Creation of a Forensic Pathology Biobank in Switzerland: which issues and research opportunities?

A biobank is a collection of biological material associated with health database. The field of biobanking has significantly developed over the past 30 years. Research based on biobank material gives access to data of a large number of people and can often significantly accelerate the understanding of disease and improve the quality of care. In the University Center of Legal Medicine Lausanne-Geneva, samples collected during autopsies are used for forensic investigations. The legal and ethical framework to use these samples for research is often complex and confused, which is unfortunate given the potential of these biospecimens. Indeed, forensic samples are valuable for research because they originate in part from young (including pediatrics cases) and healthy people who are poorly represented in worldwide institutional biobanks. In this context at the beginning of the year 2019, the Forensic Pathology Biobank was created. Creation of a forensic pathology biobank is the best way to standardize local conservation practices and improve personal data management, thus providing a very valuable biological material for scientific projects. Its development gives rise to many questions about technical standards, ethical and legal issues but also many research opportunities.

Individual and cumulative measures of knee joint load associate with T2 relaxation times of knee cartilage in young, uninjured individuals: A pilot study.

BACKGROUND: Articular cartilage structure and chondrocyte health are sensitive and reliant on dynamic joint loading during activities. The purpose of this pilot study was to determine the association between measures of individual and cumulative knee joint loading with T2 relaxation times in the knee cartilage of young individuals without knee injury. METHODS: Twelve participants (17-30 years old) without history of knee injury or surgery completed MRI, physical activity (PA), and biomechanical gait testing. T2 relaxation times were calculated in the cartilage within the patella and lateral and medial compartments. Accelerometry was used to measure mean daily step counts, minutes of PA, and % sedentary time over 7 days. Vertical ground reaction force, external knee joint moments and peak knee flexion angle were measured during stance phase of gait using three-dimensional motion capture. Cumulative knee joint loading was calculated as daily step count by external knee joint moment impulse. The relationship between measures of knee joint loading and T2 relaxation times was assessed using Pearson correlations. RESULTS: Higher T2 relaxation times in the femoral and tibial cartilage were consistently correlated to greater body mass, daily step counts, moderate and vigorous PA, and peak knee joint moments (r = 0.10-0.84). Greater cumulative knee flexion and adduction loading was associated with higher T2 relaxation times in the femoral and tibial cartilage (r = 0.16-0.65). CONCLUSION: Preliminary findings suggest that individual loading factors and cumulative knee joint loading are associated with higher T2 relaxation times in the articular cartilage of young, healthy knees.

New formula for cardiothoracic ratio for the diagnosis of cardiomegaly on post-mortem CT.

The cardiothoracic ratio (CTR) is considered to be a reliable detector of cardiomegaly on computed tomography for livings, with a threshold of 0.5. Our study aimed to establish an adjusted CTR-based score to predict cardiac hypertrophy at PMCT. We selected adult's autopsy cases examined between 2009 and 2016. Two groups were considered, a normal heart weight group and an overweighed heart group. The CTR was measured on axial images. Logistic regression analysis was performed to investigate the discriminating power of the CTR between groups when adjusted to the confounding factors. Sixty-six cases with normal heart weight and 94 cases with overweighed heart were analyzed. The factors associated to the cardiac hypertrophy are CTR (p value 0.003, OR 3.57), BMI (p value 0.055, OR 1.09), age (p value < 0.001, OR 1.67), and gender (p value 0.002, OR 4.85). The area under the ROC curve (receiver operating characteristic curve) was 0.77 when using CTR alone and 0.88 when considering BMI, age, and gender. In conclusion, CTR alone cannot be used to discriminate between normal heart weight and overweighed heart at PMCT. A new formula has been developed, including age, gender, and BMI. Dilatation of the cardiac chambers, which is a subjective evaluation, influences the CTR measure and could be not related to a pre-existing cardiac hypertrophy. This new score formula allows to overpasses this subjective step. We proposed a cut-off value of the score of 32 for the diagnosis of cardiac hypertrophy. The Internet/smartphone application (http://calc.chuv.ch/CTR) facilitates its routine application.

Post-traumatic stress disorder and serum cytokine and chemokine concentrations in patients with rheumatoid arthritis✰.

OBJECTIVE: Although post-traumatic stress disorder (PTSD) is identified as a risk factor in the development of rheumatoid arthritis (RA), associations of PTSD with disease progression are less clear. To explore whether PTSD might influence disease-related measures of systemic inflammation in RA, we compared serum cytokine/chemokine (cytokine) concentrations in RA patients with and without PTSD. METHODS: Participants were U.S. Veterans with RA and were categorized as having PTSD, other forms of depression/anxiety, or neither based on administrative diagnostic codes. Multiplex cytokines were measured using banked serum. Associations of PTSD with cytokine parameters (including a weighted cytokine score) were assessed using multivariable regression, stratified by anti-CCP status and adjusted for age, sex, race, and smoking status. RESULTS: Among 1,460 RA subjects with mean (SD) age of 64 (11) years and disease duration of 11 (11) years, 91% were male, 77% anti-CCP positive, and 80% ever smokers. Of these, 11.6% had PTSD, 23.7% other depression/anxiety, and 64.7% had neither. PTSD, but not depression/anxiety, was associated with a higher cytokine score and number of high-concentration analytes in adjusted models, though this was limited to anti-CCP positive subjects. PTSD was associated with heightened expression of several individual cytokines including IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-17, IFN-γ, GM-CSF, MCP-1, and TNF-α. CONCLUSION: Anti-CCP positive RA patients with PTSD have higher serum cytokine concentrations than those without PTSD, demonstrating that systemic inflammation characteristic of RA is heightened in the context of this relatively common psychiatric comorbidity.

Towards standardized patient reported physical function outcome reporting: linking ten commonly used questionnaires to a common metric.

OBJECTIVES: Outcomes obtained using different physical function patient reported outcome measures (PROMs) are difficult to compare. To facilitate standardization of physical function outcome measurement and reporting we developed an item response theory (IRT) based standardized physical function score metric for ten commonly used physical function PROMs. METHODS: Data of a total of 16,386 respondents from representative cohorts of patients with rheumatic diseases as well as the Dutch general population were used to map the items of ten commonly used physical function PROMs on a continuous latent physical function variable. The resulting IRT based common metric was cross-validated in an independent dataset of 243 patients with gout, osteoarthritis or polymyalgia in which four of the linked PROMs were administered. RESULTS: Our analyses supported that all 97 items of the ten included PROMs relate to a single underlying physical function variable and that responses to each item could be described by the generalized partial credit IRT model. In the cross-validation analyses we found congruent mean scores for four different PROMs when the IRT based scoring procedures were used. CONCLUSIONS: We showed that the standardized physical function score metric developed in this study can be used to facilitate standardized reporting of physical function outcomes for ten commonly used make physical function PROMs.

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty

OBJECTIVE: This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). METHODS: A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. RESULTS: The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. CONCLUSION: This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty

OBJECTIVE: This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). METHODS: A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. RESULTS: The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. CONCLUSION: This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data.

The cardiothoracic ratio on post-mortem computer tomography.

In clinical practice, the cardiothoracic ratio (CTR) was first utilized on plain chest radiography, and subsequently with computed tomography (CT) to diagnose cardiomegaly with a threshold of 0.5. Using CTR in forensic practice could help to detect cardiomegaly on post-mortem CT (PMCT) prior to the autopsy. However, an adaption of the threshold could be necessary because of post-mortem changes. Our retrospective study aimed to measure the CTR on PMCT and test the possible influence of variables. We selected 109 autopsy cases in which the heart weight was within normal limits. A forensic pathologist and a radiologist measured separately the CTR on axial and scout views on PMCT. We tested the statistical concordance between the two readers and between the axial and scout view and identified factors that could be associated with a modification of the CTR. The CTR measurements revealed an overestimation of the measurements made on scout compared to axial view. The inter-reader correlation was very high for both views. Among the different variables statistically tested, heart dilatation and body mass index (BMI) were the only two factors statistically associated with an augmentation of the CTR. The CTR can be useful in the diagnosis of cardiomegaly on PMCT. However, dilatation of the cardiac chambers caused by acute heart failure may be misinterpreted radiographically as cardiomegaly. Inter-observer reliability in our study was very high. CTR may be overestimated when measured on the scout view. Further investigations with larger cohorts, including cases with cardiac hypertrophy, are necessary to better understand the relationship between radiological CTR and the morphology of the heart.

Application of multi-phase postmortem CT-angiography in the investigation of vascular pathology and modified vascular anatomy: a special case of "vascular patchwork".

Multi-phase postmortem CT-angiography (MPMCTA) is used routinely for investigating cases of traumatic and natural death at the University Centre of Legal Medicine, Lausanne-Geneva. Here, we report the case of a patient affected by Leriche syndrome, with a history of numerous cardiovascular interventions, including an axillobifemoral bypass. The multiple cardiovascular changes presented by the patient were visualised by this relatively new technique and they were shown not to be related to the cause of death. This case demonstrated the utility of MPMCTA for investigating bodies with suspected vascular pathologies. Moreover, it revealed the advantages of MPMCTA over conventional autopsy to investigate a modified vascular anatomy. This was the first case in which MPMCTA was performed by injecting a contrast-agent mixture into a vascular prosthesis.

Longitudinal patterns of analgesic and central acting drug use and associated effectiveness in fibromyalgia.

BACKGROUND: We describe the changing pattern of analgesic and new central acting drug (NCAD) use (pregabalin, duloxetine, milnacipran) in fibromyalgia and measure NCAD effectiveness in clinical practice. METHODS: About 3123 US adult patients with fibromyalgia participated in an 11-year longitudinal study of fibromyalgia outcomes. We assessed severity-adjusted treatment prevalence and measured the effect of any use of NCAD on pain and fatigue, and functional status using the Health Assessment Questionnaire (HAQ) disability index. RESULTS: In 2010, 46.7% of patients used opioids, including 12.5% who used strong opioids. During the 11 years, severity-adjusted strong opioid use increased from 6.3% to 11.7% and any opioid use from 40.0% to 46.6%. Nonsteroidal anti-inflammatory drug (NSAID) use decreased from 74% to 44%. Tricyclic use dropped in half, from 27% to 15%, while NCAD use increased from less than 10% to 39%. The estimated 25th and 50th percentiles for NCAD discontinuation time were 1 and 2.5 years. Overall pain, fatigue and HAQ scores were unchanged over the 11 years. For patients treated with NCAD, pain scores were reduced significantly by 0.17 (0.03, 0.30) units following the start of NCAD, an improvement of 2.8%. Some sensitivity analyses showed improvements of up to 4.3%. There was no significant improvement in fatigue or functional status. CONCLUSIONS: There is a changing pattern of drug treatment in fibromyalgia, consisting mostly of decreased NSAID and amitriptyline use and an increase in NCAD. Drug costs are substantially higher because of NCAD use, but we found no evidence of clinical benefit for NCAD compared with prior therapy.

Increased incidence of herpes zoster among patients with systemic lupus erythematosus.

Herpes zoster (HZ) is the painful reactivation of latent varicella zoster virus infection. The incidence of HZ may be increased in some autoimmune diseases, including systemic lupus erythematosus (SLE). We examined the incidence and risk factors for HZ in a prospective cohort of patients with physician-diagnosed SLE compared to those diagnosed with non-inflammatory musculoskeletal conditions (MSK). After excluding participants with a history of prior HZ at enrollment, we followed 1485 SLE patients and 2775 MSK with semi-annual mailed questionnaires for incident HZ between 2001 and 2010. Age-adjusted incidences were calculated for each group and Cox proportional hazard models were used to identify predictors of HZ. Zostavax® vaccination rates were compared between groups. Participants had a mean age of 60 years at enrollment, with 13.9 years of disease. SLE patients had more HZ at all ages, with an age-adjusted incidence of 12.0/1000 person-years compared to MSK (8.7/1000 person-years) and a hazard ratio of 1.7 (95% CI 1.08-2.71) for SLE. Increasing age and reduced functional status were independent predictors of HZ. In SLE, prednisone and mycophenolate mofetil use conferred additional risk. SLE had the lowest HZ vaccination rates among age-eligible subjects.

Sudden death: ethical and legal problems of post-mortem forensic genetic testing for hereditary cardiac diseases.

Hereditary non-structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young. In these cases, genetic testing can be useful and does not require proxy consent if it is carried out at the request of judicial authorities as part of a forensic death investigation. Mutations in several genes are implicated in arrhythmic syndromes, including SCN5A, KCNQ1, KCNH2, RyR2, and genes causing HCM. If the victim's test is positive, this information is important for relatives who might be themselves at risk of carrying the disease-causing mutation. There is no consensus about how professionals should proceed in this context. This article discusses the ethical and legal arguments in favour of and against three options: genetic testing of the deceased victim only; counselling of relatives before testing the victim; counselling restricted to relatives of victims who tested positive for mutations of serious and preventable diseases. Legal cases are mentioned that pertain to the duty of geneticists and other physicians to warn relatives. Although the claim for a legal duty is tenuous, recent publications and guidelines suggest that geneticists and others involved in the multidisciplinary approach of sudden death (SD) cases may, nevertheless, have an ethical duty to inform relatives of SD victims. Several practical problems remain pertaining to the costs of testing, the counselling and to the need to obtain permission of judicial authorities.

Poor to modest agreement between rheumatoid arthritis response measures in clinical practice.

OBJECTIVE: To evaluate the agreement among several rheumatoid arthritis (RA) response measures in a clinical setting. METHODS: 529 patients with RA were seen at 2 regular visits where the following response measures were determined: ACR-20, EULAR good or moderate (EULAR-GM), Simplified Disease Activity Index moderate (SDAI-M), Clinical DAI moderate (CDAI-M), and Patient Reported Outcomes Index-M 20 (PRO-IM-20). Each measure was modified to include a "worse" response, i.e. the inverse of the respective guidelines for a positive improvement response.Introduced for comparison was the Real-time Assessment of Disease Activity in Rheumatoid Arthritis (RADARA), a response measure that registers improvement if the patient's tender and swollen joint counts and HAQ score all improve and worsening if all three increase. Contingency tables comparing the three responses (worse, no change, and improvement) along with Cohen's kappa were calculated. RESULTS: The mean (SD) baseline characteristics of the patients included: age 66.5 (10.7) years, RA duration 12.9 (11.0) years, 91.3% male, 84.1% rheumatoid factor positive, and a Disease Activity Score-28 of 3.5 (1.3). The percentage of patients who improved/worsened were as follows: ACR-20 4.7/9.1, EULAR-GM 23.4/26.3, SDAI-M 16.1/20.6, CDAI-M 16.3/20.0, PRO-IM-20 22.5/34.4, and RADARA 7.0/11.5. Agreement (kappa) was poor to slight (

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, which use a three-step approach: (1) expert-based definition of relevant research questions (November 2006); (2) systematic literature search (November 2006 to May 2007); and (3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature the expert panel recommended that each trial should report the following items: (1) disease activity response and disease activity states; (2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; (3) baseline disease activity levels (in general); (4) the percentage of patients achieving a low disease activity state and remission; (5) time to onset of the primary outcome; (6) sustainability of the primary outcome; (7) fatigue. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION: These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Quality of life in patients with rheumatoid arthritis: does abatacept make a difference?

Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disease that, in addition to causing joint damage, is associated with pain, fatigue, disability and functional loss, which can substantially decrease a patient's quality of life (QoL). Along with improvements in signs and symptoms, QoL benefits have become increasingly important in optimizing treatment outcomes in RA. Measurements of QoL have previously been under-used in all areas of medicine and only recently have clinical trials included them as a measure of treatment effectiveness. The existence of a positive relationship between improvements in signs and symptoms and concomitant improvements in QoL provides additional evidence that QoL measures are useful benchmarks for evaluating the effectiveness of treatment for RA. Furthermore, since these outcome measures evaluate the real-life, patient-centered benefits of RA therapies, they are likely to become increasingly central to the assessment of disease impact in clinical trials and practice, and to both drug approval and reimbursement decisions. This article reviews the impact of abatacept, a selective co-stimulation modulator, on the QoL of patients with active RA across a number of pivotal clinical trials. Firstly, an overview of the key QoL measurements used in abatacept clinical trials is provided, including those such as the Short Form-36, Health Assessment Questionnaire and Visual Analog Scale for pain, sleep and fatigue. We then present QoL data obtained in a wide range of patients with RA, including those with an inadequate response to either methotrexate or anti-tumor necrosis factor therapy, who have been treated with abatacept. Analysis of these data demonstrates that abatacept therapy has the potential to improve QoL across a range of patients with RA.

Rheumatoid arthritis treatment and the risk of severe interstitial lung disease.

OBJECTIVES: Interstitial lung disease (ILD) is an important complication of rheumatoid arthritis (RA) or its treatment, and is associated with substantially increased mortality. Reports have suggested that infliximab with or without azathioprine might lead to rapidly progressive or fatal ILD. We used an RA data bank to assess the associations of treatments for RA and severe ILD. METHODS: ILD was identified in hospitalisations and death records in 100 of 17,598 RA patients and studied in relation to RA therapy with Cox regression analyses. RESULTS: The incidence of hospitalisation for ILD (HILD) was 260 per 100,000 patient years. Among those hospitalised for ILD, 27.0% died. In multivariable models of current and past RA treatment, the only current treatment associated with HILD was prednisone: hazard ratio (HR) 2.5 [95% confidence interval (CI) 1.5-4.1]. Among past therapies, prednisone (HR 3.0, 95% CI 1.0-8.9), infliximab (HR 2.1, 95% CI 1.1-3.8), etanercept (HR 1.7, 95% CI 1.0-3.0), and cyclophosphamide (HR 3.7, 95% CI 0.9-15.5) were associated with HILD. Pre-existing lung problems were identified in 67% of HILD. Only one case of HILD in the 100 hospitalisations suggested a possible temporal relationship between infliximab and HILD. CONCLUSIONS: Associations between RA treatment and HILD are confounded by the prescription of treatments for ILD such as prednisone, infliximab, etanercept, and cyclophosphamide. There is no clear pattern of causal association of treatment and ILD, and there is no clear evidence to support a causal relationship between infliximab, azathioprine, and HILD.

Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders.

OBJECTIVES: Herpes zoster (HZ) is a common disorder that causes substantial pain and morbidity. We examined its rate and predictors in rheumatoid arthritis (RA) and non-inflammatory musculoskeletal (MSK) disorders to determine if HZ was increased in RA and whether treatment contributed to the risk of HZ. METHODS: After excluding patients witzh prior HZ, we assessed 10 614 RA and 1721 MSK patients by semi-annual questionnaires during 33 825 patient-years of follow-up. Predictors of HZ were determined by Cox regression and expressed as hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: The annualized incidence rate per 1000 patient-years was 13.2 (95% CI 11.9-14.5) in RA and 14.6 (95% CI 11.2-18.1) in MSK, and did not differ significantly after adjustment for age and sex. HZ was predicted by impaired functional status, as measured by the Health Assessment Questionnaire (HAQ), [HR 1.3 (95% CI 1.1-1.5)] and by the use of COX-2-specific non-steroidal anti-inflammatory drugs (NSAIDs) [HR 1.3 (95% CI 1.1-1.6)] in RA and MSK. In multivariable analyses in patients with RA, cyclophosphamide HR 4.2 (95% CI 1.6-11.5), azathioprine HR 2.0 (1.2-3.3), prednisone HR 1.5 (1.2-1.8), leflunomide HR 1.4 (1.1-1.8) and COX-2 NSAIDs HR 1.3 (95% CI 1.1-1.6) were significant predictors of HZ. CONCLUSION: The incidence of HZ is increased in RA and MSK compared with population-based rates. However, the rate of HZ in RA is not increased compared with MSK. After adjustment for severity, various treatments, but not methotrexate or biologics, were risk factors for HZ.

Towards an epidemiology of rheumatoid arthritis outcome with respect to treatment: randomized controlled trials overestimate treatment response and effectiveness.

The results and outcomes of randomized clinical trials of leflunomide and anti-TNF therapy are much better than are seen in rheumatoid arthritis patients in the community. This appears to be an effect of the clinical trial system. The consequence of deriving effectiveness estimates from clinical trials is to overestimate the effectiveness and thereby the cost-effectiveness of rheumatoid arthritis treatments.