Ragnar Gunnarsson

The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients

Objectives Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown aetiology. As the epidemiology of the disease is largely unknown, the authors performed a nationwide cross-sectional retrospective study to assess the prevalence and incidence of MCTD in Norway. Methods Every adult patient (≥18 years) with MCTD seen at one of the departments of rheumatology was reviewed for inclusion. Only patients who satisfied the following four criteria were included: clinical diagnosis of MCTD verified by a rheumatologist; positive serum anti-ribonucleoprotein antibody test; fulfilment of at least one of three of following criteria sets: the modified Sharps criteria, the criteria of Alarcón-Segovia and Villareal and those of Kasukawa; and exclusion of other connective tissue diseases. Results The four inclusion criteria were fulfilled by 147 adult Caucasian patients. The female to male ratio was 3.3 and the mean age at diagnosis of adult-onset MCTD was 37.9 years (95% CI 35.3 to 40.4 years). At the end of 2008, the point prevalence of living adult MCTD patients in Norway was 3.8 (95% CI 3.2 to 4.4) per 100 000 adults. The incidence of adult-onset MCTD in Norway during the period from 1996 to 2005 was 2.1 (95% CI 1.7 to 2.5) per million per year. Conclusions MCTD has a female predominance and the incidence and prevalence of MCTD is low, and lower than reported figures for polymyositis, dermatomyositis, systemic sclerosis and systemic lupus erythematosus. The prevalence estimates were similar across the three criteria sets of MCTD.

Performance of the 2013 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis (SSc) in Large, Well-defined Cohorts of SSc and Mixed Connective Tissue Disease

Objective. To assess the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria for Systemic Sclerosis (SSc) on defined subgroups of SSc and in mixed connective tissue disease (MCTD) as an SSc-related disease. Methods. The 2013 ACR/EULAR criteria were assessed in 425 consecutive patients suspected to have SSc and seen at Oslo University Hospital, and in the nationwide Norwegian MCTD cohort (n = 178). In the SSc group, 239/425 patients had disease duration < 3 years (in 82 of these, duration was < 1 yr). Patients were subgrouped as limited SSc (n = 294), diffuse SSc (n = 97), SSc sine scleroderma (n = 10), and early SSc (prescleroderma; n = 24). Item data were complete, except nailfold capillaroscopy and telangiectasia results, missing in the MCTD cohort. Results. The 2013 ACR/EULAR SSc criteria were met by 409/425 patients (96%) in the SSc group. For comparison, only 75% (293/391) met the 1980 ACR SSc classification criteria. All the novel items in the 2013 ACR/EULAR criteria were frequent in the SSc cohort. Considering that there were missing data on 2 items, 10% (18/178) of the MCTD cohort met the 2013 ACR/EULAR criteria, giving an estimated specificity of 90% toward this SSc-like disorder. Conclusion. In our large and representative group of consecutive patients with SSc, the 2013 ACR/EULAR SSc criteria were more sensitive than the ACR 1980 criteria. However, the new criteria did not completely segregate SSc from MCTD, making specificity a potential issue.

Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian cross-sectional multicentre study and review of current literature

OBJECTIVES The aim of this study was to assess the overall prevalence of pulmonary hypertension (PH) in an unselected MCTD cohort and review the current knowledge with a systematic database search. METHODS A nationwide multicentre cohort of 147 adult MCTD patients were initially screened for PH by echocardiography, high-resolution computed tomography (HRCT), pulmonary function tests and N-terminal pro-brain natriuretic peptide (NT-proBNP) and then followed up for a mean of 5.6 years. Right-sided heart catheterization was performed when estimated pulmonary artery systolic pressure was >40 mmHg on echocardiography. PH was diagnosed according to the 2009 European Society of Cardiology and European Respiratory Society guidelines. RESULTS At inclusion, 2.0% (3/147) had established PH. Two additional PH patients were identified during follow-up, giving a total PH frequency in the cohort of 3.4% (5/147). All five had elevated serum NT-proBNP. Two had isolated pulmonary arterial hypertension (PAH) and three PH associated with interstitial lung disease (PH-ILD). Three PH patients died during follow-up. Nine other patients in the cohort also died, but none of them had echocardiographic signs of PH prior to death. CONCLUSION The data from the current unselected MCTD cohort suggest that the prevalence of PH is much lower than expected from previous studies but confirm the seriousness of the disease complication.

The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases

OBJECTIVE The Norwegian nationwide MCTD cohort was established to obtain unbiased data on key disease issues, and thereby reappraise the concept of MCTD. In the current study, the aims were to obtain detailed HLA profile data on the large Norwegian MCTD cohort and compare these with the HLA profiles of ethnically matched healthy controls and related CTD controls. METHODS HLA profiles, determined by sequence-based typing of HLA-B* and DRB1*, were compared between four control groups of Norwegian ancestry, SLE (n = 96), SSc (n = 95), PM/DM (n = 84), healthy individuals (n = 282), the complete MCTD cohort (n = 155) and MCTD subsets defined by key clinical parameters. RESULTS HLA-B*08 [odds ratio (OR) 2.05, P = 1.31 × 10(-4)) and DRB1*04:01 (OR 2.82, P = 3.64 × 10(-8)) were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE and PM/DM were B*08 and DRB1*03:01. SSc risk was associated with DRB1*08:01. Analyses of MCTD subsets identified B*18 [OR 3.32 (95% CI 1.38, 8.01)] and DRB1*03:01 [OR 1.83 (95% CI 1.03, 3.25)] as independent risk factors for lung fibrosis. CONCLUSION Novel HLA alleles associated with MCTD and disease subsets were identified and DRB1*04:01 was confirmed as a major risk allele. Altogether, the data reinforce the notion of MCTD as a disease entity distinct from SLE, SSc and PM/DM.

Associations between anti-Ro52 antibodies and lung fibrosis in mixed connective tissue disease

OBJECTIVE MCTD is a chronic, immune-mediated disorder defined by the combined presence of serum anti-RNP antibodies and distinct clinical features, including progressive lung fibrosis. The aim of the study was to evaluate the potential impact of anti-SSA (i.e. Ro52 and Ro60) and anti-SSB autoantibodies as markers for disease outcomes in MCTD. METHODS Stored serum samples from 113 patients included in the cross-sectional, nationwide Norwegian MCTD cohort were screened for the presence of anti-Ro52, anti-Ro60 and anti-SSB by a commercial line immunoassay. Correlation analyses were carried out with clinical parameters, including quantitative lung fibrosis scores by high-resolution CT. Lung fibrosis was defined by reticular pattern changes according to the Fleischner Society CT criteria for interstitial lung disease. RESULTS Anti-Ro52 antibodies were present in 29%, anti-Ro60 in 19% and anti-SSB in 6% of the MCTD sera. High-resolution CT scoring identified lung fibrosis in 38 of 113 (34%) MCTD patients. Anti-Ro52 antibodies were detected in 50% (19 of 38) of the MCTD patients with lung fibrosis and in 19% (14 of 75) without lung fibrosis (P < 0.001). The odds ratio for the presence of anti-Ro52 antibodies in lung fibrosis was 4.4 (95% CI 1.8, 10.3). Anti-Ro52 antibodies were equally frequent in patients with mild to moderate (eight of 17; 44%) and severe fibrosis (11 of 21; 52%). Anti-Ro52 was not associated with any of the other clinical parameters assessed, nor was anti-Ro60 or anti-SSB. CONCLUSION Our cross-sectional data suggest that anti-Ro52 antibodies may serve as a potential marker for lung fibrosis in MCTD.

[A man with erythrodermia, muscle weakness and weight loss].

A man in his late fifties was treated with acitretin for psoriasis. The treatment was discontinued when liver enzymes started to increase. He subsequently developed erythrodermia, weakness of proximal muscle groups, heliotrope rash, Gottrons papules and elevation of creatine kinase to more than 9000 U/L. However, histological examination of a muscle biopsy displayed neuropathic atrophy and only a few scattered necrotic fibers. Alpha 1 foetoprotein was substantially elevated (1600 kU/L) and computed tomography showed two hepatic tumors, lytic lesions in the spine and in the ninth rib. Although no chronic liver disease could be documented, the patient was found to have a hepatocellular carcinoma which presented as dermatomyositis and erythrodermia.

Progression and mortality of interstitial lung disease in mixed connective tissue disease: a long-term observational nationwide cohort study

Objectives To assess the prevalence, extent, progression, functional impact and mortality of interstitial lung disease (ILD) in a nationwide unselected MCTD cohort. Methods The study cohort included patients with high-resolution CT lung scans available at baseline (n = 135) and at follow-up (n = 119). The extent of disease was expressed as percentage of total lung volume (TLV). Results ILD was present in 41% of MCTD patients at follow-up. Median (interquartile) extent (% of TLV) was 5 (8) at baseline and 7 (17) at follow-up, mean length 6.4 years later. The lung disease progressed in 19% of patients across the observation period. Predictors of ILD progression were elevated anti-RNP titre [hazard ratio (HR) 1.5, 95% CI: 1.1, 2.0; P = 0.008], presence of anti-ro52 antibodies (HR = 3.5, 95% CI: 1.2, 10.2; P = 0.023), absence of arthritis (HR = 0.2, 95% CI: 0.1, 0.6; P = 0.004) and male gender (HR = 4.0, 95% CI: 1.4, 11.5; P = 0.011) after age and baseline disease adjustments. The risk of death increased by 2.9 (95% CI: 1.1, 7.9; P = 0.038) in patients where disease involved ⩾5% of TLV. Conclusion Lung disease extent and progression in MCTD are modest. Yet, the extension continues several years after MCTD diagnosis causing lung function decline and increasing the risk of mortality. The study identified male gender, elevated anti-RNP titre, presence of anti-ro52 antibodies and absence of arthritis as the strongest predictors of ILD progression.

Frequencies of borderline pulmonary hypertension before and after the DETECT algorithm: results from a prospective systemic sclerosis cohort

Objective The DETECT algorithm was developed for screening patients with SSc at high risk of pulmonary arterial hypertension (PAH). We evaluated the impact of this algorithm in a SSc population. Methods Patients from the unselected, prospective Oslo University Hospital SSc study were divided into the Early and DETECT cohorts, respectively, depending on whether an incident right heart catheterization (RHC) was performed before (2009-13) or after (2014-17) the DETECT algorithm was instituted. A PAH diagnosis and patient risk stratification (low, intermediate and high risk) were performed according to 2015 European Society of Cardiology guidelines. Results At the time of the incident RHC, PAH frequency was similar between the DETECT (15/84 with PAH; 18%) and Early (16/77; 21%) cohorts, but more patients had borderline pulmonary hypertension (PH) in the DETECT (31%) than in the Early (17%) cohort. PAH risk levels were distributed differently. In the DETECT cohort, 27% and 27% were at low and high risk, respectively, at the time of PAH diagnosis. In the Early cohort, 19 and 44% were at low and high risk, respectively. A follow-up RHC, performed after [mean (SD)] 2.4 (1.8) years, showed that 39% of patients with borderline PH in the Early cohort had developed PAH. Conclusion The DETECT algorithm did not alter PAH incidence in this unselected SSc population. However, it appeared to affect the risk distribution at the time of PAH diagnosis and increased the frequency of borderline PH cases. These findings may translate into novel opportunities for earlier PAH treatment and, possibly, prevention.

Mortality and causes of death across the systemic connective tissue diseases and the primary systemic vasculitides

Objectives Studies assessing relative mortality risks across the spectrum of systemic inflammatory rheumatic diseases are largely missing. In this study, we wanted to estimate standard mortality ratios (SMRs) and causes of death in an ethnically homogeneous cohort covering all major CTDs and primary systemic vasculitides (PSVs). Methods We prospectively followed all incident CTD and PSV cases included in the Norwegian CTD and vasculitis registry (NOSVAR) between 1999 and 2015. Fifteen controls for each patient matched for sex and age were randomly drawn from the Norwegian National Population Registry. Causes of death were obtained from the National Cause of Death Register, death certificates and hospital charts. Results The cohort included 2140 patients (1534 with CTD, 606 with PSV). During a mean follow-up time of 9 years, 279 of the patients (13%) died, compared with 2864 of 32 086 (9%) controls (P < 0.001). Ten years after diagnosis, the lowest survival was 60% in dcSSc, 73% in anti-synthetase syndrome (ASS) and 75% in lcSSc. In the CTD group, the highest SMRs were observed in dcSSc (SMR 5.8) and ASS (SMR 4.1). In the PSV group, Takayasu arteritis (SMR 2.5) and ANCA-associated vasculitis (SMR 1.5) had the highest SMRs. Major causes of death were cardiovascular disease (CTD 27%, PSV 28%), neoplasms (CTD 25%, PSV 27%), chronic respiratory disease (CTD 20%, PSV10%) and infections (CTD 9%, PSV 16%). Conclusion We observed premature deaths across the spectrum of CTDs and PSVs, with highest SMRs in dcSSc and ASS. The overall mortality was highest in the CTD group.

FRI0495 Anti-Ro52 Antibodies Are Strongly Associated with Lung Fibrosis in a Nation-Wide Cohort of Mixed Connective Tissue Disease (MCTD)

Background MCTD is a disorder characterized by serum auto-antibodies directed against ribonucleoprotein and distinct clinical features including: Raynauds phenomenon, “puffy hands”, arthritis, pleuritis, pericarditis, myositis, esophageal dysmotility, pulmonary hypertension and interstitial lung disease (ILD) (1). Anti-SSA antibodies are directed to two different antigens (Ro52 or Ro60). The Ro52 antigen, a 52 kDa protein, is a part of the tripartite motif protein (TRIM21) family (2). Recent studies have shown that anti-Ro52 antibodies are associated with ILD in systemic sclerosis (3) but were not found to be associated with ILD in a cohort of anti-Jo1-positive patients with antisynthetase syndrome (4). Objectives To evaluate the association between lung fibrosis and presence of the anti-Ro52 antibody in a well-defined MCTD cohort. Methods 126 patients, 75% female with a mean disease duration of 9.0 years, were included in the cross-sectional nation-wide unselected Norwegian MCTD cohort, and were examined by high-resolution CT (1). The extent and type of lung abnormalities were scored according to the CT criteria of ILD recommended by the Fleischner Society (5) with reticular patterns consistent with lung fibrosis (1). Serum samples were accessible in 113/126 (90%). The presence of anti-Ro52 and anti-SSB by line immunoassay (ANA Profile 5 Euroline Blot test kit, Euroimmun, Lübeck, Germany). Statistical analyses were performed by SPSS/PASW version 20. Differences between groups were tested by Mantel-Haenszel chi square or Fishers exact test with two-tailed 95% significance. Results 57.6% (95%CI; 40.8% to 72.8%) of the MCTD patients with positive anti-Ro52 antibody had lung fibrosis and the risk (odds ratio) was 2.42 higher (95%CI; 1.49 to 3.96) than in those without the antibody. 76.3% (95%CI; 65.8% to 84.3%) of the MCTD patients without the presence of anti-Ro52 did not have lung fibrosis. Lung fibrosis No fibrosis Fibrosis Total Anti-Ro52 Positive 14 19 33 Negative 61 19 80 Total 75 38 113 2-tailed p-value by Fisher exact test 0.0014. Conclusions In MCTD, anti-Ro52 antibodies may be a marker of ILD. As this is a cross-sectional study and the patients could develop ILD in time, the study would probably underestimate the predictive value of positive Ro52 antibody. References Gunnarsson R et al. Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study. Ann Rheum Dis. 2012;71(12):1966-72. Rhodes DA et al. The 52 000 MW Ro/SS-A autoantigen in Sjogrens syndrome/systemic lupus erythematosus (Ro52) is an interferon-gamma inducible tripartite motif protein associated with membrane proximal structures. Immunology. 2002;106(2):246-56. Hudson M et al. Clinical significance of antibodies to Ro52/TRIM21 in systemic sclerosis. Arthritis Res Ther. 2012;14(2):R50. Marie I, et al. Short-Term and Long-Term Outcome of Anti-Jo1-Positive Patients with Anti-Ro52 Antibody. Semin Arthritis Rheum. 2012;41(6):890-9. Hansell DM et al. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008;246(3):697-722. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4660