Michael M. Ward

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.

Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus

OBJECTIVE To determine rates of morbidity due to cardiovascular and cerebrovascular diseases among women with systemic lupus erythematosus (SLE). METHODS I used the California Hospital Discharge Database, which contains information on all discharges from acute care hospitals in California, to identify women with SLE who had been hospitalized for treatment of either acute myocardial infarction (AMI), congestive heart failure (CHF), or cerebrovascular accident (CVA) from 1991 to 1994. I compared the proportions of hospitalizations for each cause among women with SLE with those in a group of women without SLE, for 3 age strata (18-44 years, 45-64 years, and > or =65 years). RESULTS Compared with young women without SLE, young women with SLE were 2.27 times more likely to be hospitalized because of AMI (95% confidence interval [95% CI] 1.08-3.46), 3.80 times more likely to be hospitalized because of CHF (95% CI 2.41-5.19), and 2.05 times more likely to be hospitalized because of CVA (95% CI 1.17-2.93). Among middle-aged women with SLE, the frequencies of hospitalization for AMI and CVA did not differ from those of the comparison group, but the risk of hospitalization for CHF was higher (odds ratio [OR] 1.39, 95% CI 1.05-1.73). Among elderly women with SLE, the risk of hospitalization for AMI was significantly lower (OR 0.70, 95% CI 0.51-0.89), the risk of hospitalization for CHF was higher (OR 1.25, 95% CI 1.01-1.49), and the risk of hospitalization for CVA was not significantly different from those in the comparison group. CONCLUSION Young women with SLE are at substantially increased risk of AMI, CHF, and CVA. The relative odds of these conditions decrease with age among women with SLE.

Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

The shortened disabilities of the arm, shoulder and hand questionnaire (QuickDASH): validity and reliability based on responses within the full-length DASH.

BackgroundThe 30-item disabilities of the arm, shoulder and hand (DASH) questionnaire is increasingly used in clinical research involving upper extremity musculoskeletal disorders. From the original DASH a shorter version, the 11-item Quick DASH, has been developed. Little is known about the discriminant ability of score changes for the Quick DASH compared to the DASH. The aim of this study was to assess the performance of the Quick DASH and its cross-sectional and longitudinal validity and reliability.MethodsThe study was based on extracting Quick DASH item responses from the responses to the full-length DASH questionnaire completed by 105 patients with a variety of upper extremity disorders before surgery and at follow-up 6 to 21 months after surgery. The DASH and Quick DASH scores were compared for the whole population and for different diagnostic groups. For longitudinal construct validity the effect size and standardized response mean were calculated. Analyses with ROC curves were performed to compare the ability of the DASH and Quick DASH to discriminate among patients classified according to the magnitude of self-rated improvement. Cross-sectional and test-retest reliability was assessed.ResultsThe mean DASH score was 34 (SD 22) and the mean Quick DASH score was 39 (SD 24) at baseline. For the different diagnostic groups the mean and median Quick DASH scores were higher than the corresponding DASH scores. For the whole population, the mean difference between the Quick DASH and DASH baseline scores was 4.2 (95% CI 3.2–5.3), follow-up scores was 2.6 (1.7–3.4), and change scores was 1.7 (0.6–2.8).The overall effect size and standardized response mean measured with the DASH and the Quick DASH were similar. In the ROC analysis of change scores among patients who rated their arm status as somewhat or much better and those who rated it as unchanged the difference in the area under the ROC curve for the DASH and Quick DASH was 0.01 (95% CI -0.05–0.07) indicating similar discriminant ability.Cross-sectional and test-retest reliability of the DASH and Quick DASH were similar.ConclusionThe results indicate that the Quick DASH can be used instead of the DASH with similar precision in upper extremity disorders.

Patient Participation in Medical Consultations: Why Some Patients are More Involved Than Others

Background:Patients vary in their willingness and ability to actively participate in medical consultations. Because more active patient participation contributes to improved health outcomes and quality of care, it is important to understand factors affecting the way patients communicate with healthcare providers. Objectives:The objectives of this study were to examine the extent to which patient participation in medical interactions is influenced by 1) the patients personal characteristics (age, gender, education, ethnicity); 2) the physicians communication style (eg, use of partnership-building and supportive talk); and 3) the clinical setting (eg, the health condition, medical specialty). Research Design and Subjects:The authors conducted a post hoc cross-sectional analysis of 279 physician–patient interactions from 3 clinical sites: 1) primary care patients in Sacramento, California, 2) patients with systemic lupus erythematosus (SLE) from the San Francisco Bay area, and 3) patients with lung cancer from a VA hospital in Texas. Main Outcome Measures:The outcome measures included the degree to which patients asked questions, were assertive, and expressed concerns and the degree to which physicians used partnership-building and supportive talk (praise, reassurance, empathy) in their consultations. Results:The majority of active participation behaviors were patient-initiated (84%) rather than prompted by physician partnership-building or supportive talk. Patients who were more active participants received more facilitative communication from physicians, were more educated, and were more likely to be white than of another ethnicity. Women more willingly expressed negative feelings and concerns. There was considerable variability in patient participation across the 3 clinical settings. Female physicians were more likely to use supportive talk than males, and physicians generally used less supportive talk with nonwhite compared with white patients. Conclusions:Patient participation in medical encounters depends on a complex interplay of personal, physician, and contextual factors. Although more educated and white patients tended to be more active participants than their counterparts, the strongest predictors of patient participation were situation-specific, namely the clinical setting and the physicians communicative style. Physicians could more effectively facilitate patient involvement by more frequently using partnership-building and supportive communication. Future research should investigate how the nuances of individual clinical settings (eg, the health condition, time allotted for the visit) impose constraints or opportunities for more effective patient involvement in care.

Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

Health‐related quality of life in ankylosing spondylitis: A survey of 175 patients

OBJECTIVE To identify aspects of health-related quality of life that are most commonly affected in patients with ankylosing spondylitis (AS). METHODS One hundred seventy-five participants in a longitudinal study of health status in AS completed a cross-sectional survey that asked them to rate the presence and importance of problems in 23 aspects of quality of life, including symptoms, disability, mood, relations with others, and concerns about treatments and the future. Participants also completed the Medical Outcomes Study Short Form 36 Health Survey (SF-36). RESULTS The mean age of the participants was 51.1 years, and the mean duration of AS was 23.7 years; 119 (68%) were men. The most prevalent quality of life concerns included stiffness (90.2%), pain (83.1%), fatigue (62.4%), poor sleep (54.1%), concerns about appearance (50.6%), worry about the future (50.3%), and medication side effects (41%). Compared with those who had some college education, participants with 12 years of education or less were 2 to 4 times more likely to have problems or concerns with medication side effects, mobility, housework and self-care tasks, coping with illness, anxiety, payment for treatment, and relationships with spouses, family, and friends. Mean scores on the 8 domains of the SF-36 (range 0-100; higher scores indicate better function) ranged from 49 (energy/fatigue) to 77 (role limitations due to emotional problems). Patients with 12 years of education or less had significantly lower scores than those with some college on all domains except general health. CONCLUSIONS In addition to pain and stiffness, fatigue and sleep problems are important concerns in patients with AS, while few reported problems with mood or social relationships. Less educated patients had lower quality of life in many different aspects.

The Impact of Tumor Necrosis Factor α Inhibitors on Radiographic Progression in Ankylosing Spondylitis

OBJECTIVE To study the effect of tumor necrosis factor α (TNFα) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS). METHODS All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNFα inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ≥1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNFα inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model. RESULTS TNFα inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNFα inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNFα inhibitors was stronger after propensity score matching. CONCLUSION Treatment with TNFα inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup.

Patient education interventions in osteoarthritis and rheumatoid arthritis: a meta-analytic comparison with nonsteroidal antiinflammatory drug treatment.

OBJECTIVE To compare the effects of education interventions and nonsteroidal antiinflammatory drug (NSAID) treatment on pain and functional disability in patients with osteoarthritis (OA), and on pain, functional disability, and tender joint counts in patients with rheumatoid arthritis (RA). METHODS Two meta-analyses were performed: one of controlled trials of patient education interventions and one of placebo-controlled trials of NSAID treatments. RESULTS Nineteen patient education trials comprised of 32 treatment arms and 28 NSAID trials comprised of 46 treatment arms were included. The weighted average effect size for pain was 0.17 in the education trials and 0.66 in the NSAID trials. The average effect size for functional disability was 0.03 in the education trials and 0.34 in the NSAID trials; effects of education were much larger in RA studies than in OA studies. In RA studies, the average effect size for the tender joint count was 0.34 in the education trials and 0.43 in the NSAID trials. Because most patients in the education trials were being treated with medications, the effect sizes of these trials represent the additional, or marginal, effects of patient education interventions beyond those achieved by medication. CONCLUSIONS Based on this meta-analysis, patient education interventions provide additional benefits that are 20-30% as great as the effects of NSAID treatment for pain relief in OA and RA, 40% as great as NSAID treatment for improvement in functional ability in RA, and 60-80% as great as NSAID treatment in reduction in tender joint counts in RA.

Mortality and causes of death in systemic lupus erythematosus.

Cohort studies of survival in systemic lupus erythematosus (SLE) often have been limited by methodologic problems. In studies of inception cohorts of patients followed since 1980, survival at 5 years has exceeded 90%. These estimates are generally higher than survival estimates from earlier studies, suggesting that short-term survival in SLE has improved. There is less evidence to support major improvements over time in survival after 10 years or more of SLE. Infections, atherosclerotic disease, and active systemic lupus erythematosus or organ damage caused by SLE are the main causes of death in patients with SLE, but the proportion of early deaths caused by active SLE has decreased over time.