Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren's syndrome.

OBJECTIVES: Fatigue is common and severe in primary Sjögren's syndrome (pSS). The aim of this study was to identify genetic determinants of fatigue in pSS through a genome-wide association study. METHODS: Patients with pSS from Norway, Sweden, UK and USA with fatigue and genotype data available were included. After genotype imputation and quality control, 682 patients and 4 966 157 genetic markers were available. Association analysis in each cohort using linear regression with fatigue as a continuous variable and meta-analyses between the cohorts were performed. RESULTS: Meta-analysis of the Norwegian and Swedish cohorts identified five polymorphisms within the same linkage disequilibrium block at the receptor transporter protein 4 (RTP4)/MASP1 locus associated with fatigue with genome-wide significance (GWS) (p<5×10-8). Patients homozygous for the major allele scored 25 mm higher on the fatigue Visual Analogue Scale than patients homozygous for the minor allele. There were no variants associated with fatigue with GWS in meta-analyses of the US/UK cohorts, or all four cohorts. RTP4 expression in pSS B cells was upregulated and positively correlated with the type I interferon score. Expression quantitative trait loci effects in whole blood for fatigue-associated variants at RTP4/MASP1 and levels of RTP4 and MASP1 expression were identified. CONCLUSION: Genetic variations at RTP4/MASP1 are associated with fatigue in Scandinavian pSS patients. RTP4 encodes a Golgi chaperone that influences opioid pain receptor function and MASP1 is involved in complement activation. These results add evidence for genetic influence over fatigue in pSS.

[A woman in her thirties with pain in her fingers and toes]. / En kvinne i 30-årene med smerter i fingre og tær.

Hand pain is a relatively common complaint, and careful anamnesis and clinical examination may reveal its aetiology. Multiple joint involvement suggests either osteoarthritis or inflammatory arthritis. In the returning traveller, a more exotic explanation might be the case. A 31 year old woman was referred to our outpatient clinic for evaluation due to peripheral joint arthralgia. The symptoms started six months earlier, on the same day she returned from a three-week holiday in India. There were no signs of inflammatory arthritis or osteoarthritis. Blood tests were normal. Chikungunya virus serology was positive. The patient received symptomatic treatment with nonsteroid anti-inflammatory drugs and improved over a period of months. We describe the first case of Chikungunya fever diagnosed in our hospital.

A five-year prospective study of fatigue in primary Sjögren's syndrome.

INTRODUCTION: Fatigue is prevalent in primary Sjögren's syndrome (pSS), and contributes to the considerably reduced health related quality of life in this disease. The symptom is included in proposed disease activity and outcome measures for pSS. Several studies indicate that there is an inflammatory component of fatigue in pSS and other chronic inflammatory rheumatic diseases. The purpose of this study was to investigate fatigue change in pSS in a longitudinal study, and explore whether any clinical or laboratory variables at baseline, including serum cytokines, were associated with a change in fatigue scores over time. METHODS: A clinical and laboratory investigation of 141 patients fulfilling the American-European consensus criteria of pSS was undertaken in the period May 2004 to April 2005. Median time since diagnosis was 5.5 years. Examinations included the fatigue questionnaires: fatigue severity scale (FSS), fatigue visual analogue scale (VAS), functional assessment of chronic illness therapy-fatigue (FACIT-F) and medical outcome study short form-36 (SF-36) vitality, which were repeated in a follow-up investigation in January and February 2010. RESULTS: A total of 122 patients (87%) responded at both time-points. Thirty-five percent of patients experienced a clinically significant FSS increase. On the group level, fatigue measures did not change except that there was a slight deterioration in SF-36 vitality score. High serum anti-Sjögren's syndrome A antigen (anti-SSA) showed weak associations with high baseline fatigue, and patients with increasing fatigue had lower baseline unstimulated whole salivary volume. Weak associations between increasing fatigue and serum immunoglobulin G (IgG), and the pro-inflammatory cytokine interleukin-17 (IL-17), were observed. Baseline sicca symptoms correlated with higher fatigue both at baseline and with increasing fatigue over time. Linear regression analysis did not identify any predictive ability of clinical or laboratory measures on fatigue change over time. CONCLUSIONS: Fatigue remained mainly unchanged over time. Using multivariate models did not reveal any clinical or laboratory predictors of fatigue change over time.

MRI of the transverse and alar ligaments in rheumatoid arthritis: feasibility and relations to atlantoaxial subluxation and disease activity.

INTRODUCTION: Dysfunctional transverse and alar craniovertebral ligaments can cause instability and osseous destruction in rheumatoid arthritis (RA). This study examined (1) the feasibility of high-resolution magnetic resonance imaging (MRI) of these ligaments in RA and (2) the relation between ligament high-signal changes and atlantoaxial subluxation and RA duration/severity. METHODS: Consecutive RA patients (n=46) underwent clinical examination, functional radiography, and high-resolution MRI. Two blinded radiologists rated MRI image quality, graded ligament high-signal changes 0-3 on proton-weighted sequences using an existing grading system, and assessed cervical spine rheumatic changes on short tau inversion recovery images. Agreement was analyzed using kappa and relations using multiple logistic regression. RESULTS: MRI images had good quality in 42 (91.3%) of 46 patients and were interpretable in 44 (32 women and 12 men, median age/disease duration 60.4/9.1 years). MRI grades 2-3 changes of the transverse and alar ligaments showed moderate and good interobserver agreement (kappa 0.59 and 0.78), respectively, and prevalence 31.8% and 34.1%. Such ligament changes were more frequent with increasing anterior atlantoaxial subluxation (p=0.012 transverse, p=0.028 alar), higher erythrocyte sedimentation rate (p=0.003 transverse), positive rheumatoid factor (p=0.002 alar), and neck pain (p=0.004 alar). CONCLUSION: This first study of high-resolution MRI of these ligaments in RA showed high feasibility and relations with atlantoaxial subluxation, RA disease activity, and neck pain. The clinical usefulness of such MRI needs further evaluation.

Anti-tumor necrosis factor-alpha therapy in the ordinary clinical setting: Three-year effectiveness in patients with rheumatoid arthritis.

OBJECTIVES: The aim was to estimate the proportion of patients with rheumatoid arthritis (RA) achieving low disease activity by anti-tumor necrosis factor-alpha (TNF-alpha) therapy in an ordinary clinical setting. METHODS: Thirty-three patients with active RA despite methotrexate treatment were included in an open phase IV study of infliximab in combination with methotrexate. The mean age was 53years (range 21-71) and mean disease duration 10.7years (1-32). Treatment was changed in cases of insufficient response or intolerable adverse events. Response status to infliximab was assessed according to the American College of Rheumatology (ACR 20). Disease activity score (DAS28) was assessed at baseline and at weeks 26, 54, 80, 106 and 158. Low disease activity is defined as DAS28