Thomas Skogh

Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)

Objectives: To evaluate the diagnostic sensitivity of antibodies to cyclic citrullinated peptide (CCP) in recent onset rheumatoid arthritis (RA) at diagnosis and 3 years later, and to evaluate anti-CCP antibody as a predictor of the disease course during 3 years. Methods: 242 patients with recent onset (⩽1 year) RA were followed up regularly during 3 years after inclusion in the Swedish multicentre study “TIRA” 1996–98. Anti-CCP antibodies were analysed by an enzyme immunoassay (EIA). Rheumatoid factors (RFs) were analysed by latex agglutination and two isotype-specific (IgM and IgA) EIAs. Disease activity was assessed by plasma CRP, ESR, 28 joint disease activity score, and the physician’s global assessment of disease activity. Functional ability was evaluated by the Health Assessment Questionnaire. Results: Overall, the diagnostic sensitivity of anti-CCP antibodies was 64% and the proportion of positive tests increased with the number of fulfilled classification criteria according to the American College of Rheumatology. The anti-CCP antibody results correlated with RF, but were better than RF as predictor of a more aggressive disease course. After 3 years 5/97 patients had changed anti-CCP status: 2 from negative to positive and 3 from positive to negative. The mean level of anti-CCP antibodies declined by 131 U/ml during the 3 year follow up (95% CI 34 to 228 U/ml). Conclusion: The anti-CCP antibody assay has a similar diagnostic sensitivity to that of RF in early RA, but is better as a predictor of the disease course over 3 years. Although the mean serum level declines, anti-CCP antibody positivity remains essentially unaltered 3 years after diagnosis and start of antirheumatic treatment.

Annual incidence of inflammatory joint diseases in a population based study in southern Sweden

Objective: To estimate the annual incidence of inflammatory joint diseases in a population based prospective referral study in an adult population in Kronoberg County in southern Sweden. Methods: The patients were referred from primary healthcare centres to the rheumatology department in Växjö Central Hospital or to the one private rheumatologist in Växjö participating in the study. Additionally, the hospital records for patients with joint aspirates during the inclusion period were checked. The patients were registered as incident cases if the onset of the joint inflammation was between 1 May 1999 and 1 May 2000. A systematic follow up of incoming referrals was conducted up to 31 January 2001. Children under the age of 16 and patients with septic arthritis, crystal arthropathies, and osteoarthritis were excluded from the study. Results: A total of 151 new cases with inflammatory joint diseases were identified during one year, corresponding to a total annual incidence of 115/100 000. Of these, 31 patients (21%) had rheumatoid arthritis, the annual incidence being 24/100 000 (for women 29/100 000, and for men 18/100 000). Reactive arthritis was diagnosed in 37 patients (24%, annual incidence 28/100 000) and 54 patients had undifferentiated arthritis (36%, annual incidence 41/100 000). Eleven patients presented with psoriatic arthritis (7%, annual incidence 8/100 000). The incidence of Lyme arthritis was small in this non-endemic area, and the incidence of sarcoid arthritis corresponded to that in earlier studies. Conclusion: This is the first prospective population based annual incidence study of early arthritis in Sweden. In this population, 36% of the incident cases had undifferentiated arthritis, whereas rheumatoid arthritis and reactive arthritis accounted for 45% of the cases. The incidence figures compare well with figures reported from other countries.

Comorbidity and lifestyle, reproductive factors, and environmental exposures associated with rheumatoid arthritis

OBJECTIVE To evaluate the influence of lifestyle, reproduction, and some external factors on the development of rheumatoid arthritis (RA) and to describe its comorbidity. METHODS Cases were identified retrospectively from 1980 to 1995 at the University Hospital in Linköping, Sweden. The study comprised 422 cases and 859 randomly selected population referents. Data on possible aetiological factors and comorbidity were collected by postal questionnaire. RESULTS The response rates were 67% among cases and 59% among referents. A decrease in the occurrence of atopic allergy was seen in the cases (odds ratio (OR) 0.6, 95% confidence interval (CI) 0.4 to 1.0). There was a positive association between RA and insulin treatment (OR 10.2, 95% CI 1.7 to 60.8) in women, and women with a short fertile period had an increased risk of RA (OR 2.5, 95% CI 1.1 to 5.4). Current and previous smoking were associated with increased risks for RA in both sexes, and in men a dose-response relationship was found with number of tobacco pack years (p for trend <0.005). The risk for RA decreased with increasing level of education in both men and women. Increased risks were seen in men born into households with private wells (OR 2.8, 95% CI 1.5 to 5.2), residentially exposed to mould (OR 4.6, 95% CI 1.1 to 20.2), or exposed to farm animals (OR 3.3, 95% CI 0.7 to 16.6). In women there were positive associations between RA and reporting a previous joint injury (OR 2.5, 95% CI 1.0 to 6.6) and prolonged exposure to hair dyes (OR 1.9, 95% CI 0.8 to 4.5). CONCLUSIONS RA, a disease with features of T helper 1 (Th1) dominated immune response, was inversely associated with atopic allergy, a Th2 dominated condition, while there were indications of a strong positive association with Th1 related diabetes mellitus. The results support a causal relationship between smoking and RA. The level of education was inversely associated with RA, while there was a positive association between RA and certain residential factors in men and a short fertile period in women.

Is small bowel biopsy necessary in adults with suspected celiac disease and IgA anti-endomysium antibodies? 100% positive predictive value for celiac disease in adults.

The comparative diagnostic value of IgA anti-endomysium and IgA antigliadin antibodies in adults with histologically confirmed celiac disease is reported. Sera from 144 adult patients (without concurrent dermatitis herpetiformis or IgA deficiency) who underwent small bowel biopsy were analyzed for both IgA anti-endomysium and IgA anti-gliadin antibodies. Nineteen patients (13%) had celiac disease. The presence of IgA antiendomysium antibodies had a sensitivity of 74% and a specificity of 100%. The positive and negative predictive values were 100% and 96%, respectively, and the diagnostic accuracy was 97%. In contrast, IgA anti-gliadin antibodies had positive and negative predictive values of 28% and 96%, respectively, with a diagnostic accuracy of 71%. Based on these data, we suggest that small bowel biopsy is not necessary to diagnose celiac disease in symptomatic adults with IgA antiendomysium antibodies. Due to a negative predictive value of 96%, some symptomatic adults lacking anti-endomysium antibodies will not be correctly diagnosed without small bowel biopsy.

Serum levels of autoantibodies against monomeric C-reactive protein are correlated with disease activity in systemic lupus erythematosus

This study was performed to investigate the relation between IgG autoantibodies against human C-reactive protein (anti-CRP) and disease activity measures in serial serum samples from 10 patients with systemic lupus erythematosus (SLE), of whom four had active kidney involvement during the study period. The presence of anti-CRP was analysed by enzyme-linked immunosorbent assay. The cut-off for positive anti-CRP test was set at the 95th centile of 100 healthy blood donor sera. Specificity of the anti-CRP antibody binding was evaluated by preincubating patient sera with either native or monomeric CRP. Disease activity was determined by the SLE disease activity index (SLEDAI), serum levels of CRP, anti-DNA antibodies, complement components and blood cell counts. Of 50 serum samples, 20 (40%) contained antibodies reactive with monomeric CRP, and 7 of 10 patients were positive on at least one occasion during the study. All patients with active lupus nephritis were positive for anti-CRP at flare. Frequent correlations between anti-CRP levels and disease activity measures were observed in anti-CRP-positive individuals. Accumulated anti-CRP data from all patients were positively correlated with SLEDAI scores and anti-DNA antibody levels, whereas significant inverse relationships were noted for complement factors C1q, C3 and C4, and for lymphocyte counts. This study confirms the high prevalence of anti-CRP autoantibodies in SLE and that the antibody levels are correlated with clinical and laboratory disease activity measures. This indicates that anti-CRP antibodies might have biological functions of pathogenetic interest in SLE. Further prospective clinical studies and experimental studies on effects mediated by anti-CRP antibodies are warranted.

Occupations and exposures in the work environment as determinants for rheumatoid arthritis

Background and Aims: Several occupational categories have been associated with rheumatoid arthritis (RA); this study was conducted to further evaluate these associations. Methods: Lifelong occupational history together with exposure experiences were collected through a postal questionnaire answered by 293 incident cases and 1346 population based referents. Occupational determinants were evaluated through stratified and multivariate analyses; pooled analyses with previously gathered data on 422 prevalent cases and 858 referents were also performed. Results: In both materials, significantly increased logistic odds ratios (LORs) were seen for male conductors, freight and transport workers (LOR 17.8, 95% CI 1.5 to 207.8 and LOR 4.7, 95% CI 1.4 to 16.3, respectively), and farmers and farm workers (LOR 2.4, 95% CI 1.1 to 5.2, and LOR 2.2, 95% CI 1.3 to 3.5, respectively). Among women, increased LORs were seen in the separate and the pooled material for printmakers and process engravers (LOR 5.5, 95% CI 0.9 to 32.6, and LOR 3.0, 95% CI 0.9 to 10.3, respectively). Increased risks were seen in both materials for men exposed to asbestos (LOR 2.5, 95% CI 1.0 to 6.8, and LOR 1.6, 95% CI 0.8 to 3.3, respectively), and vibrations (LOR 2.0, 95% CI 0.9 to 4.4, and LOR 2.2, 95% CI 1.3 to 3.8, respectively). The risk for RA increased with increasing duration of exposure to vibrations and mineral dust, respectively. Conclusions: There was evidence of a causal relation between exposures to vibrations and mineral dust and development of RA among men. Occupational factors seem to be aetiologically more important for men, and most occupations at risk involve multiple exposures. Several exposures associated with an increased risk for RA are frequent among farmers, and some of the occupations at risk include exposure to organic dust.

Comparison between women and men with recent onset rheumatoid arthritis of disease activity and functional ability over two years (the TIRA project)

Objective: To describe the course of recent onset rheumatoid arthritis (RA) and to compare consequences of the disease in men and women. Methods: 284 patients with recent onset RA were followed up prospectively for two years from the time of diagnosis. Measures of disease activity (for example, 28 joint disease activity score (DAS28), C reactive protein, morning stiffness, physician’s global assessment) and function outcome (for example, range of movement, hand function, walking time) were determined. The patients’ self reported assessment of functional capacity (Health Assessment Questionnaire (HAQ)) and grading of wellbeing and pain (visual analogue scale) were registered. Changes over time and differences between men and women were evaluated. Results: Improvements were seen for all variables within the first three months. Disease activity then remained unchanged. Function variables followed the same pattern during the first year, but then tended to worsen. HAQ scores were similar at baseline, but significantly worse in women than in men at the one and two year follow ups. Conclusions: Disease activity was well managed and had improved substantially after two years, whereas function seemed slowly to deteriorate. Although disease variables were similar for men and women, functional ability (HAQ) had a less favourable course in women.

Lymphocyte subsets and autoantibodies in pregnancies complicated by placental disorders.

PROBLEM: The survival of the fetoplacental unit might partly depend on down‐regulation of rejection reactions. Pathological maternal cellular immune response mechanisms could therefore be of pathogenic importance in pregnancies complicated by placental disorders.

Improved outcome in Wegener's granulomatosis and microscopic polyangiitis? A retrospective analysis of 95 cases in two cohorts

Objectives.  Mortality rates for Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) have decreased after the introduction of cyclophosphamide. Standardized mortality ratio (SMR) expresses the overall mortality of patients compared with the general population. The aims of this study were to compare survival in an old and a recent cohort of patients with WG and MPA using SMR and to determine predictors for death in both groups combined.

Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?

OBJECTIVE C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFNalpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. METHODS The interference of all 12 IFNalpha subtypes with CRP promoter activity induced by IL-6 and IL-1beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. RESULTS CRP promoter activity was inhibited by all single IFNalpha subtypes, as well as by 2 different mixtures of biologically relevant IFNalpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFNalpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFNalpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFNalpha. CONCLUSION The current study demonstrates that IFNalpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFNalpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFNalpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.