M Stone

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10−8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10−6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27–positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Dissemination and evaluation of the ASAS/EULAR recommendations for the management of ankylosing spondylitis : results of a study among 1507 rheumatologists

Background: Ten ASAS/EULAR recommendations for the management of ankylosing spondylitis (AS) were published in 2006. Objectives: (a) To disseminate and (b) to evaluate conceptual agreement with, and (c) application of, these recommendations as well as (d) potential barriers to the application. Methods: A questionnaire was sent to rheumatologists in 10 countries. It included (a) the text of the recommendations; (b) rheumatologists’ demographic variables; (c) two numerical rating scales from 1 to 10 for each recommendation: conceptual agreement with, and application of, the recommendation (10 indicates maximal agreement and maximal application); and (d) a list of potential barriers to the application of the recommendation. Statistical analysis included descriptive and multivariate analyses. Results: 7206 questionnaires were sent out; 1507 (21%) were returned. Of the 1507 answering rheumatologists, 62% were men, mean (SD) age 49 (9) years, and 34% had an academic position. Conceptual agreement with the recommendations was high (mean (SD) for all recommendations 8.9 (0.9)). Self-reported application was also high (8.2 (1.0)). The difference between agreement and application varied across recommendations and countries. The most pronounced discrepancies were reported for use of anti-tumour necrosis factor drugs in a few countries, with funding as the most commonly reported barrier for application of this recommendation. Conclusion: This large project has helped the dissemination of the ASAS/EULAR recommendations for the management of AS and shows that conceptual agreement with the recommendations is very high. The project also highlights inequalities in access to healthcare for European citizens with AS.

An international study on starting tumour necrosis factor-blocking agents in ankylosing spondylitis

Objectives: To determine the type and proportion of patients with ankylosing spondylitis who rheumatologists consider to be candidates for treatment with tumour necrosis factor (TNF)-blocking agents, and to what extent this is in agreement with the ASsessment in Ankylosing Spondylitis (ASAS) international working group recommendations on initiation of treatment with anti-TNF agents. Methods: Participants were rheumatologists from 10 different countries, who were considered to be experts in treating patients with ankylosing spondylitis and in the use of anti-TNF treatment, but were unaware of the ASAS recommendations (unpublished at the time of study in 2003). The first 10 consecutive patients with ankylosing spondylitis seen by the rheumatologist were evaluated as to whether the patient was a candidate for anti-TNF treatment. Thereafter, a metrologist assessed the patient for disease activity and severity, and collected data on demographics and treatment. Results: Complete data were available for 1207 of the 1284 patients and were used for analysis. Overall, the rheumatologists indicated that they would initiate TNF-blocking agents in 49.3% of patients, ranging from 37.2% patients in Canada to 78.3% in Australia. These candidates had higher disease activity, higher levels of acute-phase reactants, worse spinal mobility, worse function, more often hip involvement and a higher prevalence of sick leave. Of all patients considered to be candidates, 40% did not fulfil ASAS recommendations with respect to previous use of non-steroidal anti-inflammatory drugs (NSAIDs; at least two NSAIDs) or Bath Ankylosing Spondylitis Disease Activity Index (⩾4). Conversely, 36% of patients who did not fulfil the NSAID or BASDAI recommendations were still considered to be candidates for TNF-blocking treatment. Objective variables, such as C reactive protein, erythrocyte sedimentation rate or magnetic resonance activity, were considered less important than disease activity in the decision on starting TNF-blocking drugs. The only important objective criterion was rapid radiographic progression. Conclusion: Rheumatologists wanted to initiate TNF-blocking drugs in roughly half of the patients with ankylosing spondylitis. However, there was a wide variation across countries and doctors. Rheumatologists considered both disease activity and severity to be determinants of starting TNF blockers, but their decision was often in disagreement with ASAS recommendations.

The assessment of ankylosing spondylitis in clinical practice.

Ankylosing Spondylitis (AS) is a chronic inflammatory arthritis that predominantly affects the axial skeleton in adolescent patients causing spinal pain and stiffness. There is a marked delay, on average 8 years, between onset of disease symptoms and clinical diagnosis. The distinction between the symptoms of mechanical and inflammatory back pain remains one of the main contributing factors for the delay in diagnosis. Several classification criteria exist to aid the diagnosis of AS, but their accuracy is poor. The Ankylosing Spondylitis Assessment Study group (ASAS) has defined a core set of domains for clinical outcome measurement in AS in order to assess the disease process in individual patients and to identify those with rapidly progressive disease. New therapies, such as the tumor necrosis factor (TNF) inhibitors, have transformed the treatment paradigm in AS, especially for those patients with aggressive disease. Thus, the definition of both patient selection criteria for these agents and the development of clinical methods to assess response to therapy have become a priority. This Review focuses on measuring the degree of disease activity, function and damage in patients with AS in an ambulatory care setting, and the assessment of suitability of various outcome measures for monitoring response to treatment with TNF inhibitors.

Bcl-x(L) expression in vivo in rheumatoid synovium

To examine the expression of the apoptosis regulatory protein, Bcl-xL, in the synovium of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Immunohistochemistry for Bcl-xL was carried out on synovial samples from patients with RA and OA. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis were performed to qualitatively examine the expression of Bcl-xL. Bcl-xL expression was detected in the lining, endothelium and inflammatory cells of both RA (n=20) and OA (n=10) samples. However, there was significantly more expression in the lining of RA synovium compared to OA (77 vs 61%, p<0.05). Many of the positive cells in the RA subsynovium were noted to be plasma cells. There was a significant correlation between Bcl-xL expression and the number of inflammatory cells in the subsynovium of RA and OA patients (rs=0.376, p<0.05, n=30). Age and disease duration did not correlate with Bcl-xL expression in rheumatoid patients. Bcl-xL may play a role in the extended survival of synoviocytes and inflammatory cells in rheumatoid synovium.

Innate immunity in host-microbial interactions: Beyond B27 in the spondyloarthropathies

The spondyloarthropathies are diseases influenced by genetic predisposition and, to a varying extent, infectious triggers. A causal role for bacterial infections is most clear for reactive arthritis. Recent insights into arthritogenic components of bacteria may set the stage for a better understanding of disease pathogenesis, the role of heat shock proteins in antigen processing and immune activation, and the adjuvant effect of CpG-DNA. Recent developments in the area of innate immunity broaden current concepts of genetically defined factors in host-pathogen interactions. In particular, the biology of toll-like receptors as important elements in the innate immune response to pathogens is being defined. These factors in innate immunity may have important implications for sequelae of infections, such as reactive arthritis.

Recent advances in the treatment of the spondyloarthropathies

Purpose of reviewRecently, there has been renewed interest in the spondyloarthropathy family of chronic inflammatory rheumatic conditions, which has been fueled to a large extent by the biologic era. Over the period of the past 2 years in particular, there have been several notable advances. First, there have been a number of large, high-quality randomized controlled trials evaluating the tumor necrosis factor (TNF) blockers and conservative treatments such as physiotherapy and nonsteroidal anti-inflammatory drugs for use in spondyloarthropathy. This has paved the way for the development of better tools to assess outcome in these patients both in daily practice and in the context of clinical trials. This review uses a systematic approach to outline the most recent (within the last 2 years) and the most pertinent advances in the treatments of the spondyloarthropathies, with particular emphasis on ankylosing spondylitis and psoriatic arthritis. Recent findingsSupervised group exercise programs maintain flexibility and posture in patients with ankylosing spondylitis, and spa therapy is a cost-effective treatment option in ankylosing spondylitis. Nonsteroidal anti-inflammatory drugs have a role in symptom modification and, more importantly, may prevent structural disease progression in patients with ankylosing spondylitis when administered continuously at a fixed dose. TNF blockers have been evaluated in a number of randomized controlled trials in ankylosing spondylitis and psoriatic arthritis and have been demonstrated to be safe and effective in the short-term management of these diseases. Longer-term trials are awaited with radiographic outcomes to comment on their disease-modifying properties and their long-term safety and efficacy profiles. SummaryThere has been renewed interest in the spondyloarthropathy family of disorders, with an explosion in the number of trials evaluating outcome with the TNF blockers. To date, no cure has been found for the disease, but these agents are emerging as the best therapeutic option available for patients with ankylosing spondylitis and psoriatic arthritis to date.

Significance of Clinical Evaluation of the Metacarpophalangeal Joint in Relation to Synovial/Bone Pathology in Rheumatoid and Psoriatic Arthritis Detected by Magnetic Resonance Imaging

Objective. Rheumatologists base many clinical decisions regarding the management of inflammatory joint diseases on joint counts performed at clinic. We investigated the reliability and accuracy of physically examining the metacarpophalangeal (MCP) joints to detect inflammatory synovitis using magnetic resonance imaging (MRI) as the gold standard. Methods. MCP joints 2 to 5 in both hands of 5 patients with rheumatoid arthritis (RA) and 5 with psoriatic arthritis (PsA) were assessed by 5 independent examiners for joint-line swelling (visually and by palpation); joint-line tenderness by palpation (tender joint count, TJC) and stress pain; and by MRI (1.5 Tesla superconducting magnet). Interrater reliability was assessed using kappa statistics, and agreement between examination and corresponding MRI assessment was assessed by Fisher’s exact tests (p < 0.05 considered statistically significant). Results. Interrater agreement was highest for visual assessment of swelling (κ = 0.55–0.63), slight-fair for assessment of swelling by palpation (κ = 0.19–0.41), and moderate (κ = 0.41–0.58) for assessment of joint tenderness. In patients with RA, TJC, stress pain, and visual swelling assessment were strongly associated with MRI evaluation of synovitis. Visual swelling assessment demonstrated high specificity (> 0.8) and positive predictive value (= 0.8). For PsA, significant associations exist between TJC and MRI synovitis scores (p < 0.01) and stress pain and MRI edema scores (p < 0.04). Assessment of swelling by palpation was not significantly associated with synovitis or edema as determined by MRI in RA or PsA (p = 0.54–1.0). Conclusion. In inflammatory arthritis, disease activity in MCP joints can be reliably assessed at the bedside by examining for joint-line tenderness (TJC) and visual inspection for swelling. Clinical assessment may have to be complemented by other methods for evaluating disease activity in the joint, such as MRI, particularly in patients with PsA.

LRTae: improving statistical power for genetic association with case/control data when phenotype and/or genotype misclassification errors are present.

BackgroundIn the field of statistical genetics, phenotype and genotype misclassification errors can substantially reduce power to detect association with genetic case/control studies. Misclassification also can bias population frequency parameters such as genotype, haplotype, or multi-locus genotype frequencies. These problems are of particular concern in case/control designs because, short of repeated sampling, there is no way to detect misclassification errors.We developed a double-sampling procedure for case/control genetic association using a likelihood ratio test framework. Different approaches have been proposed to deal with misclassification errors. We have chosen the likelihood framework because of the ease with which misclassification probabilities may be incorporated into in the statistical framework and hypothesis testing. The statistic is called the Likelihood Ratio Test allowing for errors (LRTae) and is freely available via software download.ResultsWe applied our procedure to 10,000 replicates of simulated case/control data in which we introduced phenotype misclassification errors. The phenotype considered is Ankylosing Spondylitis (AS). The LRTae method power was always greater than LRTstd power for the significance levels considered (5%, 1%, 0.1%, 0.01%). Power gains for the LRTae method over the LRTstd method increased as the significance level became more stringent. Multi-locus genotype frequency estimates using LRTae method were more accurate than estimates using LRTstd method.ConclusionThe LRTae method can be applied to single-locus genotypes, multi-locus genotypes, or multi-locus haplotypes in a case/control framework and can be more powerful to detect association in case/control studies when both genotype and/or phenotype errors are present. Furthermore, the LRTae method provides asymptotically unbiased estimates of case and control genotype frequencies, as well as estimates of phenotype and/or genotype misclassification rates.

A functional polymorphism of TIR-domain-containing adaptor protein is not associated with axial spondyloarthritis

Objective: A genetic variant of the toll-like receptor (TLR)2/4 adaptor protein TIRAP (single nucleotide polymorphism (SNP) C539T) was identified in a UK and in several African populations. The heterozygous genotype of this SNP has been associated with protection from severe infections. This allele results in an attenuated response to bacterial pathogens. As an exaggerated innate immune response to pathogens has been implicated in spondyloarthritis (SpA) pathogenesis, we analysed if the heterozygous C/T genotype was underrepresented in axial SpA compared with healthy controls. Methods: 204 patients with axial SpA and 175 population-matched controls were included. SNP C539T was determined with a sequence-specific polymerase chain reaction and direct sequencing. Results: The frequency of the haplotypes was similar in cases and controls (87% for C and 13% for T in both groups). The C/T genotype, which attenuates TLR signalling, was not underrepresented in cases versus controls (19% in controls vs 24% in cases, p = 0.44). The T/T genotype, was slightly lower in cases than in controls, although this was not significant (3.4% in controls vs 1% in cases, p = 0.15). Within the cases, there were no differences in disease phenotype or activity between patients with the C/C or C/T genotype. Conclusions: This study did not show significant associations of SNP S180L of the TLR2/4 adaptor protein TIRAP with axial SpA.