Prediction models for rheumatoid arthritis during diagnostic investigation: evaluation of combinations of rheumatoid factor, anti-citrullinated protein/peptide antibodies and the human leucocyte antigen-shared epitope.

OBJECTIVES: To calculate the probabilities for rheumatoid arthritis in a consecutive cohort of patients during diagnostic investigation. Different logistic regression models evaluating the value of human leucocyte antigen (HLA)-shared epitope determination and testing for rheumatoid factor and anti-citrullinated protein/peptide antibodies (ACPA) were fitted. METHODS: 1003 consecutive patients were included in the study, presenting a new diagnostic problem for which rheumatoid arthritis was included in the differential diagnosis. All patients were tested for ACPA, rheumatoid factor and HLA-shared epitope. RESULTS: After 1 year, diagnoses were established: 153 patients had definite rheumatoid arthritis and 629 patients had rheumatoid arthritis excluded. Rheumatoid factor, used as a continuous marker, is useful in evaluating the probability for rheumatoid arthritis. Combined rheumatoid factor and shared epitope testing may provide additional predictive information, but combined ACPA and rheumatoid factor testing is superior. The redundancy of shared epitope testing in a model that includes ACPA testing can be explained by the high association between ACPA and shared epitope both in patients with rheumatoid arthritis and in those with non-rheumatoid arthritis. The value of rheumatoid factor testing increased if patients presented with at least one swollen joint at baseline. CONCLUSION: Valid probabilities for rheumatoid arthritis during routine diagnostic investigation were calculated, and showed that the potential additional value of shared epitope testing disappears when ACPA testing is available. Combined rheumatoid factor and ACPA testing is useful, especially when rheumatoid factor is considered as a continuous parameter reflecting an increasing probability for rheumatoid arthritis at higher rheumatoid factor titres. The value of (continuous) rheumatoid factor testing increases when the a priori chance is higher.

Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: an international meta-analysis.

OBJECTIVE: To quantitatively evaluate the diagnostic accuracy of antibodies to ribosomal P proteins (anti-P) for neuropsychiatric systemic lupus erythematosus (NPSLE) in general, for psychosis, mood disorder, or both, and for other diffuse manifestations. METHODS: This international meta-analysis combined standardized data from 1,537 lupus patients contributed by 14 research teams. Weighted estimation of sensitivity and specificity with fixed-effects and random-effects models, as well as summary receiver operating characteristic (SROC) curve analysis, was used to summarize test performance. The robustness of the overall estimates was examined in sensitivity analyses that included additional studies published up to November 1, 2004 in the Medline, EMBase, and Cochrane databases. RESULTS: Combining the data from the 14 teams, the weighted sensitivity and specificity estimates for the diagnosis of NPSLE were 26% (95% confidence interval [95% CI] 15-42%) and 80% (95% CI 74-85%), respectively. For psychosis, mood disorder, or both, the sensitivity and specificity were 27% (95% CI 14-47%) and 80% (95% CI 74-85%), respectively. For other diffuse manifestations, the sensitivity was 24% (95% CI 12-42%), and the specificity was 80% (95% CI 73-85%). The proportion of patients with anti-P antibodies did not vary markedly across different presentations of NPSLE. Between-study heterogeneity was substantial, but the SROC curves were consistent with the weighted estimates. In further analyses that included another 24 published studies, only the sensitivity for psychosis and/or mood disorder was slightly improved, but it was still suboptimal (42% [95% CI 30-53%]); the specificity remained essentially the same (81% [95% CI 76-85%]). CONCLUSION: Anti-P antibody testing has limited diagnostic value for NPSLE, and it is not helpful in differentiating among various disease phenotypes.

Diagnostic classification of spondylarthropathy and rheumatoid arthritis by synovial histopathology: a prospective study in 154 consecutive patients.

OBJECTIVE: To explore prospectively the value of synovial histopathology in comparison with the value of classic parameters for diagnostic classification of spondylarthropathy (SpA) and rheumatoid arthritis (RA) in patients with an atypical disease presentation. METHODS: Synovial biopsy samples were obtained from 154 consecutive patients presenting for diagnostic evaluation; 67 patients fulfilled the classification criteria for RA, SpA, or other well-defined disease at the time of arthroscopy (cohort 1), and an additional 53 patients were classified after a full diagnostic reevaluation at 6 months (cohort 2). Synovial parameters with diagnostic value were identified in cohort 1 and were compared prospectively with classic diagnostic parameters in cohort 2. RESULTS: Staining with anticitrulline, staining with monoclonal antibody 12A (recognizing HLA-DR shared epitope-human cartilage glycoprotein 39(263-275) complexes), and crystal deposition had positive predictive values (PPVs) for diagnosis of >90% in patients with an atypical disease presentation (cohort 2). Using these 3 parameters, a diagnosis was predicted by synovial histopathology in 39.6% of cohort 2 patients and turned out to be correct in 90.5% of these patients at 6 months of followup. Using a multiparameter model rather than single histopathologic parameters, even better results were obtained, with a diagnostic prediction in 79.2% of samples and a PPV of 81.0%. In comparison, a similar multiparameter model using classic diagnostic criteria rather than synovial histopathology performed poorly in cohort 2; the sensitivity was 56.6% and the PPV was 73.3%, with an inferior capacity to predict SpA. Especially for the presence of crystals and anticitrulline staining, the analysis of synovial tissue had a clear added value to the analysis of synovial fluid or serum in patients with an atypical presentation. CONCLUSION: This proof-of-concept study indicates that synovial histopathology can contribute to the multiparametric diagnostic classification of inflammatory arthritis in patients with an atypical presentation.

Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondylarthropathy.

OBJECTIVE: To investigate the effect of infliximab treatment on antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA), antinucleosome, antihistone, and anti-extractable nuclear antigen (anti-ENA) antibodies in rheumatoid arthritis (RA) and spondylarthropathy (SpA) patients. METHODS: Sera from 62 RA and 35 SpA patients treated with infliximab were tested at baseline and week 30 (RA group) or week 34 (SpA group). ANAs were tested by indirect immunofluorescence (IIF) on HEp-2 cells. Anti-dsDNA antibodies were detected by IIF on Crithidia luciliae and by enzyme-linked immunosorbent assay (ELISA) and were further isotyped with gamma, mu, and alpha chain-specific conjugates at various time points. Antinucleosome antibodies were tested by ELISA. Antihistone and anti-ENA antibodies were detected by line immunoassay. RESULTS: Initially, 32 of 62 RA patients and 6 of 35 SpA patients tested positive for ANAs. After infliximab treatment, these numbers shifted to 51 of 62 (P < 0.001) and 31 of 35 (P < 0.001), respectively. At baseline, none of the RA or SpA patients had anti-dsDNA antibodies. After infliximab treatment, 7 RA patients (P = 0.016) and 6 SpA patients (P = 0.031) became positive for anti-dsDNA antibodies. All 7 anti-dsDNA-positive RA patients had IgM and IgA anti-dsDNA antibodies. Three of the 6 anti-dsDNA-positive SpA patients had IgM and IgA anti-dsDNA antibodies, and 2 had IgM anti-dsDNA antibodies alone. In both diseases, the IgM anti-dsDNA antibodies appeared before the IgA anti-dsDNA antibodies. During the observation period, no IgG anti-dsDNA antibodies or lupus symptoms were observed. The development of antinucleosome, antihistone, or anti-ENA antibodies following infliximab treatment was observed in some patients, but the numbers were not statistically significant. CONCLUSION: Infliximab treatment may induce ANAs, and especially IgM and IgA anti-dsDNA antibodies, in RA and SpA patients. However, no anti-dsDNA IgG antibodies or lupus symptoms were observed during the period of observation in this study, and the development of antinucleosome, antihistone, or anti-ENA antibodies was not statistically significant. These observations do not exclude potential induction of clinically significant lupus in the long term, and further followup is therefore mandatory.

Detection of specific antinuclear reactivities in patients with negative anti-nuclear antibody immunofluorescence screening tests.

BACKGROUND: For detection of anti-nuclear antibodies (ANAs) and antibodies to extractable nuclear antigens (ENAs), samples frequently are screened with indirect immunofluorescence (IIF); further determination of anti-ENA antibodies is performed only when the result is positive. However, because anti-ENA reactivities are found in samples with low fluorescence intensities, we determined anti-ENA antibodies in samples with negative IIF and thus calculated the sensitivity of IIF for specific ANAs. METHODS: We collected 494 samples consecutively referred by rheumatologists for routine ANA testing. IIF on HEp-2 and HEp-2000 (HEp-2 cells transfected with Ro60 cDNA) and line immunoassay (LIA) for the detection of specific ANAs were performed on all samples. RESULTS: Fluorescence intensities and patterns on HEp-2 were strongly correlated with those on HEp-2000 [Spearman rho = 0.852 (P <0.001) and 0.838 (P <0.001), respectively]. Sixty-eight of 494 samples were positive on LIA, of which only 72% (confidence interval, 68-76%) were detected with HEp-2 and 75% (confidence interval, 70-78%) with HEp-2000. Of 291 samples negative on both substrates, 12 were positive on LIA. Connective tissue diseases were diagnosed in four of these patients and suspected in at least three others. CONCLUSION: The HEp-2 and HEp-2000 substrates perform comparably for fluorescence intensities and patterns and for detecting specific ANAs, but some patients with negative IIF show reactivity on LIA. We recommend testing for fine reactivities, regardless of the IIF result, when the clinical suspicion for rheumatic connective tissue disease is high.