Diagnostic impact of contemporary biomarker assays for rheumatoid arthritis.

OBJECTIVE: The impetus towards early treatment for patients with rheumatoid arthritis (RA) requires more reliable disease markers than the non-specific immunoglobulin M (IgM) rheumatoid factor (RF). To determine the accuracy of newer biomarkers for RA testing for antibody against cyclic citrullinated peptides (anti-CCP Ab), IgA- and IgG-RF and cartilage oligomeric matrix protein (COMP) levels, measured by enzyme-linked immunosorbent assay (ELISA), were compared with IgM-RF isotyping. METHODS: Serum samples were investigated in patients with an established diagnosis of RA (n = 54), ankylosing spondylitis (AS) (n = 36), and non-inflammatory conditions (n = 18) (cohort A), and in 234 consecutive outpatients in a blinded fashion (cohort B). Non-parametric analysis of areas under the curve (AUC) of receiver operator characteristics were performed. RESULTS: The presence of anti-CCP Ab had the highest accuracy (96%) in distinguishing RA patients in cohort A and cohort B (accuracy 83%), and in both cohorts combined (accuracy 87%). This was related to the high specificity of anti-CCP Ab for RA (95-96%), even though IgM-RF was the most sensitive test (87-96%). Sensitivity (15-48%) and specificity (66-69%) of COMP as a marker for RA was low. Combining results of anti-CCP Ab and IgM-RF or any of the other assays did not increase the diagnostic accuracy for RA. CONCLUSION: The presence of anti-CCP Ab is the most accurate biomarker for RA in both selected and unselected cohorts, while the COMP assay is not very useful in RA diagnosis. Combining assays for anti-CCP Ab and IgM-RF or IgA-RF does not enhance RA diagnosis.

B-lymphocyte activating factor in systemic lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease measures and time.

Overexpression of B-lymphocyte activating factor (BAFF) results in arthritis, glomerulonephritis and autoantibody formation in mice, but its role in human autoimmune disease is less obvious. Serum BAFF levels in patients with systemic lupus erythematosus (SLE) (n=42) and rheumatoid arthritis (RA) (n=60) were related to levels of disease activity, anti-dsDNA Ab, anti-ENA Ab, rheumatoid factor (RF) and anti-CCP Ab. BAFF levels were also followed over time in 19 SLE patients. BAFF levels correlated inversely with age, were higher in SLE than RA (median 2.7 versus 1.4 ng/mL, P < 0.01) and more SLE than RA patients had increased BAFF levels (57% versus 10%, P < or = 0.01). In SLE, BAFF levels correlated with SLEDAI scores but not with anti-dsDNA Ab levels. SLE patients with increased BAFF levels had higher SLEDAI and CRP levels. In RA, BAFF levels correlated weakly with anti-CCP levels (Rs 0.27, P = 0.07), but not with joint counts, ESR, CRP or RF levels. Longitudinal BAFF levels remained unaltered in two thirds of SLE patients and changes in BAFF levels were unrelated to disease flares. These findings suggest that BAFF stimulation of B-cells may contribute to SLE by other mechanisms than autoantibody production.

Epidemiology and outcome of adult-onset Still's disease in Northern Norway.

BACKGROUND: Adult-onset Still's disease (AOSD) is considered a rare disease, but few data exist on the incidence and prevalence of AOSD. This study has analysed the epidemiology, disease presentation, and outcome of AOSD in a stable homogeneous population in Northern Norway. METHODS: A retrospective cohort study of all AOSD patients registered in 1990-2000 at the only hospital in the region with a Rheumatology Service. Clinical diagnosis and exclusion of patients were directed by the Yamaguchi criteria for AOSD. Demographic and clinical data at baseline were extracted from patient records and supplemented with data gathered at control visits. Data were analysed with nonparametric methods. RESULTS: AOSD was ascertained in 13 patients; the estimated annual AOSD incidence was 0.4/100,000 adults (95% CI 0.11-0.97), while point prevalence of AOSD increased from 3.4/100,000 (95% CI 0.8-9.4) in 1990 to 6.9/100,000 in 2000 (95% CI 2.7-14.2). Mean diagnostic delay was 5.2 months (range 0.5-18). Serum ferritin > 5 times the normal upper level had 63% diagnostic sensitivity. During 69 months' follow-up, one patient died, 6/13 patients achieved sustained remission, while six patients developed a chronic progressive (n = 3) or a relapsing/remitting disease course (n = 3). Four of these six patents had to enter social security programmes. CONCLUSION: The annual incidence of AOSD in Northern Norway is at least 0.4/100,000 adults. AOSD in this region is more prevalent than in France or Japan, affects more males, and approximates to the prevalence of juvenile Still's disease. Half of all patients have a monocyclic disease course, while mortality and invalidity occur in patients with chronic disease.

Rheumatoid factor by laser nephelometry and Waaler-Rose assay: prognostic value in patients with recent-onset rheumatoid arthritis.

OBJECTIVE: To evaluate the prognostic value of rheumatoid factor (RF), detected in the Waaler-Rose agglutination assay and by nephelometry, in patients with recent-onset rheumatoid arthritis (RA). METHODS: Consecutive patients with new-onset RA between 1993 and 1997 were followed for a median period of 4.7 years. Clinical data at baseline and drug use during the disease course were recorded. Outcome parameters studied were disease process, damage (erosions, joint surgery, extra-articular manifestations, and new co-morbidity), and death. Cut-off levels for RF were >40 IU/mL (nephelometry) and titres 1:160 (Waaler-Rose haemagglutination). RESULTS: RF tests were negative by both methods in 22% of RA patients (RF- group), while 33% were RF positive by nephelometry only (RF+ group) and 45% were positive by Waaler-Rose and nephelometry (RF++ group). Baseline clinical and laboratory findings as well as the number of subsequently used disease-modifying anti-rheumatic drugs (DMARDs), the number of patients starting and the time spent on steroid therapy were similar in the three RF groups. Odd ratios for death (n = 23), erosions (n = 62), and serious extra-articular disease manifestations (EAMs) (n = 13) as well as patient survival, erosion-free or surgery-free survival rates did not differ between the RF groups. Only rheumatoid nodules were more frequent in RF++ patients. CONCLUSION: The baseline presence of RF by either Waaler-Rose or nephelometry was not associated with differences in drug therapy, morbidity other than rheumatoid nodules, or mortality in RA patients in the first 5 years of disease. Being immunoglobulin M (IgM) RF positive thus had little impact on RA patient outcome.

Pulmonary function and high-resolution CT findings five years after disease onset in patients with Wegener's granulomatosis.

OBJECTIVE: Although pulmonary involvement is common in Wegener's granulomatosis (WG), little is known about the pulmonary outcome. We evaluated the relationship between clinical disease characteristics and pulmonary function and high-resolution computed tomography (HRCT) findings after disease duration of 5 years. METHODS: A pulmonary function test (PFT) and pulmonary HRCT were performed in 41 patients from a population-based register of WG. Clinical predictors for abnormal PFT and HRCT were tested by logistic regression. RESULTS: Previous WG-related lung involvement (PLI) had occurred in 80% of patients, but only 24% of patients still reported pulmonary symptoms at the research visit. One-third of patients had abnormal PFT findings, with reduced alveolar diffusion by KCO (transfer coefficient) being most common (24%). The number of PLI episodes was associated with reduced KCO and reduced FEV1% (forced expiratory volume in 1 s as a percentage of forced vital capacity) (overall presence 10%). Reduced KCO was also associated with disease duration. Reduced total lung capacity (TLC) (overall presence 8%) was only related to prior WG-related lung nodules. Pulmonary HRCT was abnormal in 80%, but with more severe abnormalities in only 30%. Pleural thickening and parenchymal bands were associated with PLI. None of the treatment variables was associated with the PFT or HRCT findings. CONCLUSION: Five years after disease onset a quarter of the WG patients reported pulmonary symptoms, had severe abnormalities on HRCT, and abnormal PFT. The correlation between these abnormalities was poor, but the number of pulmonary involvements was a risk factor for reduced gas diffusion, obstructive lung disease, parenchymal bands, and pleural thickening. Treatment variables had no discernible negative pulmonary effects.

Systemic lupus erythematosus in the Arctic region of Norway.

OBJECTIVE: The marked regional variation in the incidence, prevalence, and presentation of systemic lupus erythematosus (SLE) is possibly related to differing spectra of local environmental factors. The aim of this study was to describe such features in a homogenous Caucasian population exposed to an Arctic climate. METHODS: The study area consisted of the 2 northernmost counties of Norway (middle population 222,403) where 4 hospitals (containing only one rheumatology service) provide specialized health care. Retrieval sources were (1) hospital inpatient discharge registries; (2) hospital outpatient registries; (3) mortality database of the National Office for Statistics. Databases were searched with codes for SLE, S ogren's syndrome, unclassified connective tissue disease, and discoid lupus for the period 1978-96. Only patients meeting 1982 American College of Rheumatology criteria for SLE were included in the analysis. Annual incidence rate (AIR), point prevalence (PP), and mortality rates were estimated per 100,000 at risk. RESULTS: Eighty-three incident cases of adult SLE (87% female, mean age 40.6 yrs at diagnosis) were encountered. Crude AIR of SLE in the whole study period was 2.6 (95% CI 1.9-2.9) for adults. Sex-specific AIR was 4.6 for adult women and 0.6 for adult men. AIR in the first (2.4) and second 9-year period (2.7) was similar (p > 0.2). The crude overall PP for SLE at January 1, 1996, was 44.9 and was highest in women aged 3149 (PP 102.5). Mortality in incident cases was 9.6% (after a mean followup of 99 mo) with overall 10-year survival estimated at 75%. CONCLUSION: In a Caucasian population exposed to the Arctic climate incidence of SLE is rather low and stable. Course and presentation of SLE in the Arctic is not different from similar populations in the Western world. Improved outcome now makes SLE a disease present in 1 per 1,000 Norwegian women aged > 30 years.

Efficacy of methylprednisolone pulse therapy versus infliximab in the treatment of severe flares of chronic polyarthritis.

BACKGROUND: To compare short term efficacy of pulse intravenous (iv) Methylprednisolone (MP) versus Infiximab in flares of polyarthritis. PATIENTS-METHODS: Observational study of consecutive patients admitted with flares of chronic polyarthritis. Treatment consisted of three iv doses of MP 1000mg on alternate days (MP-group, n = 10) or of Infliximab will be 3 mg/kg at baseline, two, and six weeks later (I-group, n=9). DMARD therapy was initiated/continued in all patients. Disease parameters at baseline (t=0), two weeks (t=1) and twelve weeks (t=2) were compared by non-parametric testing. RESULTS: Reductions in disease parameters at both t=1 and t=2, the occurrence of side effects and the proportion of patients reaching ACR 20, 50 or 70% response criteria were similar in both groups. CONCLUSION: Pulse MP resulted in a symptomatic response similar to Infliximab in our patients. The benefit of MP was observed for up to 3 months.

Long-term efficacy of azathioprine treatment for proliferative lupus nephritis.

BACKGROUND: Combination therapy with cytotoxic drugs and corticosteroids reduces the risk for renal failure in patients with proliferative lupus nephritis (PLN), but uncertainty remains about the best mode of immunosuppression and its long-term effects. We report long-term results of combined azathioprine-prednisolone treatment for PLN, which has been the therapy of choice for the treatment of PLN at our centre for 15 yr. PATIENTS AND METHODS: A retrospective cohort study was carried out of 26 lupus patients, seen between 1978 and 1993, with histological and/or clinical evidence of PLN. Therapy consisted of prednisolone 1 mg/kg daily, tapered after 4 weeks to the lowest possible maintenance dose combined with azathioprine up to 2.5 mg/kg. Median duration of azathioprine treatment was 53 months. Standard statistical lifetable analyses were performed. RESULTS: Median follow-up on 1 January 1998 was 119 months. Patient survival estimates after 5, 10 and 15 yr of follow-up were 96, 91 and 82%, respectively. Four patients (15%) developed end-stage renal failure and three received renal transplants after a mean period of 27 months on haemodialysis. Renal survival estimates after 5, 10 and 15 yr of follow-up were 92, 87 and 87%, respectively. No malignancies were seen during the study period. CONCLUSION: Azathioprine treatment for 4-1/2 yr was well tolerated in this cohort of Caucasian patients with PLN and was associated with outcomes similar to those reported for pulse cyclophosphamide therapy.

Acute chest syndrome in adult Afro-Caribbean patients with sickle cell disease. Analysis of 81 episodes among 53 patients.

BACKGROUND: To evaluate the frequency, presentation, and course of the acute chest syndrome (ACS) in adult Afro-Caribbean patients with sickle cell disease (SCD). PATIENTS AND METHODS: Retrospective cohort study during a 12-year period in patients with SCD at least 14 years of age, discharged with a diagnosis of ACS from the only hospital on the Caribbean island of Curaçao, where 109 patients with SCD (62 HbSS, 47 HbSC) were observed. RESULTS: Eighty-one episodes of ACS occurred (57 in 34 patients with HbSS and 24 in 19 patients with HbSC). The risk (odds ratio, 1.80; P = .13) and incidence (7.6 vs 4.2 per 100 patient-years; P > .2) of ACS did not differ between patients with HbSS and HbSC, but recurrent ACS affected patients with HbSS more (odds ratio, 2.96; P = .09). Abnormal chest sounds (mainly bilateral crepitations) were found in 91% of cases at diagnosis, but 48% had normal chest roentgenograms at that time and had delayed development (5.4 +/- 3.4 days) of radiologic abnormalities. Patients with HbSS and HbSC had similar clinical presentations. Mortality (6%) and hospital stay (20 days) were not influenced by the use of transfusions or anticoagulation. All five nonsurviving female patients with HbSS had had more previous admissions for SCD and ACS. CONCLUSIONS: Acute chest syndrome occurs in 42% of adult Afro-Caribbean patients with SCD; patients with HbSS are more prone to recurrences. Delayed development of radiologic infiltrates is common. Interventions apart from supportive care do not influence the course of ACS. Fatal ACS occurs in patients with a more severe form of SCD.

Systemic lupus erythematosus after renal transplantation: patient and graft survival and disease activity. The Dutch Working Party on Systemic Lupus Erythematosus.

OBJECTIVE: To determine the outcome of renal transplantation in patients with systemic lupus erythematosus and end-stage renal failure and to compare disease activity after transplantation with disease activity before transplantation. DESIGN: Retrospective case finding using data for an 8-year period from the central registry for renal replacement therapy in The Netherlands. SETTING: Tertiary care hospitals with facilities for renal transplantation in the Netherlands. PATIENTS: Twenty-eight patients who fulfilled at least four of the American Rheumatology Association's criteria for the classification of systemic lupus erythematosus and who received a renal transplant. MEASUREMENTS: Actuarial survival rates for grafts and patients after transplantation, maximal nonrenal scores on the Systemic Lupus Erythematosus Disease Activity Index, and time-adjusted disease exacerbation rates in all patients before and after transplantation. RESULTS: The actuarial graft survival rate at 1 year and 5 years was 68% (95% CI, 47% to 82%) and 54% (CI, 25% to 77%), respectively, whereas the actuarial patient survival rate was 87% (CI, 69% to 96%) at 1 and 5 years. High disease activity was not found to affect graft survival adversely before the start of renal replacement therapy or during dialysis. After transplantation, disease activity per patient and the overall incidence of disease exacerbations decreased. One case of recurrent lupus nephritis was seen. CONCLUSIONS: Patients with systemic lupus erythematosus and end-stage renal failure are excellent candidates for renal transplantation; disease activity after transplantation is sporadic and low, and the recurrence of lupus nephritis is rare.

Systemic lupus erythematosus: analysis of disease activity in 55 patients with end-stage renal failure treated with hemodialysis or continuous ambulatory peritoneal dialysis. Dutch Working Party on SLE.

PURPOSE: To compare disease activity in patients with systemic lupus erythematosus (SLE) (1) before and after the onset of end-stage renal failure and (2) during hemodialysis and continuous ambulatory peritoneal dialysis (CAPD). PATIENTS AND METHODS: Records of 55 patients with SLE currently being treated with dialysis were reviewed. Disease activity was measured according to the SLE Disease Activity Index, event rates per 1,000 months' patient observation, and use of medication. RESULTS: In the majority of patients, deterioration of renal function was slowly progressive over more than 2 years. After the initiation of dialysis for end-stage renal failure, maximal extrarenal disease activity and use of medication decreased markedly, but event rates for specific nonrenal manifestations of lupus did not decrease. Overall survival with dialysis was 89% after 5 years. During dialysis no difference was found in disease activity and use of medication between treatment with either hemodialysis of CAPD. Thrombocytopenia and elevated levels of anti-double-stranded DNA, however, occurred more frequently during CAPD. CONCLUSION: Patients with SLE have excellent survival rates with dialysis; their disease activity is diminished during dialysis but not abolished. No difference in survival or disease activity was found between patients undergoing hemodialysis or CAPD.

Contribution of renal biopsy data in predicting outcome in lupus nephritis. Analysis of 116 patients.

We reassessed renal biopsy specimens from 116 patients with systemic lupus erythematosus and clinical manifestations of lupus nephritis to determine the contributions of the World Health Organization classification system, the activity and chronicity indexes of the National Institutes of Health scoring system, and various clinical parameters at the time of biopsy to predicting disease outcome. Multivariate analysis showed that only a chronicity index greater than 3 was predictive for decreased renal survival, while age greater than 31 years at biopsy and a chronicity index greater than 3 were associated with decreased patient survival. Clinical tests of renal function were not reliable in discriminating between active lesions and chronic renal damage.

Systemic lupus erythematosus. VI. Analysis of the interrelationship with pregnancy.

The influence of systemic lupus erythematosus (SLE) on pregnancy and vice versa was examined during 39 pregnancies in 19 patients, and outcome was compared with 24 pregnancies in 18 other patients before SLE was established. No difference in fetal loss or premature birth rate was found, although more babies were born with low birth weight after SLE was diagnosed; there was a preponderance of female babies in both groups. Pregnancy during SLE was accompanied by disease exacerbations in up to 74% of all patients. These exacerbations concerned mostly musculoskeletal (41%) and hematological abnormalities (36%), while organ involvement occurred in 13% of all exacerbations. No differences in pregnancy outcome during SLE were found between patients with active or quiescent disease, as established by the lupus activity criteria count (LACC). The presence of antibodies to SSA in the mother was associated with the occurrence of congenital heart block; no association was found between antiphospholipid antibodies and fetal loss.