerous attempts at isolating an agent have been unsuccessful. Our purpose was to identify a virus from diseased tissue from a patient with RA. METHODS: Diseased tissue taken at the time of knee replacement surgery from a patient with RA was inoculated into several cell lines and observed for cytopathic effect. Cells from the tissue were also grown as explants and were examined for viruses. Synovial fluid drawn 4 years prior to the surgery and frozen at -70 degrees C was also inoculated into cell lines. Following the development of a cytopathic effect and identification of the agent, sera from 50 patients with rheumatoid factor (RF)-negative RA were examined for IgM antibodies to the agent. RESULTS: After many inoculations and numerous subpassages, measles virus was identified in 6 cell lines inoculated with either the minced tissue or synovial fluid. Six cell lines co-cultivated with one or more of 9 explants also showed the presence of measles virus. Measles virus was confirmed by immunofluorescence and by neutralization. Eleven of 50 (22%) sera samples from patients with RF-negative RA had IgM antibodies to measles virus recombinant nucleoprotein. CONCLUSION: There is an association between measles virus and RA.

Rosenau BJ, Schur PH. · Department of Medicine, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, USA. · J Rheumatol. · Pubmed #19273453 No free full text.

Abstract: OBJECTIVE: To detect autoantibodies to tumor necrosis factor (TNF) in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and to determine their clinical correlates. METHODS: Ninety-two patients with RA and 62 with SLE were studied. Sera were examined for autoantibodies to TNF by enzyme linked immunoassay. Levels of these autoantibodies were analyzed in respect to markers of inflammation such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and joint erosions, as well as other clinical, laboratory, and therapeutic aspects of RA and SLE. RESULTS: Anti-TNF levels were higher in those RA patients without erosions, but did not correlate with ESR or CRP. CONCLUSION: These observations suggest that autoantibody anti-TNF may be part of the innate immune system and may contribute to decreased inflammation in patients with RA.

Chibnik LB, Mandl LA, Costenbader KH, Schur PH, Karlson EW. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA. · J Rheumatol. · Pubmed #19228654 No free full text.

Abstract: OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are strongly associated with increased risk of rheumatoid arthritis (RA).While the anti-CCP level is commonly dichotomized for clinical use, the best threshold for and utility of the titer as a continuous variable to predict development of RA are uncertain. METHODS: Using data from the Nurses' Health Study and Nurses' Health Study II longitudinal cohorts, we examined the sensitivity, specificity, and hazard of RA at various thresholds of the anti-CCP. Incident RA was confirmed using the Connective Tissue Disease Screening Questionnaire and medical record review in 93 women from among 62,437 participants with blood samples. Three controls per case were randomly chosen, matching on cohort, age, and menopausal status. Stored plasma was tested for anti-CCP antibodies with the second-generation Diastat ELISA. Five threshold values were assessed for sensitivity, specificity, and time to diagnosis of RA. Hazard of RA was assessed with conditional logistic regression models adjusting for smoking and reproductive factors. RESULTS: Using the suggested threshold of >5 U/ml for anti-CCP positivity, specificity was 100%, but sensitivity was only 28%. A threshold of >2 U/ml had a higher sensitivity (51%), and similar specificity (80%), with an odds ratio of 11.2 (95% confidence interval 4.7-26.9) for RA. Anti-CCP level as an ordinal variable was strongly associated with time to RA onset, with higher values predicting shorter time to RA onset. CONCLUSION: A lower threshold for anti-CCP positivity was more sensitive in predicting RA development. Higher ranges of the level were informative in predicting time to RA onset.

Lee DM, Phillips R, Hagan EM, Chibnik LB, Costenbader KH, Schur PH. · Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith 552B, 1 Jimmy Fund Way, Boston, Massachusetts 02115, USA. · Ann Rheum Dis. · Pubmed #18390910 No free full text.

Abstract: OBJECTIVE: To determine the significance of quantitative levels of antibodies to cyclic citrullinated peptides (anti-CCP) in a population of patients with rheumatoid arthritis (RA). METHODS: A total of 241 consecutive sera from patients with RA sent from a large rheumatology clinic for laboratory testing were selected for precisely quantifying anti-CCP antibody titres with the anti-CCP2 assay. Patient charts were reviewed for demographic information, smoking history, clinical diagnosis, rheumatoid factor (RF) titre, radiographic information and other laboratory information (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level). Correlations with anti-CCP titre and RF titre, disease parameters and smoking history were assessed. RESULTS: We confirm previous findings that anti-CCP seropositivity is associated with a higher incidence of erosions in patients with RA (56% vs 20% CCP+ vs CCP-, kappa = 0.297, p<0.001). We also found a moderate correlation between anti-CCP titre and RF titre. However, we failed to find an association between anti-CCP titre and presence of erosions, between anti-CCP titre and CRP or ESR level, or between anti-CCP titre and age or disease duration. Interestingly, we did find significantly higher anti-CCP titres in patients with a history of smoking (452 units/ml vs 229 units/ml, smokers vs non-smokers, respectively; p = 0.02). CONCLUSIONS: Although anti-CCP titres were not associated with clinical parameters of disease, they are increased in patients with RA with exposure to tobacco. By contrast, no elevation in RF was noted in patients with a history of smoking. These observations are consistent with a pathogenic contribution of smoking to RA and suggest the immune stimulus for anti-CCP is distinct from that for RF.

Rosenau BJ, Costenbader KH, Schur PH. · Division of Rheumatology, Immunology, and Allergy, Department of Medicine and the Division of Laboratory Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. · Vasc Med. · Pubmed #18372435 No free full text.

Abstract: There has been considerable interest in the relationship between C-reactive protein (CRP) and atherosclerosis. We have previously demonstrated that individuals, especially those with rheumatoid arthritis and systemic lupus erythematosus, may produce antibodies to CRP. This study was therefore undertaken to determine the possible association between anti-CRP antibodies and atherosclerosis. A total of 103 individuals were identified with or without atherosclerosis, and without clinical rheumatic diseases. They were evaluated with respect to cholesterol, HDL, LDL, high-sensitivity (hs)CRP, and anti-CRP antibody levels, as well as use of statin medications. Individuals with atherosclerosis were much more likely to be taking a statin, and thus have lower lipid levels. However, there was no association between hsCRP or anti-CRP antibody levels with atherosclerosis, statin use, or each other. These observations suggest that anti-CRP antibody is not involved in atherosclerosis, and may represent an epiphenomenon.

Liao KP, Batra KL, Chibnik L, Schur PH, Costenbader KH. · Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. · Ann Rheum Dis. · Pubmed #18234714 No free full text.

Abstract: OBJECTIVE: The classification of rheumatoid arthritis (RA) is increasingly important as new therapies can halt the disease in its early stages. Antibodies to cyclic citrullinated peptides (anti-CCP) are widely used for RA diagnosis, but are not in the 1987 American College of Rheumatology (ACR) Criteria for RA Classification. We developed and tested the performance characteristics of new criteria for RA classification, incorporating anti-CCP. METHODS: We identified all subjects seen in our arthritis centre with rheumatoid factor (RF) and anti-CCP tested simultaneously between 1 January and 30 June 2004 and reviewed their medical records for the ACR criteria, rheumatologists' diagnoses, RF and anti-CCP. We revised the ACR criteria in two ways: (a) adding anti-CCP, and (b) replacing rheumatoid nodules and erosions with anti-CCP (CCP 6 criteria). We compared sensitivity and specificity of all criteria, in all subjects and in subjects with arthritis symptoms </=6 months. RESULTS: Medical records of 292 subjects were analysed: mean age was 54 years, 82% were women, and mean symptom duration was 4.1 years. 17% were RF positive and 14% were anti-CCP positive at initial testing. 78 (27%) had definite RA per treating rheumatologist at latest follow-up. The CCP 6 criteria increased sensitivity for RA classification for all subjects regardless of symptom duration: 74% vs 51% for ACR criteria with a loss in specificity (81% vs 91%). Sensitivity was greatly improved in subjects with symptoms < or =6 months: 25% vs 63% for ACR criteria with a decrease in specificity. CONCLUSIONS: The CCP 6 criteria improved upon the sensitivity of the ACR criteria, most remarkably for subjects with symptoms < or =6 months and could be used for the classification of subjects for RA in clinical studies.

Rosenau BJ, Schur PH. · Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Ann Rheum Dis. · Pubmed #16176996 links to  free full text

Abstract: BACKGROUND: C reactive protein (CRP) is a known indicator of inflammation. Serum CRP is often raised in patients with inflammatory conditions. OBJECTIVE: To determine whether individuals make antibodies to CRP and whether this might affect serum CRP concentrations. METHODS: An enzyme linked immunosorbent assay was developed for the detection of antibodies to CRP. Specificity of the reaction was determined by inhibition of the reaction. RESULTS: Sera from 413 patients were tested and 25 were found to be positive, particularly in patients with rheumatic diseases. Levels of anti-CRP did not correlate with serum CRP levels. CONCLUSIONS: The presence of low CRP levels may not reflect the presence of antibodies to CRP.

Lee DM, Schur PH. · Department of Medicine, Division of Rheumatology, Immunology and Allergy Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Ann Rheum Dis. · Pubmed #12922961 links to  free full text

Abstract: OBJECTIVES: To determine the frequency of antibodies to cyclic citrullinated peptides (CCP) in a group of patients with a diversity of rheumatic diseases. METHODS: 249 consecutive sera from an arthritis clinic sent for rheumatology testing were selected for testing with the anti-CCP2 assays and for the presence of rheumatoid factor (RF). Patient charts were reviewed for demographic information, clinical diagnosis, radiographic information, and other laboratory data. RESULTS: The sensitivity and specificity of anti-CCP reactivity for the diagnosis of rheumatoid arthritis (RA) were 66.0% and 90.4%, respectively. This compared with the sensitivity and specificity of RF for RA at 71.6% and 80.3%. Furthermore, 10/29 (34%) RF- patients with RA demonstrated reactivity to CCP. The presence of either anti-CCP or RF increased testing sensitivity for diagnosis of RA to 81.4%; the presence of both RF and anti-CCP demonstrated a testing specificity similar to that of anti-CCP reactivity alone for the diagnosis of RA (91.1%). CONCLUSIONS: The detection of anti-CCP is useful for the diagnosis of RA, in fact even more so than RF, because of its higher specificity.

Matsumoto I, Lee DM, Goldbach-Mansky R, Sumida T, Hitchon CA, Schur PH, Anderson RJ, Coblyn JS, Weinblatt ME, Brenner M, Duclos B, Pasquali JL, El-Gabalawy H, Mathis D, Benoist C. · Joslin Diabetes Center and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA. · Arthritis Rheum. · Pubmed #12687536 links to  free full text

Abstract: OBJECTIVE: Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins that recognize glucose-6-phosphate isomerase (GPI), a glycolytic enzyme residing in the cytoplasm of all cells. Antibodies directed against GPI can, alone, transfer arthritis to healthy recipients. Previous experiments have revealed significant titers of anti-GPI antibodies in the serum of many patients with rheumatoid arthritis (RA). We evaluated the generality of these observations in cohorts of patients with 12 different arthritic and chronic autoimmune diseases and in population-matched healthy control subjects. METHODS: Anti-GPI antibodies were assayed in 811 individual serum samples by enzyme-linked immunosorbent assay with 2 forms of GPI, recombinant and native. Results were confirmed by immunoblotting. RESULTS: Several patients had significantly elevated anti-GPI antibody titers, but without the prevalence or the specificity reported previously. Only 15% of RA patients had anti-GPI antibodies (range 12-29% in different cohorts), with a higher prevalence in patients with active disease. Psoriatic arthritis, undifferentiated arthritis, and spondylarthropathy patients also displayed anti-GPI antibodies at similar frequencies (12-25%). Similar titers were detected in a proportion (5-10%) of control subjects or patients with Crohn's disease or sarcoidosis. Very high titers were found in rare cases of RA and systemic lupus erythematosus. CONCLUSION: No disease-specific pattern of antibody positivity to GPI was apparent. While the antibody-mediated mechanism at play in the mouse model may exemplify a generic mechanism for some forms of arthritis in humans, GPI itself does not appear to be a target common to the majority of RA patients.

Solomon DH, Shmerling RH, Schur PH, Lew R, Fiskio J, Bates DW. · Robert B. Brigham Multipurpose Arthritis and Musculoskeletal Diseases Center, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · J Rheumatol. · Pubmed #10606365 No free full text.

Abstract: OBJECTIVE: Laboratory testing is important in the evaluation of patients with possible systemic rheumatic disease, but uncritical use of any test may result in misleading information and unnecessary costs. We attempted to reduce the number of unnecessary antinuclear antibody, rheumatoid factor, and complement level tests ordered by house officers at a large teaching hospital, where inpatient orders are written through a computer based order entry system. METHODS: We conducted a prospective cohort study of an interactive test ordering program. The intervention consisted of displaying post-test probability estimates during the usual physician order entry session. These estimates were based on pretest probabilities entered by the ordering physician and sensitivities and specificities derived from a literature review. Another group of test orders did not prompt the intervention and were considered controls. The outcome of interest was the percentage of tests canceled in the intervention group versus the control group. RESULTS: Eleven percent (11/99) of intervention orders were canceled, versus only one order among 236 controls (p = 0.001). However, there was no association between the physicians' pretest probability estimates and whether test orders were canceled (p = 0.59). Additionally, 43 of the 335 orders (13%) yielded positive tests, but only 4 patients (1%) were given new diagnoses of rheumatic disease. CONCLUSION: The computer based intervention significantly reduced orders for antinuclear antibody and rheumatoid factor levels by 10%. Further reductions without clinical harm are probably possible, since the yield of testing for new rheumatic diseases was low.

Karlson EW, Hankinson SE, Liang MH, Sanchez-Guerrero J, Colditz GA, Rosenau BJ, Speizer FE, Schur PH. · Department of Medicine, Multipurpose Arthritis and Musculoskeletal Diseases Center, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Am J Med. · Pubmed #10320112 No free full text.

Abstract: PURPOSE: To study the possible association of silicone-breast-implant exposure and immunologic abnormalities within the Nurses' Health Study, an ongoing prospective cohort study of women. SUBJECTS AND METHODS: From this cohort, we randomly selected 200 women who had been exposed to silicone breast implants and who had never reported connective tissue diseases during 14 years of follow-up, and 500 age-matched, nonexposed women, including 100 with definite connective tissue diseases validated by medical record review, 100 with at least one symptom of a connective tissue disease, 100 with diabetes, and 200 healthy controls. Assays for antinuclear antibodies (ANA), including anti-dsDNA, anti-ssDNA, anti-Sm/RNP/Ro/La, and anti-Scl-70, rheumatoid factor, immunoglobulins, serum complement, and C-reactive protein level, and anticardiolipin, antithyroglobulin, antithyroid microsomal, and antisilicone antibodies were performed by standard techniques in blood samples collected in 1989 or 1990 before collection of silicone-breast-implant exposure data in 1992. RESULTS: ANA was positive (> or = 1:40) in 14% of women with silicone breast implants compared with 20% of healthy women (P = 0.11). Rheumatoid factor was positive (> or = 1:40) in 5% of women with silicone breast implants and 2% of healthy women (P = 0.16). Women with silicone breast implants had a significantly higher frequency of anti-ssDNA antibodies than healthy women (41% and 29%, P = 0.012). Duration of implant was associated with a higher frequency of anti-ssDNA antibodies (P = 0.03) but not with ANA or rheumatoid factor. No other significant differences in the frequencies of autoantibodies were observed in silicone breast implant-exposed women. Antisilicone antibodies were not found in any sample. CONCLUSION: We found no increased frequency of any immunologic abnormalities in women exposed to silicone breast implants, except for anti-ssDNA, which has unknown clinical relevance.