Marius C. Wick

Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression

Objective: To study serum levels of citrullinated protein/peptide antibodies (anti-CP) during up to 5 years’ follow up of patients with early rheumatoid arthritis (RA), and to relate serum levels to disease course and to treatments in clinical practice. Methods: 279 patients with early RA were followed up with clinical investigations, radiographs, and measurement of anti-CP at baseline and after 3 months, 1, 2, 3, and 5 years. Results: 160/279 (57.3%) patients were anti-CP positive at the first visit (mean 5 months after first symptoms). During follow up only 11/279 (3.9%) of the patients changed their anti-CP status. Anti-CP levels fell significantly during the first year, and this drop correlated with the extent of sulfasalazine treatment but not with other drugs or clinical indices. Anti-CP positive and negative patients had similar disease activities at baseline, but during follow up the anti-CP positive patients had worse clinical disease and greater radiological progression, despite at least equally intensive antirheumatic treatment. Conclusions: Anti-CP are stable during the first 5 years of RA, suggesting that events before rather than after onset of clinical manifestations of disease determine this phenotype. The presence of anti-CP at diagnosis predicts a less favourable disease course and greater radiological progression despite antirheumatic treatment, but subsequent changes in antibody levels do not reflect changes in disease activity. Taken together, these observations suggest that anti-CP positive RA is a distinct clinical and pathophysiological entity.

Antibodies against citrullinated vimentin in rheumatoid arthritis: Higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides

OBJECTIVE The Sa autoantigen can be found in inflamed synovium of patients with rheumatoid arthritis (RA), and at least part of the humoral RA-specific anti-Sa response is directed against citrullinated vimentin. This study was undertaken to evaluate the sensitivity, specificity, and prognostic value of determination of levels of antibodies against modified citrullinated vimentin (anti-MCV) as compared with antibodies against cyclic citrullinated peptides (anti-CCP) in an inception cohort of patients with early RA. METHODS Clinical data, radiographs, and measurements of levels of anti-MCV and anti-CCP antibodies were obtained in 273 patients with early RA at baseline, after 3 months, and after 1, 2, 3, and 5 years. Autoantibodies were also analyzed in 100 healthy controls. RESULTS Of the 273 patients, 193 (70.7%) were anti-MCV positive and 158 (57.9%) were anti-CCP positive at the time of diagnosis, with nearly equal specificities (95% and 96%, respectively). Forty (14.7%) were anti-MCV positive only, and 5 (1.8%) were anti-CCP positive only. Anti-MCV-positive and anti-MCV-negative patients had similar disease activity at baseline, but presence of anti-MCV was predictive of subsequent high disease activity and continued radiographic progression. Changes in anti-MCV level showed stronger correlation with changes in clinical parameters than did changes in anti-CCP level. The subgroup of patients who were anti-MCV positive and anti-CCP negative showed a higher rate of radiographic destruction than did patients who were negative for both anti-MCV and anti-CCP. CONCLUSION These findings show that when patients with early RA are compared with healthy controls, analysis of anti-MCV yields greater sensitivity and unchanged specificity as compared with analysis of anti-CCP. Anti-MCV also appears to perform better than anti-CCP in identifying poor radiographic prognosis in patients with early RA.

Adalimumab (Humira®) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade®) or etanercept (Enbrel®): results from the STURE registry at Karolinska University Hospital

Objectives: To determine whether the tumour necrosis factor‐α (TNF‐α) antagonist adalimumab (Humira®) can be efficacious after secondary loss of efficacy (i.e. loss of clinical response in patients who had initially demonstrated clinical response) to infliximab (Remicade®) or etanercept (Enbrel®). Patients and methods: We studied 36 patients from the Stockholm TNF‐α follow‐up registry (STURE) who received adalimumab after secondary loss of efficacy to infliximab (group A, n = 27) or etanercept (group B, n = 9), and 26 patients who were started on adalimumab as the first TNF‐α antagonist (group C). Results: In group A, the baseline disease activity score 28 (DAS28) at infliximab institution was 5.5±0.2. During infliximab treatment, the mean best DAS28 was 3.7±0.2 (p<0.001), but increased to 5.2±0.3 when infliximab was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.5±0.3 (p<0.003), and then to 4.2±0.2 at 6 months (p<0.001). In group B, the baseline DAS28 at etanercept institution was 6.6±0.5. During etanercept treatment, the mean best DAS28 was 4.6±0.5 (p<0.01), but increased to 5.7±0.4 by the time etanercept was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.8±0.3 (p<0.005), and to 4.1±0.2 at 6 months (p<0.001). In group C, the mean baseline DAS28 was 5.6±0.3. After 6 months of adalimumab therapy, the DAS28 decreased to 3.5±0.4 (p<0.001). ACR20 responses with adalimumab in groups A, B, and C were similar (70–78%). Conclusions: For patients with secondary loss of efficacy from infliximab or etanercept, switching to adalimumab can restore a good clinical response.

EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice

A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9–9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners.

Orthopaedic surgery of the lower limbs in 49,802 rheumatoid arthritis patients : results from the Swedish National Inpatient Registry during 1987 to 2001

Objectives: To analyse changes in the rates of hospital admission and use of orthopaedic surgery to the lower limbs in Swedish patients with rheumatoid arthritis between 1987 and 2001. Methods: Data for all rheumatoid patients admitted to hospital between 1987 and 2001 were abstracted from the Swedish National Hospital Discharge Register (SNHDR). The data in the register are collected prospectively, recording all inpatient admissions throughout Sweden. The SNHDR uses the codes for diagnoses at discharge and surgical procedures according to the Swedish version of the International Classification of Diseases (ICD). Results: In all, 49 802 individual patients with rheumatoid arthritis were identified, accounting for 159 888 inpatient visits. Hospital admissions for rheumatoid arthritis decreased by 42% (p<0.001) during the period 1987 to 2001. Twelve per cent of all admissions were for a rheumatoid arthritis related surgical procedure to the lower limbs; those admissions decreased markedly (by 16%) between 1987 and 1996, and by 12% between 1997 and 2001, as did the overall number of rheumatoid arthritis related surgical procedures to the lower limbs during both time periods. Between 1997 and 2001, 47% of all rheumatoid arthritis related surgical procedures were total joint arthroplasties. There was an overall trend towards reduced length of hospital stay after orthopaedic surgery to the lower limbs during the study period. Conclusions: Rates of hospital admission and rheumatoid arthritis related surgical procedures to the lower limbs in Swedish patients with rheumatoid arthritis decreased between 1987 and 2001. This may reflect trends in disease severity, management, and health outcomes of this disease in Sweden.

Increased Fracture Risk in Patients with Rheumatic Disorders and Other Inflammatory Diseases — A Case-Control Study with 53,108 Patients with Fracture

Objective. To identify the risk of hip and vertebral fractures in patients with rheumatic disorders (RD) and inflammatory bowel diseases (IBD). Methods. This population-based case-control study assessed the fracture risk of patients with rheumatoid arthritis, juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), systemic lupus erythematosus, polymyositis/dermatomyositis (PM/DM), systemic sclerosis (SSc), Crohn’s disease, and ulcerative colitis (UC). The study cohort comprised 53,108 patients with fracture (66% women) and 370,602 age-matched and sex-matched controls. Conditional logistic regression analysis was performed and results were expressed as OR with corresponding 95% CI. Results. There was a statistically significant increased fracture risk for all RD and for IBD compared with controls. The magnitude of fracture risk was higher for patients with RD (OR 3, 95% CI 2.9–3.2) than for those with IBD (OR 1.6, 1.4–1.8). The OR in RD ranged from 2.6 (1.3–4.9) for SSc to 4 (3.4–4.6) for AS. The largest increased fracture risk for vertebral fractures was seen in AS (OR 7.1, 6–8.4) and for hip fractures in JIA (OR 4.1, 2.4–6.9). Conclusion. Our results highlight the existence of an increased fracture risk from a variety of underlying causes in patients with RD and IBD. In many inflammatory diseases, implementation of fracture prevention strategies may be beneficial.

Decrease of RA-related orthopaedic surgery of the upper limbs between 1998 and 2004: data from 54 579 Swedish RA inpatients

OBJECTIVES To describe the overall use and temporal trends in orthopaedic upper limb surgery associated with RA on a nation wide basis in Sweden between 1998 and 2004. METHODS Data for all inpatient visits during 1998-2004 for patients older than 18 yrs with RA-related diagnoses were extracted from the Swedish National Hospital Discharge Registry (SNHDR). The SNHDR prospectively collects data on all hospital admissions in Sweden according to the International Classification of Diseases (ICD). Data were analysed with respect to orthopaedic surgery of the hand, elbow and shoulder. RESULTS During the study period, 54,579 individual RA patients were admitted to a Swedish hospital and 9% of these underwent RA-related surgery of the upper limbs. The RA patient cohort underwent a total of 8251 RA-related upper limb surgical procedures. The hand (77%) was most frequently operated on, followed by the shoulder (13%) and the elbow (10%). There was a statistically significant decrease of 31% for all admissions associated with RA-related upper limb surgery during 1998-2004 (P = 0.001). Some 10% of all RA-related upper limb surgery was due to total joint arthroplasties (TJAs), mostly for the elbow (59%). During 1998-2004, all TJAs, elbow-TJAs and shoulder-TJAs had a stable occurrence. In contrast, the overall numbers of hand-TJAs significantly increased (P = 0.009). CONCLUSIONS Rates of RA-related upper limb surgery decreased and TJAs had a stable occurrence in Sweden during 1998-2004. The findings of this study may reflect trends in disease management and health outcomes of RA patients in Sweden.

The role of heat shock proteins in atherosclerosis

Atherosclerosis is a chronic, multifactorial disease that starts in youth, manifests clinically later in life, and can lead to myocardial infarction, stroke, claudication, and death. Although inflammatory processes have long been known to be involved in atherogenesis, interest in this subject has grown in the past 30–40 years. Animal experiments and human analyses of early atherosclerotic lesions have shown that the first pathogenic event in atherogenesis is the intimal infiltration of T cells at arterial branching points. These T cells recognize heat shock protein (HSP)60, which is expressed together with adhesion molecules by endothelial cells in response to classic risk factors for atherosclerosis. Although these HSP60-reactive T cells initiate atherosclerosis, antibodies to HSP60 accelerate and perpetuate the disease. All healthy humans develop cellular and humoral immunity against microbial HSP60 by infection or vaccination. Given that prokaryotic (bacterial) and eukaryotic (for instance, human) HSP60 display substantial sequence homology, atherosclerosis might be the price we pay for this protective immunity, if risk factors stress the vascular endothelial cells beyond physiological conditions.

Sonoelastography: Musculoskeletal Applications

All participants for image samplings provided written informed consent. Conventional B-mode ultrasonography (US) has been widely utilized for musculoskeletal problems as a first-line approach because of the advantages of real-time access and the relatively low cost. The biomechanical properties of soft tissues reflect to some degree the pathophysiology of the musculoskeletal disorder. Sonoelastography is an in situ method that can be used to assess the mechanical properties of soft tissue qualitatively and quantitatively through US imaging techniques. Sonoelastography has demonstrated feasibility in the diagnosis of cancers of the breast and liver, and in some preliminary work, in several musculoskeletal disorders. The main types of sonoelastography are compression elastography, shear-wave elastography, and transient elastography. In this article, the current knowledge of sonoelastographic techniques and their use in musculoskeletal imaging will be reviewed.

Anti-type II collagen antibodies are associated with early radiographic destruction in rheumatoid arthritis

IntroductionWe have previously reported that high levels of antibodies specific for native human type II collagen (anti-CII) at the time of RA diagnosis were associated with concurrent but not later signs of inflammation. This was associated with CII/anti-CII immune complex (IC)-induced production of pro-inflammatory cytokines in vitro. In contrast, anti-cyclic citrullinated peptide antibodies (anti-CCP) were associated both with late inflammation and late radiological destruction in the same RA cohort. We therefore hypothesized that anti-CII are also associated with early erosions.MethodsTwo-hundred-and-fifty-six patients from an early RA cohort were included. Baseline levels of anti-CII, anti-CCP and anti-mutated citrullinated vimentin were analyzed with ELISA, and rheumatoid factor levels were determined by nephelometry. Radiographs of hands and feet at baseline, after one and after two years were quantified using the 32-joints Larsen erosion score.ResultsLevels of anti-CII were bimodally distributed in the RA cohort, with a small (3.1%, 8/256) group of very high outliers with a median level 87 times higher than the median for the healthy control group. Using a cut-off discriminating the outlier group that was associated with anti-CII IC-induced production of proinflammatory cytokines in vitro, baseline anti-CII antibodies were significantly (p = 0.0486) associated with increased radiographic damage at the time of diagnosis. Anti-CII-positive patient had also significantly increased HAQ score (p = 0.0303), CRP (p = 0.0026) and ESR (p = 0.0396) at the time of diagnosis but not during follow-up. The median age among anti-CII-positive subjects was 12 years higher than among the anti-CII-negative patients.ConclusionIn contrary to anti-CCP, anti-CII-positive patients with RA have increased joint destruction and HAQ score at baseline. Anti-CII thus characterizes an early inflammatory/destructive phenotype, in contrast to the late appearance of an inflammatory/destructive phenotype in anti-CCP positive RA patients. The anti-CII phenotype might account for part of the elderly acute onset RA phenotype with rather good prognosis.