Karl Gaffney

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.

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Benchmarking: the five year outcome of rheumatoid arthritis assessed using a pain score, the Health Assessment Questionnaire, and the Short Form-36 (SF-36) in a community and a clinic based sample

BACKGROUND Treatment, and therefore outcome, of rheumatoid arthritis (RA) will improve in the next few years. However, improvement in outcome can only be judged against the probability of certain outcomes with current conventional treatment. AIM To document the five year outcome of RA in the late 1990s. SETTING Norfolk Arthritis Register (NOAR). DESIGN Longitudinal observational cohort study. METHODS 318 patients with recent onset inflammatory polyarthritis recruited by NOAR in 1990–91 completed five years of follow up. Four groups were assessed: the whole cohort, all those referred to hospital, those who satisfied criteria for RA at baseline, and those referred to hospital who satisfied criteria for RA at baseline. Outcome was assessed with a visual analogue scale for pain, the Health Assessment Questionnaire (HAQ), and the Short Form-36 (SF-36). RESULTS Of the RA hospital attenders, 50% had a visual analogue scale pain score of 5 cm or less and an HAQ score of 1.125 or less. SF-36 scores were reduced in all domains. Results are presented as cumulative percentages. CONCLUSIONS These results can be used for comparison and to set targets for improvement.

Recognition of inflammatory back pain and ankylosing spondylitis in primary care

OBJECTIVE The diagnosis of AS is often delayed in primary care. This may partly be due to inability to differentiate inflammatory back pain (IBP) from mechanical. The aim of this study was to assess current practice of general practitioners (GPs) in using clinical, radiological and laboratory investigations to assess patients with IBP. METHODS A postal questionnaire was sent to all GPs in Norfolk. It was designed to test GPs ability to identify symptoms suggestive of IBP in patients with back pain. It also enquired whether GPs considered other features of SpA. Their perceptions of usefulness of various investigations when considering a diagnosis of AS, management and their unmet needs were recorded. RESULTS A total of 62% of completed questionnaires were returned. Only 5% of GPs could identify all eight features known to be indicative of IBP, 78% between four and eight and 17% identified less than four features. GPs had a range of views regarding the utility of a positive family history, HLA-B27, use of X-ray and physiotherapy in patients with suspected IBP. GPs awareness of the associated features of SpA was low. There were inconsistencies in the use of diagnostic tests and management of AS. Improving musculoskeletal education in primary care was identified as one of the unmet needs by the majority of GPs. CONCLUSIONS In a survey of GPs, we identified inconsistencies in their perceptions and approach to the diagnosis and management of AS. Education in primary care and the wider use of diagnostic algorithms may improve early detection and hence outcome of AS.

Services for people with ankylosing spondylitis in the UK—a survey of rheumatologists and patients

OBJECTIVE . To investigate the services offered to patients with AS in the UK in 2010. METHODS Two thousand non-health-care professional members of the National Ankylosing Spondylitis Society (NASS) were sent a questionnaire asking about their experiences surrounding diagnosis, treatment and access to therapies (response rate 40%). A separate questionnaire was sent to a consultant rheumatologist in every acute NHS trust in the UK, asking about services offered to patients with AS (response rate 68%). RESULTS Overall, there was a mean diagnostic delay of 8.57 years. Almost one-third (32.2%) of patients were not reviewed in secondary care. Non-attendance was associated with increasing age and longer disease duration. Twenty per cent of patients were taking anti-TNF drugs, but 18.8% of departments reported that their ability to give anti-TNF therapy was restricted (64% reported primary-care trust rationing and 14% lack of staff). Almost all rheumatology departments had access to MRI, but 70.9% still used X-ray radiographs as their first-line investigation. A minority (5.6%) of patients reported they had never seen a physiotherapist, but less than one-third could self-refer for treatment during a flare. CONCLUSION This is the first study to explore the services available to people with AS in the UK. Almost one-third of patients are not seen in rheumatology departments and therefore may be under-treated. For those who are seen, access to anti-TNF drugs and other therapies remains an issue.

The prevalence of inflammatory back pain in a UK primary care population

OBJECTIVE Inflammatory back pain (IBP) is the earliest and most common symptom of axial SpA. However, there is very little information about the prevalence of IBP in the UK. In this cross-sectional cohort study we examined the prevalence of IBP in a UK primary care population using three published IBP criteria. METHODS Potential participants aged 18-80 years were identified from the records of a large general practice in Norfolk, UK, with 17 177 patients. Read codes were used to identify those who had consulted their general practitioner on at least one occasion with back pain. A self-completed screening questionnaire was sent to a sample of 978 patients, enquiring about symptoms of IBP and extra-spinal manifestations of SpA. Questionnaire responses were used to determine whether patients met the Assessment of SpondyloArthritis international Society (ASAS), Calin and Berlin IBP criteria. RESULTS Five hundred and five completed questionnaires were returned (response rate 51.6%). The median age of respondents was 60 years [interquartile range (IQR) 48-67] and 44.8% were male. The minimum prevalence of IBP among patients with at least one previous consultation for back pain was 7.7% (95% CI 6.2, 9.5) using the ASAS criteria, 13.5% (11.5, 15.8) using the Calin criteria and 15.4% (13.3, 17.8) using the Berlin criteria. There was no significant difference in prevalence between men and women, and between different age groups. Extrapolated to the practice population as a whole, the minimum prevalence of IBP in a UK primary care population is 1.7-3.4%. CONCLUSION The prevalence of IBP varies significantly depending on the criteria used for classification.

Predicting outcome in ankylosing spondylitis

Ankylosing spondylitis (AS) has an estimated prevalence of 0.2–0.86% for adult Caucasian populations of western European extraction [1]. The ability of anti-TNF treatment to dramatically suppress symptoms in AS [2–4] and improve quality of life [5–7] is now beyond doubt. However, the high costs and potentially serious side-effects [8], combined with uncertainties over any longterm ‘disease modifying’ effects [9] make careful selection of patients for treatment absolutely critical if needless toxicity and expense are to be avoided. Inevitably, funding bodies are reluctant to commit huge funds to this relatively obscure and formerly ‘cheap’ disease; therefore, it is encumbent on rheumatologists to avoid exposing patients who will do well without biologic therapy to unnecessary risk. In practice, most patients do well on anti-TNF treatment, However there are very few guides to long-term prognosis [10]. Current approaches to patient selection are based on the severity of symptoms ‘now’ rather than taking into account likely longer term outcomes. While the current approach may turn out to be the right one, replacing short-term subjective criteria for treatment with outcome-based objective criteria is plainly a highly desirable goal. To achieve this we need to be able to predict which AS sufferers will do ‘well’ and which ‘badly’ if managed conventionally. As a secondary issue we also need to determine more precisely what the terms ‘well’ and ‘badly’ mean when placed in the cost–benefit balance [11].

Is Etanercept 25 mg Once Weekly as Effective as 50 mg at Maintaining Response in Patients with Ankylosing Spondylitis? A Randomized Control Trial.

Objective. To investigate, in a pilot randomized controlled trial, whether etanercept (ETN) 25 mg once weekly is effective at maintaining a clinical response in patients with ankylosing spondylitis (AS) who have responded to the standard 50 mg dose. Methods. Adults with AS not responding to conventional therapies were prescribed ETN 50 mg once weekly for 6 months. Responders as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were randomly assigned to taper to 25 mg once weekly or continue on 50 mg and followed for a further 6 months. The primary outcome measure was maintenance of a 50% reduction in the BASDAI or fall in BASDAI by ≥ 2 units and a ≥ 2-unit reduction in BASDAI spinal pain as measured on a 10-point visual analog scale at 6 months postrandomization. Results. Of 89 patients assessed for eligibility, 59 were enrolled; 47 (80%) had sufficient clinical response and were eligible for randomization, 24 were assigned to continue receiving ETN 50 mg, and 23 to taper to 25 mg. After 6 months, 20 (83%) of the 50 mg arm maintained clinical response compared with 12 (52%) of the 25 mg arm (a difference of −31%, 95% CI −58% – −5%). Conclusion. Although this pilot study demonstrates that treatment with ETN 25 mg was less effective at maintaining treatment response in the stepdown phase, 52% of participants maintained treatment response. Future research should address which patients are suitable for tapering.

Validation of a patient self-reported screening questionnaire for axial spondyloarthropathy in a UK Population.

Study Design. Cross-sectional cohort study. Objective. The aim of this study was to develop and validate a patient-completed screening questionnaire for axial spondyloarthropathy for use in the United Kingdom. Summary of Background Data. Axial spondyloarthropathy (axial SpA) can be difficult to diagnose in the early stages of disease, leading to diagnostic delay and morbidity. Existing population screening tools lack sensitivity or have not been validated in the UK population. Methods. Questionnaires were sent to 295 patients with definite ankylosing spondylitis (meeting modified New York criteria), nonradiographical axial SpA (sacroiliitis on magnetic resonance imaging), or mechanical back pain. Responses from 190 patients were analyzed. Binary logistic regression was used to develop a model differentiating inflammatory from mechanical pain. Results. The final model (male sex, onset of symptoms by age 33 years, no radiation of pain, pain gets better as day goes on, pain increases with rest, and personal history of iritis) correctly classified 86% of cases with Nagelkerke R2 = 0.486. A numerical score (with 1 point assigned for each feature present) was calculated and receiver operating characteristic curve was constructed, with area under the curve of 0.911 (95% confidence interval: 0.87–0.96). A score of ≥3/6 had sensitivity of 75.6% and specificity of 87.9% for inflammation. Conclusion. We have developed a model that differentiates patients with ankylosing spondylitis/axial SpA from those with mechanical spinal disease and can be used as a self-completed screening tool.

Demographics and environmental factors in a Wegener’s granulomatosis cluster

Wegener’s granulomatosis is a multiorgan systemic disease of unknown aetiology, characterised by granulomatous inflammation and vasculitis in small or medium-sized blood vessels. Available evidence suggests a role for genetics, microbial pathogens and environmental exposures in its aetiology.1 Agents including silica,2 hydrocarbons,3 pesticides,4 fumes4 and farming5 have been implicated. We describe the demographic details and environmental exposures of a cluster of patients with Wegener’s granulomatosis cases diagnosed in Norfolk, UK. Cluster analysis enables identification of common environmental exposures that may be temporally and spatially related to disease features. We identified eight patients who were diagnosed with Wegener’s granulomatosis between February 2005 and February 2006. All patients fulfilled the …