Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia: PR3-versus MPO-ANCA-associated vasculitis, an exploratory cross-sectional study.

Background: Persistent fatigue is a common complaint in ANCA-vasculitis (AAV) patients and has a profound impact on patient's quality of life. The symptoms associated with this fatigue mirror those found in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. Etiologic and pathophysiologic differences exist between PR3- and MPO-ANCA disease, yet differences in their fatigue manifestations have not been well researched. We compared fatigue and its associations in healthy controls, AAV patients and fibromyalgia controls. Methods: The Canadian consensus criteria were used for ME/CFS diagnosis, and American College of Rheumatology criteria for fibromyalgia diagnosis. Factors such as cognitive failure, depression, anxiety, and sleep disturbances were assessed by patient reported questionnaires. Clinical factors such as BVAS, vasculitis damage index, CRP and BMI were also collected. Findings: Our AAV cohort comprised 52 patients, with a mean age of 44.7 (20-79), 57% (30/52) of the patients were female. We found 51.9% (27/52) of patients fulfilled the diagnostic criteria for ME/CFS, with 37% (10/27) of those having comorbid fibromyalgia. Rates of fatigue were higher in MPO-ANCA patients, than in PR3-ANCA patients, and their symptoms were more similar to the fibromyalgia controls. Fatigue in PR3-ANCA patients was related to inflammatory markers. These differences may be due to the varied pathophysiology of the PR3- and MPO-ANCA serotypes. Interpretation: A large proportion of AAV patients suffer from debilitating fatigue consequential enough to meet the diagnostic criteria for ME/CFS. Fatigue associations were not the same between PR3- and MPO-ANCA patients, suggesting that the underlying mechanisms may be different. Future studies should consider ANCA serotype, as further research may inform different clinical treatment strategies for AAV patients suffering from ME/CFS. Funding: This manuscript was funded by the Dutch Kidney Foundation (17PhD01).

Revised chronic widespread pain criteria: development from and integration with fibromyalgia criteria.

Background and aims Persons with chronic widespread pain (CWP) have poor medical outcomes and increased mortality. But there are no universally accepted criteria for CWP or of methods to assess it. The most common criteria come from the 1990 American College of Rheumatology (ACR) fibromyalgia (FM) criteria, but that method (WP1990) can identify CWP with as few as three pain sites, and in subjects with wide differences in illness severity. Recently, to correct WP1990 deficiencies, the 2016 fibromyalgia criteria provided a modified CWP definition (WP2016) by dividing the body into five regions of three pain sites each and requiring a minimum of four regions of pain. Although solving the geographic problem of pain distribution, the problem of just how many pain sites (pain diffuseness) are required remained a problem, as WP2016 required as few as four painful sites. To better characterize CWP, we compared four CWP definitions with respect to symmetry, extent of pain sites and association with clinical severity variables. Methods We characterized pain in 40,960 subjects, including pain at 19 individual sites and five pain regions, and calculated the widespread pain index (WPI) and polysymptomatic distress scales (PDS) from epidemiology, primary care and rheumatology databases. We developed and evaluated a new definition for CWP, (WP2019), defined as pain in four or five regions and a pain site score of at least seven of 15 sites. We also tested a definition based on the number of painful sites (WPI ≥ 7). Results In rheumatology patients, WP1990 and WPI ≥ 7 classified patients with <4 regions as WSP. CWP was noted in 51.3% by WP1990, 41.7% by WP2016, 37.6% of WPI ≥ 7 and 33.9% by WP2019. 2016 FM criteria was satisfied in WP1990 (51.1%), WP2016 (63.3%), WPI ≥ 7 (69.0%) and WP2019 (76.6%). WP2019 positive patients had more severe clinical symptoms compared with WP1990, WP2016 and WPI ≥ 7, and similar to but less than FM 2016 positive patients. In stepwise fashion, scores for functional disability, visual analog scale fatigue and pain, WPI, polysymptomatic distress score and Patient Health Questionnaire 15 (PHQ-15) worsened from WP1990 through WP2016, WPI ≥ 7 and WP2019. Conclusions WP2019 combines the high WPI scores of WPI ≥ 7 and the symmetry of WP2016, and is associated with the most abnormal clinical scores. The WP1990 does not appear to be an effective measure. We suggest that CWP can be better defined by combining 4-region pain and a total pain site score ≥7 (WP2019). This definition provides a simple, unambiguous measure that is suitable for clinical and research use as a standalone diagnosis that is integrated with fibromyalgia definitions. Implications Definitions of CWP in research and clinic care are arbitrary and have varied, and different definitions of CWP identify different sets of patients, making a universal interpretation of CWP uncertain. In addition, CWP is a mandatory component of some fibromyalgia criteria. Our study provides quantitative data on the differences between CWP definitions and their criteria, allowing better understanding of research results and a guide to the use of CWP in clinical care.

Comparing Strategies Targeting Osteoporosis to Prevent Fractures After an Upper Extremity Fracture (C-STOP Trial): A Randomized Controlled Trial.

We compared osteoporosis care after upper extremity fragility fracture using a low-intensity Fracture Liaison Service (FLS) versus a high-intensity FLS in a pragmatic patient-level parallel-arm comparative effectiveness trial undertaken at a Canadian academic hospital. A low-intensity FLS (active-control) that identified patients and notified primary care providers was compared to a high-intensity FLS (case manager) where a specially-trained nurse identified patients, investigated bone health, and initiated appropriate treatment. A total of 361 community-dwelling participants 50 years or older with upper extremity fractures who were not on bisphosphonate treatment were included; 350 (97%) participants completed 6-month follow-up undertaken by assessors blinded to group allocation. The primary outcome was difference in bisphosphonate treatment between groups 6 months postfracture; secondary outcomes included differences in bone mineral density (BMD) testing and a predefined composite measure termed "appropriate care" (taking or making an informed decision to decline medication for those with low BMD; not taking bisphosphonate treatment for those with normal BMD). Absolute differences (%), relative risks (RR with 95% confidence intervals [CIs]), number-needed-to-treat (NNT), and direct costs were compared. A total of 181 participants were randomized to active-control and 180 to case-manager using computer-generated randomization; the groups were similar on study entry. At 6 months, 51 (28%) active-control versus 86 (48%) case-manager participants started bisphosphonate treatment (20% absolute difference; RR 1.70; 95% CI, 1.28 to 2.24; p < 0.0001; NNT = 5). Of active-controls, 108 (62%) underwent BMD testing compared to 128 (73%) case-managed patients (11% absolute difference; RR 1.17; 95% CI, 1.01 to 1.36; p = 0.03). Appropriate care was received by 76 (44%) active-controls and 133 (76%) case-managed participants (32% absolute difference; RR 1.73; 95% CI, 1.43 to 2.09; p < 0.0001). The direct cost per participant was $18 Canadian (CDN) for the active-control intervention compared to $66 CDN for the case-manager intervention. In summary, case-management led to substantially greater improvements in bisphosphonate treatment and appropriate care within 6 months of fracture than the active control. © 2018 American Society for Bone and Mineral Research.

Long-term evaluation of a Canadian back pain mass media campaign.

PURPOSE: This paper evaluates the long-term impact of a Canadian mass media campaign on general public beliefs about staying active when experiencing low back pain (LBP). METHODS: Changes in beliefs about staying active during an episode of LBP were studied using telephone and web-based surveys. Logistic regression analysis was used to investigate changes in beliefs over time and the effect of exposure to campaign messaging. RESULTS: The percentage of survey respondents agreeing that they should stay active through LBP increased annually from 58.9 to ~72.0%. Respondents reporting exposure to campaign messaging were statistically significantly more likely to agree with staying active than respondents who did not report exposure to campaign messaging (adjusted OR, 95% CI = 1.96, 1.73-2.21). CONCLUSION: The mass media campaign had continued impact on public LBP beliefs over the course of 7 years. Improvements over time were associated with exposure to campaign messaging.

Treating Psoriasis and Psoriatic Arthritis: Position Paper on Applying the Treat-to-target Concept to Canadian Daily Practice.

OBJECTIVE: To develop preliminary treat-to-target (T2T) recommendations for psoriasis and psoriatic arthritis (PsA) for Canadian daily practice. METHODS: A task force composed of expert Canadian dermatologists and rheumatologists performed a needs assessment among Canadian clinicians treating these diseases as well as an extensive literature search on the outcome measures used in clinical trials and practice. RESULTS: Based on results from the needs assessment and literature search, the task force established 5 overarching principles and developed 8 preliminary T2T recommendations. CONCLUSION: The proposed recommendations should improve management of psoriasis and PsA in Canadian daily practice. However, these recommendations must be further validated in a real-world observational study to ensure that their use leads to better longterm outcomes.

2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria.

OBJECTIVES: The provisional criteria of the American College of Rheumatology (ACR) 2010 and the 2011 self-report modification for survey and clinical research are widely used for fibromyalgia diagnosis. To determine the validity, usefulness, potential problems, and modifications required for the criteria, we assessed multiple research reports published in 2010-2016 in order to provide a 2016 update to the criteria. METHODS: We reviewed 14 validation studies that compared 2010/2011 criteria with ACR 1990 classification and clinical criteria, as well as epidemiology, clinical, and databank studies that addressed important criteria-level variables. Based on definitional differences between 1990 and 2010/2011 criteria, we interpreted 85% sensitivity and 90% specificity as excellent agreement. RESULTS: Against 1990 and clinical criteria, the median sensitivity and specificity of the 2010/2011 criteria were 86% and 90%, respectively. The 2010/2011 criteria led to misclassification when applied to regional pain syndromes, but when a modified widespread pain criterion (the "generalized pain criterion") was added misclassification was eliminated. Based on the above data and clinic usage data, we developed a (2016) revision to the 2010/2011 fibromyalgia criteria. Fibromyalgia may now be diagnosed in adults when all of the following criteria are met: CONCLUSIONS: The fibromyalgia criteria have good sensitivity and specificity. This revision combines physician and questionnaire criteria, minimizes misclassification of regional pain disorders, and eliminates the previously confusing recommendation regarding diagnostic exclusions. The physician-based criteria are valid for individual patient diagnosis. The self-report version of the criteria is not valid for clinical diagnosis in individual patients but is valid for research studies. These changes allow the criteria to function as diagnostic criteria, while still being useful for classification.

Comparison of Physician-Based and Patient-Based Criteria for the Diagnosis of Fibromyalgia.

OBJECTIVE: The American College of Rheumatology (ACR) 2010 preliminary fibromyalgia diagnostic criteria require symptom ascertainment by physicians. The 2011 survey or research modified ACR criteria use only patient self-report. We compared physician-based (MD) (2010) and patient-based (PT) (2011) criteria and criteria components to determine the degree of agreement between criteria methodology. METHODS: We studied prospectively collected, previously unreported rheumatology practice data from 514 patients and 30 physicians in the ACR 2010 study. We evaluated the widespread pain index, polysymptomatic distress (PSD) scale, tender point count (TPC), and fibromyalgia diagnosis using 2010 and 2011 rules. Bland-Altman 95% limits of agreement (LOA), kappa statistic, Lin's concordance coefficient, and the area under the receiver operating curve (ROC) were used to measure agreement and discrimination. RESULTS: MD and PT diagnostic agreement was substantial (83.4%, κ = 0.67). PSD scores differed slightly (12.3 MD, 12.8 PT; P = 0.213). LOA for PSD were -8.5 and 7.7, with bias of -0.42. The TPC was strongly associated with both the MD (r = 0.779) and PT PSD scales (r = 0.702). CONCLUSION: There was good agreement in MD and PT fibromyalgia diagnosis and other measures among rheumatology patients. Low bias scores indicate consistent results for physician and patient measures, but large values for LOA indicate many widely discordant pairs. There is acceptable agreement in diagnosis and PSD for research, but insufficient agreement for clinical decisions and diagnosis. We suggest adjudication of symptom data by patients and physicians, as recommended by the 2010 ACR criteria.

Fibromyalgia and physical trauma: the concepts we invent.

Despite weak to nonexistent evidence regarding the causal association of trauma and fibromyalgia (FM), literature and court testimony continue to point out the association as if it were a strong and true association. The only data that appear unequivocally to support the notion that trauma causes FM are case reports, cases series, and studies that rely on patients' recall and attribution - very low-quality data that do not constitute scientific evidence. Five research studies have contributed evidence to the FM-trauma association. There is no scientific support for the idea that trauma overall causes FM, and evidence in regard to an effect of motor vehicle accidents on FM is weak or null. In some instances effect may be seen to precede cause. Alternative causal models that propose that trauma causes "stress" that leads to FM are unfalsifiable and unmeasurable.

Long-term safety and efficacy of abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: a 7-year extended study.

OBJECTIVES: To assess the safety and efficacy of intravenous (IV) abatacept plus methotrexate (MTX) over 7 years, the longest observational period to date, in patients with established rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: Patients randomised to IV abatacept (10 or 2 mg/kg) or placebo, plus MTX, during the 1-year double-blind (DB) period of a Phase 2b study could enter the long-term extension (LTE) and receive IV abatacept 10 mg/kg monthly. Safety was assessed in patients who received ≥1 dose of abatacept; efficacy was assessed in patients originally randomised to 10 mg/kg abatacept (as-observed data). RESULTS: A total of 219 patients entered the LTE; 114 (52.1%) completed 7 years of treatment with abatacept plus MTX. Cumulative (DB + LTE) incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 17.6, 3.2, 1.8, and 1.2/100 patient-years, respectively. Safety was consistent between the DB (n=220) and cumulative (n=287) periods. Improvements in American College of Rheumatology responses, disease activity, and normalisation of physical function and health-related quality of life were maintained over time. Approximately 80% of patients who achieved low disease activity or normalised modified Health Assessment Questionnaire scores at Year 1, and who remained in the study, sustained these responses in each subsequent year. CONCLUSIONS: IV abatacept in combination with MTX demonstrated consistent safety and sustained efficacy over 7 years in MTX inadequate responders with established RA. Furthermore, some patients demonstrated a normalisation of physical function and health-related quality of life that was sustained over time.

The challenge of indication extrapolation for infliximab biosimilars.

A biosimilar is intended to be highly similar to a reference biologic such that any differences in quality attributes (i.e., molecular characteristics) do not affect safety or efficacy. Achieving this benchmark for biologics, especially large glycoproteins such as monoclonal antibodies, is challenging given their complex structure and manufacturing. Regulatory guidance on biosimilars issued by the U.S. Food and Drug Administration, Health Canada and European Medicines Agency indicates that, in addition to a demonstration of a high degree of similarity in quality attributes, a reduced number of nonclinical and clinical comparative studies can be sufficient for approval. Following a tiered approach, clinical studies are required to address concerns about possible clinically significant differences that remain after laboratory and nonclinical evaluations. Consequently, a critical question arises: can clinical studies that satisfy concerns regarding safety and efficacy in one condition support "indication extrapolation" to other conditions? This question will be addressed by reviewing the case of a biosimilar to infliximab that was approved recently in South Korea, Europe, and Canada for multiple indications through extrapolation. The principles discussed should also apply to biosimilars of other monoclonal antibodies that are approved to treat multiple distinct conditions.

Longterm safety, efficacy, and inhibition of structural damage progression over 5 years of treatment with abatacept in patients with rheumatoid arthritis in the abatacept in inadequate responders to methotrexate trial.

OBJECTIVE: Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA). METHODS: Patients from the 1-year, double-blind Abatacept in Inadequate Responders to Methotrexate (AIM) study (NCT00048568) received open-label ABA (∼10 mg/kg) in the longterm extension (LTE). Safety was assessed for patients who received ≥ 1 ABA dose, and efficacy for patients randomized to ABA and treated in the LTE. Radiographs were evaluated for changes in Genant-modified Sharp scores. RESULTS: Out of 652 patients, 539 entered the LTE (ABA, n = 378; placebo, n = 161). At Year 5, 72.4% were ongoing; discontinuation rates declined over time. Incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 13.87, 2.84, 1.45, and 0.99 events/100 patient-years exposure, respectively. American College of Rheumatology 20 response was 82.3% (n = 373) and 83.6% (n = 268) at years 1 and 5, respectively. Disease Activity Score 28 C-reactive protein (DAS28-CRP) < 2.6 and ≤ 3.2 were achieved by 25.4% and 44.1% of patients at Year 1 (n = 370), and 33.7% and 54.7% at Year 5 (n = 267), respectively. Mean changes in DAS28-CRP and Health Assessment Questionnaire-Disability Index at Year 1 [-2.83 (n = 365) and -0.68 (n = 369)] were maintained at Year 5 [-3.14 (n = 264) and -0.77 (n = 271)] for patients continuing treatment. Of them, 59.5% (n = 291) and 45.1% (n = 235) remained free from radiographic progression at years 1 and 5, respectively. CONCLUSION: In MTX-refractory patients with RA, longterm ABA treatment was well tolerated and provided consistent safety and sustained efficacy, with high patient retention. Radiographic progression continued to be inhibited with ongoing treatment.

Canadian estimates of health care utilization costs for rheumatoid arthritis patients with and without therapy with biologic agents.

OBJECTIVE: To provide Canadian estimates of health care utilization costs associated with rheumatoid arthritis (RA)-related and non-RA-related care within 4 treatment strategies and in different physical functioning categories. METHODS: In the Alberta Rheumatoid Arthritis Biologics Pharmacosurveillance Program, clinical data were linked with provincial health care administrative databases to estimate health care costs. A propensity score matching technique was used to evaluate annual costs across 4 treatment strategies: 1) remaining on disease-modifying antirheumatic drugs and not progressing to therapy with a biologic agent (n = 75), 2) progressing to biologic agents (n = 68), 3) initiation and stabilization on a first anti-tumor necrosis factor agent (n = 731), or 4) requiring a switch to another biologic agent (n = 212). Costs were examined across levels of function and by cost attribution category (directly related to RA or not). RESULTS: Of 1,222 patients, 1,086 had at least 3 months of administrative data. The mean annual total cost per patient was $5,531 (median $2,568), and $2,349 (median $0) was accounted for by hospitalizations, $1,716 (median $1,358) by physician visits, and $1,465 (median $949) by emergency room and other outpatient visits. Of these costs, 41% was directly related to RA itself or associated comorbidities. The importance of physical function as a determinant of health care utilization was evident, with the annual mean cost for those with low functional disability as measured by a Health Assessment Questionnaire (HAQ) score <0.5 was $4,157 compared to $14,225 for those with a HAQ score >2.0 indicating high disability. CONCLUSION: Health care costs for RA can be minimized by aiming for better disease control and maintaining physical function.

The number needed to offend: a cross-sectional study of potential offensiveness of rheumatic diagnostic labels.

This study aims to explore the different connotations and potential offensiveness of ten mechanistic labels in newly referred Mexican patients with rheumatic symptoms as well as in Mexican and Canadian rheumatologists. Patients with musculoskeletal complaints newly referred for a rheumatology assessment were interviewed consecutively before they saw the rheumatologist. Patients were asked to choose one of nine feelings provoked by ten different illness mechanism labels. Rheumatologists gave a medical diagnosis after seeing the patients. Mexican and Canadian rheumatologists were invited to answer a structured questionnaire about their feelings at the moment they identified each of the ten different provided scenarios. Patients' and rheumatologists' feelings were classified as "offended" or "nonoffended." The "offensive score" was used to calculate a "number needed to offend" (NNO). One hundred and fifty patients were included. Inherited, immunological, and inflammatory labels had the fewest negative connotations (NNOs 17, 12, and 14, respectively), and psychological, functional, idiopathic, and sleep disturbance labels had the most (NNO 2 and 3, respectively). Functional labels were almost four times more offensive than organic labels. Stratified by rheumatologist diagnosis, patients with functional disorders were more accepting of organic-based mechanistic labels. A higher potential to offend was observed when patients with functional somatic conditions were given functional mechanistic labels (NNOs 1 to 4). The survey was completed by 186 Mexican rheumatologists and 71 Canadian rheumatologists. Primarily functional disorders such as somatization and anxiety had a high potential to evoke offensive feelings (NNOs 3 to 7). No significant differences in the NNO were found between Mexican and Canadian rheumatologists. Getting or giving mechanistic/explanatory labels is emotional. Both patients and rheumatologists experienced offended feelings with functional or idiopathic labels.

A questionnaire using the modified 2010 American College of Rheumatology criteria for fibromyalgia: specificity and sensitivity in clinical practice.

OBJECTIVE: To determine the specificity and sensitivity of the Modified 2010 American College of Rheumatology (ACR) Diagnostic Criteria for Fibromyalgia (given as a self-administered questionnaire) in clinical practice. METHODS: A cohort of patients with widespread pain, referred by primary care physicians to rheumatologists, completed the questionnaire for the Modified ACR 2010 criteria. Prior to completion of the questionnaire, patients were diagnosed by at least 1 rheumatologist as either having fibromyalgia (FM) or not having FM, using the rheumatologist's clinical assessment as the gold standard for diagnosis of FM. The Modified ACR 2010 criteria were then applied to determine whether a diagnosis of FM was satisfied by the criteria. Sensitivity and specificity were determined, using the rheumatologist's clinical assessment as the gold standard. A score ≥ 12 on the Modified ACR 2010 criteria questionnaire was also tested as the criterion to satisfy a diagnosis of FM, and subsequently to determine sensitivity and specificity. We examined the effect of using a cutoff score ≥ 13, as previous research indicated that this may be a more useful cutoff value. RESULTS: A total of 451 subjects completed the questionnaire: 174 with an a priori diagnosis of FM by a rheumatologist and 277 with widespread pain who did not have an a priori clinical diagnosis of FM by a rheumatologist. The Modified ACR 2010 criteria were satisfied by 90.2% of patients with an a priori diagnosis of FM, and by 10.5% of subjects who had widespread pain, but were not diagnosed with FM when previously assessed by a rheumatologist. Thus, sensitivity and specificity are 90.2% and 89.5%, respectively, using the Modified ACR 2010 criteria. A score ≥ 12 on the Modified ACR 2010 criteria was observed in 97.4% of patients with an a priori diagnosis of FM, and 14.8% of subjects who had widespread pain, but were not diagnosed with FM when previously assessed by a rheumatologist. Thus, the sensitivity and specificity are 97.4% and 85.2%, respectively, using a cutoff score ≥ 12. Using a score of ≥ 13, however, the sensitivity was 93.1% and the specificity was 91.7%. CONCLUSION: The Modified ACR 2010 criteria questionnaire can be used in primary care as a tool to assist physicians in the diagnosis of FM with high specificity and sensitivity. Calculating the total score on a Modified ACR 2010 criteria questionnaire, and setting the value of ≥ 13 as the cutoff for a diagnosis of FM appears to be the most effective approach. The Modified ACR 2010 criteria may reduce the need for rheumatology referral simply for the diagnosis of FM.

A biologic pharmacosurveillance program for rheumatoid arthritis: a single-center experience.

We have reviewed the experience in a single center of a biologic register for rheumatoid arthritis patients. Over the past decade, the entry demographics show that we are treating patients at an earlier stage and with slightly less severe disease. Our outcomes measured by the percentage in DAS28 remission are comparable with national databases. We were surprised by the small number who were switched from their first biologic to a second (27 %), but this might reflect the lack of a firm "treat to target" approach. Our use of concomitant methotrexate/leflunomide is less than we would have liked and thought, but our use of concomitant corticosteroids is much less than normally seen. A single-center registry can provide useful monitoring and quality assurance data and stimulate change.

Cost-effectiveness of osteoporosis interventions for 'incidental' vertebral fractures.

BACKGROUND: Vertebral fractures detected "incidentally" by chest radiograph usually do not trigger osteoporosis treatment in older patients. In a 3-arm controlled trial we reported that both physician-directed and enhanced (physician plus patient activation) interventions increased treatment rates more than 10-fold (15%-20% absolute increases) compared with usual care; the cost-effectiveness of these interventions is unknown. METHODS: Incremental cost-effectiveness of these 2 interventions compared with usual care was assessed using a Markov decision-analytic model, populated with 1-year outcomes data and direct intervention costs from the trial. Costs were expressed in 2009 Canadian dollars and effectiveness based on quality-adjusted life years (QALYs) gained. The perspective was health care payer; horizon was projected lifetime; costs and benefits were discounted at 3%; and deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Per patient, the physician and enhanced interventions cost $34 and $42, respectively. Compared with usual care, for every 1000 patients exposed to the physican intervention there were 4 fewer fractures, 8 more QALYs gained, and $282,000 saved. Compared with physician interventions, for every 1000 patients exposed to enhanced interventions there were 6 fewer fractures, 6 more QALYs gained, and $339,000 saved. Both interventions dominated usual care and were cost-effective in ~80% of 10,000 probabilistic simulations. Although the enhanced intervention cost $8 more per patient, it still dominated the physician intervention and usual care, and was the most economically attractive option. CONCLUSIONS: Pragmatic and inexpensive interventions directed at patients with incidentally detected vertebral fractures and their physicians are highly cost-effective at improving osteoporosis treatment, and in most circumstances also are cost-saving.

Targeting tumour necrosis factor alleviates signs and symptoms of inflammatory osteoarthritis of the knee.

INTRODUCTION: Inflammation associated with synovial expression of TNFα is a recognised feature of osteoarthritis (OA), although no studies have yet reported beneficial effects of anti-TNFα therapy on clinical manifestations of inflammation in OA. METHODS: We conducted an open-label evaluation of adalimumab over 12 weeks in 20 patients with OA of the knee and evidence of effusion clinically. Inclusion criteria included daily knee pain for the month preceding study enrolment and a summed pain score of 125 to 400 mm visual analogue scale on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale. The primary outcome was the Osteoarthritis Research Society International/Outcome Measures in Rheumatology Clinical Trials (OARSI/OMERACT) response criterion at week 12. Secondary outcomes included the WOMAC pain score 20% and 50% improvement, WOMAC stiffness and function scores, patient and physician global visual analogue scale, as well as target joint swelling. RESULTS: Treatment was well tolerated and completed by 17 patients with withdrawals unrelated to lack of efficacy or adverse events. By intention to treat, an OARSI/OMERACT response was recorded in 14 (70%) patients. WOMAC pain 20% and 50% responses were recorded in 14 (70%) patients and eight (40%) patients, respectively. Significant improvement was observed in mean WOMAC pain, stiffness, function, physician and patient global, as well as target joint swelling at 12 weeks (P < 0.0001 for all). After treatment discontinuation, 16 patients were available for assessment at 22 weeks and OARSI/OMERACT response compared with baseline was still evident in 10 (50%) patients. CONCLUSION: Targeting TNFα may be of therapeutic benefit in OA and requires further evaluation in controlled trials. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00686439.