Evaluating surrogacy metrics and investigating approval decisions of progression-free survival (PFS) in metastatic renal cell cancer: a systematic review.

BACKGROUND: In metastatic renal cell cancer (mRCC) trials, progression-free survival (PFS) is increasingly used instead of overall survival (OS) as the approval end point. Unlike other solid tumors, there is no published demonstration of what PFS is needed across and by treatment class in mRCC. We determine this and evaluate drug approval decisions in mRCC targeted therapy. METHODS: We identified all randomized, controlled trials reporting PFS and OS in mRCC. Surrogacy metrics were the coefficient of determination and surrogate threshold effect (STE)-the PFS difference needed to predict, with 95% confidence, an OS difference. Data from regulatory commentaries, briefing documents and transcripts were extracted. RESULTS: No exclusively chemotherapy trial met criteria. Of 30 qualifying trials, 11 trials (13 comparisons) used targeted therapy. The all-trials and immunotherapy-only trials analysis failed to demonstrate a STE. The targeted trials, using the more conservative regression analysis demonstrated an STE of 3.9 months and an R(2) of 0.44. Crossover upon progression, control to active treatment, was common. Regulatory approval, accelerated or regular, labeling, interim analyses, and adjudication were context specific. CONCLUSIONS: A new targeted therapy trial showing a PFS difference of 3.9 months can claim an OS benefit in mRCC. PFS surrogacy for OS in metastatic renal cell is not generalizable across all drug classes.

Risk factors for herpes zoster in rheumatoid arthritis patients: the role of tumour necrosis factor-α inhibitors.

AIM: To determine whether exposure to tumour necrosis factor (TNF)-α inhibitors increases the risk of herpes zoster (HZ) among people with rheumatoid arthritis (RA). METHODS: We performed a cohort study of people with RA participating in the Australian Rheumatology Association Database. We identified self-reported cases of HZ and verified using medical records. For the primary analysis, we only included doctor-verified cases. For TNF-α inhibitor exposed groups, we excluded HZ episodes that occurred before TNF-α inhibitor initiation, and for the control group we excluded HZ episodes that occurred prior to 2000 or RA diagnosis. The risk of HZ among participants exposed versus not exposed to TNF-α inhibitors was compared using Cox proportional hazards models including significant covariates affecting the risk. Adjusted hazard ratios (HR) were calculated for TNF inhibitors as a class and for individual agents. RESULTS: Among 2157 active RA participants, there were 442 self-reported cases of HZ. From 346 responses from doctors, 249 cases were verified and four were false positives (false positive rate 1.6%). Crude incidence of verified HZ in the entire RA cohort was 15.9/1000 person-years (95% confidence interval (CI): 13.5-18.8). An increased risk of HZ was found for all TNF-α inhibitors combined (fully adjusted HR 1.71; 95% CI: 1.00-2.92) and adalimumab (fully adjusted HR 2.33; 95% CI: 1.22-4.45), but in the fully adjusted model was not increased with etanercept (fully adjusted HR 1.65; 95% CI: 0.90-3.03). No increased risk was found with infliximab (HR 1.29; 95% CI: 0.37-4.47). CONCLUSIONS: TNF-α inhibitors are associated with an increased risk of HZ in people with RA compared with those who have not been exposed.

How many life years are lost in patients with rheumatoid arthritis? Secular cause-specific and all-cause mortality in rheumatoid arthritis, and their predictors in a long-term Australian cohort study.

BACKGROUND: There is an excess of mortality in patients with rheumatoid arthritis (RA) but no long-term Australian cohort data. AIMS: To determine median life years lost, all-cause standardised mortality ratio (SMR) and cause-specific SMR, their predictors and secular change in Australian patients with RA. METHODS: Study population was all patients seen by a rheumatologist between 1990 and 1994. Record linkage with Australian National Death Index was performed to determine fact and cause of death up to 2004. All-cause and cause-specific SMR, and median life years lost were determined. RESULTS: There were 35 (31%) deaths in the early 1990s cohort (n = 113), SMR 1.31 (95% 0.93, 1.80). There were 216 (44%) deaths in the pre-1990s established cohort (n = 495), SMR 1.73 (1.49, 1.95). Median life years lost in the early cohort was 6 years for males and 7 years for females compared with 8 and 10 years, respectively, in the established cohort. Patients with low disease activity score at baseline (DAS < 3.2), SMR was 0.8 (0.3, 2.2) and 1.5 (1.1, 2.2) for the early and established cohorts, and if DAS ≥3.2, SMR was 1.4 (1.02, 1.98) and 1.8 (1.5, 2.1) respectively. Primary cause of death was cardiovascular disease (SMR 1.43 (1.17, 1.74). Patients at most risk were those age 45-54 years. RA was listed as a comorbid condition on the death certificate in only 16% of patients. CONCLUSIONS: Within a period of 14 years, median life expectancy of patients with RA with disease onset in the early 1990s is reduced by 6-7 years. However, our results also suggest a secular reduction in excess mortality.

Effect of treatment with biological agents for arthritis in Australia: the Australian Rheumatology Association Database.

BACKGROUND: The Australian Rheumatology Association Database (ARAD), a voluntary national registry, has been established to collect health information from Australian patients with inflammatory arthritis for the purpose of monitoring the benefits and safety of new treatments, in particular the biological disease-modifying anti-rheumatic drugs (bDMARDs). These drugs are proving to be very effective, yet little is known of their long-term effectiveness or safety. Patient registries that systematically gather data on large cohorts of unselected patients are increasingly believed to be an essential means of answering questions of the long-term effectiveness and safety of new drugs. The aim of this report is to describe the role, development and structure of ARAD and provide some preliminary data. METHODS: As of 1 August 2006, 563 patients with rheumatoid arthritis prescribed a bDMARD have been enrolled in ARAD, involving 105 rheumatologists from across Australia. RESULTS: The data collected will enable examination of multiple domains of patient responses to bDMARDs, including quality of life, health-care utilization, incidence of adverse events and the effects of therapy switching. CONCLUSION: Evidence-based information about the long-term outcome of bDMARD therapy is essential for clinicians, consumers, policy-makers, drug development companies and approval agencies, to enable better care and improved outcomes for patients with inflammatory arthritis.

Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant.

BACKGROUND: A range of treatments have been proposed to improve pregnancy outcome in recurrent pregnancy loss associated with antiphospholipid antibody (APL). Small studies have not resolved uncertainty about benefits and risks. OBJECTIVES: To examine outcomes of all treatments given to maintain pregnancy in women with prior miscarriage and APL. SEARCH STRATEGY: We searched the Pregnancy and Childbirth Group's Trials Register (30 May 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003), MEDLINE (1966 to June 2003), EMBASE (1988 to June 2003), Lupus (volume one to eight, 1991 to 1999) and conference proceedings from the International Symposium on APL up to 1999. SELECTION CRITERIA: Randomised or quasi-randomised, controlled trials of interventions in pregnant women with a history of pregnancy loss and APL. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed quality and extracted data for studies up to December 1999. One review author performed this for studies after 1999. MAIN RESULTS: Thirteen studies were found (849 participants). The quality was not high; 50% had clear evidence of allocation concealment. Participant characteristics varied between trials. Unfractionated heparin combined with aspirin (two trials; n = 140) significantly reduced pregnancy loss compared to aspirin alone (relative risk (RR) 0.46, 95% confidence interval (CI) 0.29 to 0.71). Low molecular weight heparin (LMWH) combined with aspirin compared to aspirin (one trial; n = 98) did not significantly reduce pregnancy loss (RR 0.78, 95% CI 0.39 to 1.57). There was no advantage in high-dose, over low-dose, unfractionated heparin (one trial; n = 50). Three trials of aspirin alone (n = 135) showed no significant reduction in pregnancy loss (RR 1.05, 95% CI 0.66 to 1.68). Prednisone and aspirin (three trials; n = 286) resulted in a significant increase in prematurity when compared to placebo, aspirin, and heparin combined with aspirin, and an increase in gestational diabetes, but no significant benefit. Intravenous immunoglobulin +/- unfractionated heparin and aspirin (two trials; n = 58) was associated with an increased risk of pregnancy loss or premature birth when compared to unfractionated heparin or LMWH combined with aspirin (RR 2.51, 95% CI 1.27 to 4.95). When compared to prednisone and aspirin, intravenous immunoglobulin (one trial; n = 82) was not significantly different in outcomes. AUTHORS' CONCLUSIONS: Combined unfractionated heparin and aspirin may reduce pregnancy loss by 54%. Large, randomised controlled trials with adequate allocation concealment are needed to explore potential differences between unfractionated heparin and LMWH.

Systemic disease presenting as arthritis--a diagnostic approach.

It is not uncommon for patients with 'arthritis' to be presenting with a rheumatological manifestation of a systemic disease. Frequently the pain is not even of articular origin. The diagnostic challenge for the practitioner is to determine the nature of the underlying pathologic process. This article sets out to provide some guidelines for diagnosis.

Arthroscopic estimation of the extent of chondropathy.

INTRODUCTION: Arthroscopy has been used to evaluate articular cartilage (AC) pathology in osteoarthritis (OA) for outcome measurement and validation of non-invasive imaging. However, many fundamental aspects of arthroscopic assessment remain un-validated. OBJECTIVES: This study evaluated arthroscopic estimates of extent of chondropathy. METHODS: Serial arthroscopic assessments were performed in a group of 15 sheep before and after bilateral stifle medial meniscectomy (MMx). Post-mortem assessments were performed in un-MMx sheep and 4 and 16 weeks post-MMx. Arthroscopic assessments of the extent of each grade of chondropathy were compared with a non-arthroscopic hybrid assessment that incorporated biomechanical, thickness and macroscopic assessments. RESULTS: Arthroscopy evaluated only 36% of AC and missed significant pathological changes, softening and chondro-osteophyte, occurring in peripheral regions. The patterns of change in arthroscopic assessments were similar to those of the non-arthroscopic assessment but there was a very strong tendency to over-estimate the extent of softened AC after MMx. In spite of these limitations arthroscopic assessments were responsive to change. Estimates of the extent of normal and softened AC were most responsive to change over time followed by estimates of superficial and deep fibrillation. Arthroscopy was as an excellent discriminator between normal and OA. Assessments of chondro-osteophyte and exposed bone were not responsive to change. CONCLUSIONS: Arthroscopic estimates of extent of chondropathy are prone to substantial error. While experience and training may reduce these errors other approaches may more effectively improve performance.

A users guide to measurement in medicine.

Measurement is fundamental to science. In medicine measurement underpins most clinical decisions. Outcome measures for rheumatoid arthritis clinical trials (OMERACT) is an informal collaborative group of professionals dedicated to improving outcome measurement in the rheumatic disease. The methodologic hallmark of the OMERACT process is captured in the OMERACT filter--truth, discrimination, and feasibility. Using the key elements of the OMERACT filter a comprehensive checklist for evaluating reported measures is provided. The checklist guides the potential user through a series of questions. The checklist is also an important resource for researchers working in the field of measurement.

Assessment of the radioanatomic positioning of the osteoarthritic knee in serial radiographs: comparison of three acquisition techniques.

OBJECTIVE: Recent studies using various standardized radiographic acquisition techniques have demonstrated the necessity of reproducible radioanatomic alignment of the knee to assure precise measurements of medial tibiofemoral joint space width (JSW). The objective of the present study was to characterize the longitudinal performance of several acquisition techniques with respect to long-term reproducibility of positioning of the knee, and the impact of changes in positioning on the rate and variability of joint space narrowing (JSN). METHODS: Eighty subjects were randomly selected from each of three cohorts followed in recent studies of the radiographic progression of knee osteoarthritis (OA): the Health ABC study (paired fixed-flexion [FF] radiographs taken at a 36-month interval); the Glucosamine Arthritis Intervention Trial (GAIT) (paired metatarsophalangeal [MTP] radiographs obtained at a 12-month interval), and a randomized clinical trial of doxycycline (fluoroscopically assisted semiflexed anteroposterior (AP) radiographs taken at a 16-month interval). Manual measurements were obtained from each radiograph to represent markers of radioanatomic positioning of the knee (alignment of the medial tibial plateau and X-ray beam, knee rotation, femorotibial angle) and to evaluate minimum JSW (mJSW) in the medial tibiofemoral compartment. The effects on the mean annualized rate of JSN and on the variability of that rate of highly reproduced vs variable positioning of the knee in serial radiographs were evaluated. RESULTS: Parallel or near-parallel alignment was achieved significantly more frequently with the fluoroscopically guided positioning used in the semiflexed AP protocol than with either the non-fluoroscopic FF or MTP protocol (68% vs 14% for both FF and MTP protocols when measured at the midpoint of the medial compartment; 75% vs 26% and 34% for the FF and MTP protocols, respectively, when measured at the site of mJSW; P<0.001 for each). Knee rotation was reproduced more frequently in semiflexed AP radiographs than in FF radiographs (66% vs 45%, P<0.01). In contrast, the FF technique yielded a greater proportion of paired radiographs in which the femorotibial angle was accurately reproduced than the semiflexed AP or MTP protocol (78% vs 59% and 56%, respectively, P<0.01 for each). Notably, only paired radiographs with parallel or near-parallel alignment exhibited a mean rate of JSN (+/-SD) in the OA knee that was more rapid and less variable than that measured in all knees (0.186+/-0.274 mm/year, standardized response to mean [SRM]=0.68 vs 0.128+/-0.291 mm/year, SRM=0.44). CONCLUSION: This study confirms the importance of parallel radioanatomic alignment of the anterior and posterior margins of the medial tibial plateau in detecting JSN in subjects with knee OA. The use of radiographic methods that assure parallel alignment during serial X-ray examinations will permit the design of more efficient studies of biomarkers of OA progression and of structure modification in knee OA.

Power Doppler 'blanching' after the application of transducer pressure.

The aim of this study was to determine if transducer pressure modifies power Doppler assessments of rheumatoid arthritis synovium at the metacarpophalangeal joints and metatarsophalangeal joints. Five rheumatoid arthritis patients of varying degrees of 'disease activity' and damage were assessed with power Doppler ultrasound scanning of the dominant hand second to fifth metacarpophalangeal joints. Two rheumatoid arthritis patients had their dominant foot first to fifth metatarsophalangeal joints assessed with power Doppler ultrasound. Ultrasonography was performed with a high frequency transducer (14 MHz) with a colour mode frequency of 10 Mhz, and a standard colour box and gain. In the joint that showed the highest power Doppler signal, an image was made. A further image was taken after transducer pressure was applied. In all patients, there was increased flow to at least one joint. After pressure was applied, power Doppler signal intensity markedly reduced in all images and in some there was no recordable power Doppler signal. Increased transducer pressure can result in a marked reduction or obliteration in power Doppler signal. This power Doppler 'blanching' shows the need for further studies to evaluate sources of error and standardization before power Doppler ultrasound becomes a routine measure of 'disease activity' in rheumatoid arthritis.

Arthroscopy -- a potential "gold standard" for the diagnosis of the chondropathy of early osteoarthritis.

OBJECTIVES: The aims of this study were to: 1. Evaluate the performance of arthroscopy for the diagnosis of chondropathy and to compare it to that of direct non-arthroscopic assessments; 2. Determine intra-observer reliability of arthroscopic assessments; 3. Evaluate the effects of the arthroscopic video quality and probing upon diagnostic performance. DESIGN: The ovine medial meniscectomy (MMx) model of early osteoarthritis (OA) was used assuming that pre-MMx articular cartilage (AC) was "normal" and post-MMx AC "chondropathic". Video recordings of arthroscopic assessments of each stifle compartment were evaluated. Scores were given for the quality of the video and the amount of probing. The diagnostic performances of dynamic shear modulus (G), light microscopic assessment and superficial zone collagen birefringence assessments were evaluated and compared to that of arthroscopy. Intra-observer reliability of arthroscopic assessments was also evaluated. RESULTS: Arthroscopic assessments had high sensitivity (91-100%), specificity (62-88%) and accuracy (75-93%) for the diagnosis of chondropathy 16 weeks after MMx. Arthroscopy compared favourably with the direct non-arthroscopic assessments in the lateral compartment and was found to have extremely high intra-observer reliability (kappa 0.78-1.00). The quality of arthroscopic video recordings and the amount of probing did not significantly influence accuracy or reliability. CONCLUSIONS: Arthroscopy performs as well as direct non-arthroscopic assessments of AC for diagnosis of early OA. These results suggest that arthroscopy can be used as a "gold standard" for the validation of non-invasive assessments like magnetic resonance imaging and that arthroscopic diagnosis can be based on small amounts of video footage without AC probing.

The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the metacarpophalangeal joints.

This paper presents the metacarpophalangeal (MCP) joint magnetic resonance images of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. The illustrations include synovitis in the MCP joints (OMERACT RA magnetic resonance imaging scoring system (RAMRIS), grades 0-3), bone oedema in the metacarpal head and the phalangeal base (grades 0-3), and bone erosion in the metacarpal head and the phalangeal base (grades 0-3, and examples of higher grades). The presented reference images can be used to guide scoring of MCP joints according to the OMERACT RA MRI scoring system.

Pitfalls in scoring MR images of rheumatoid arthritis wrist and metacarpophalangeal joints.

This paper outlines the most important pitfalls which are likely to be encountered in the assessment of magnetic resonance images of the wrist and metacarpophalangeal joints in patients with rheumatoid arthritis. Imaging artefacts and how these can be recognised using various sequences and views are discussed. Normal structures such as interosseous ligaments and nutrient foramina may appear prominent on certain images and need to be identified correctly. Pathological change in the rheumatoid hand involves many tissues and when substantial damage has occurred, it may be difficult to identify individual structures correctly. Bone erosion, bone oedema, synovitis, and tenosynovitis frequently occur together and in close proximity to each other, potentially leading to false positive scoring of any of these. Examples are given to illustrate the various dilemmas the user of this atlas may face when scoring the rheumatoid hand and suggestions are made to assist correct interpretation of what can be very complex images.

An introduction to the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas.

This article gives a short overview of the development and characteristics of the OMERACT rheumatoid arthritis MRI scoring system (RAMRIS), followed by an introduction to the use of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. With this atlas, MRIs of wrist and metacarpophalangeal joints of patients with rheumatoid arthritis can be scored for synovitis, bone oedema, and bone erosion, guided by standard reference images.

The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the wrist joint.

This paper presents the wrist joint MR images of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. Reference images for scoring synovitis, bone oedema, and bone erosions according to the OMERACT RA MRI scoring (RAMRIS) system are provided. All grades (0-3) of synovitis are illustrated in each of the three wrist joint areas defined in the scoring system--that is, the distal radioulnar joint, the radiocarpal joint, and the intercarpal-carpometacarpal joints. For reasons of feasibility, examples of bone abnormalities are limited to five selected bones: the radius, scaphoid, lunate, capitate, and a metacarpal base. In these bones, grades 0-3 of bone oedema are illustrated, and for bone erosion, grades 0-3 and examples of higher grades are presented. The presented reference images can be used to guide scoring of wrist joints according to the OMERACT RA MRI scoring system.

The development of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas.

Based on a previously developed rheumatoid arthritis MRI scoring system (OMERACT 2002 RAMRIS), the development team agreed which joints, MRI features, MRI sequences, and image planes would best illustrate the scoring system in an atlas. After collecting representative examples for all grades for each abnormality (synovitis, bone oedema, and bone erosion), the team met for a three day period to review the images and choose by consensus the most illustrative set for each feature, site, and grade. A predefined subset of images (for example, for erosion--all coronal slices through the bone) was extracted. These images were then re-read by the group at a different time point to confirm the scores originally assigned. Finally, all selected images were photographed and formatted by one centre and distributed to all readers for final approval.

Pooled metaanalysis of radiographic progression: comparison of Sharp and Larsen methods.

Metaanalysis refers to the statistical analysis of results from individual studies for the purpose of integrating the findings. However, numerous biases can threaten the internal validity of metaanalyses. This paper specifically addresses the issue of study heterogeneity in metaanalyses of radiographic progression. It considers the validity of pooling studies that have used either the Sharp score (or its variants) or the Larsen score (or its variants) by examining whether the 2 scoring methods are sufficiently concordant for pooling in terms of content of items, scaling and measurement properties. Despite differences between the Sharp and Larsen methods, they essentially measure the construct of radiographic damage, and as long as the spectrum of radiographic damage in the pooled series is similar, then the scoring methods are robust to pooling. However, where the spectrum of damage is not similar, for example, studies of radiographic progression of early disease compared with late disease, pooling should be exercised with caution.

Psychological measures: practical issues in observational studies and clinical monitoring.

Psychological measures are important because they can influence the expression of pain and physical function in patients with arthritis. A number of instruments are now available that measure psychological distress and how we as individuals manage stress. These instruments have undergone extensive validation, although more work is required to evaluate the performance of these instruments measuring change over time. One way to interpret psychological measures and to evaluate how they change over time is to use normative comparisons that are conditional on time and other relevant covariates, using statistical methods such as quantile regression. Such methods have been used to interpret the developmental, educational, and physical growth of children. We can use similar methods to interpret observational studies and to guide decisions within the context of clinical practice.

Recurrent calcific periarthritis, erosive osteoarthritis and hypophosphatasia: a family study.

We describe a mother and 2 daughters with familial recurrent calcific periarthritis in a family with an inherited tendency to develop generalized osteoarthritis (OA). Low levels of serum alkaline phosphatase were found in 1 of the daughters while the mother developed erosive OA in later life. HLA typing was noncontributory. However, the 3 individuals with periarthritis possessed blood group A+, while the 6 unaffected family members were O+. The experience of this family adds weight to the case that recurrent calcific periarthritis may be due to an inherited abnormality of alkaline phosphatase production and suggest that this may also be responsible for the recently observed association of calcific periarthritis and erosive OA.

Measurements of rheumatoid arthritis disease activity and damage using magnetic resonance imaging. Truth and discrimination: does MRI make the grade?

Magnetic resonance imaging (MRI) is a tool with unprecedented capabilities. Rheumatoid arthritis (RA) abnormalities that can be measured with MRI include erosions, articular cartilage thickness, synovial membrane volume, and pannus. However, as access to MRI increases, there is a risk that its use will not be evaluated using rigorous scientific measurement principles. We reviewed published MRI measurement methods for RA and investigated whether the methods were systematically evaluated for reliability, validity, and responsiveness to change--components of the OMERACT filter. Medline and Embase databases were searched from 1966 to 1999. Titles and abstracts were scanned to identify publications on MRI methods used to assess either disease activity or damage in RA. A data extraction template was developed and 68 peer reviewed publications from 40 research groups were appraised; 40 addressed RA disease activity, 4 RA damage, and 24 both activity and damage. Joints most frequently assessed were knee (32 publications) and wrist (31 publications). Ninety-one percent of publications evaluated either reliability or validity or responsiveness to change. Thirteen percent evaluated all 3 and only 9% evaluated none of these measurement properties. Validity was evaluated in 85%, responsiveness to change in 37%, and reliability in 35% of publications. Only 12% of publications evaluated both intra and inter-reliability. Few publications of MRI measures of disease activity or damage in RA met the OMERACT filter for all measurement properties. It would be regrettable if MRI measures are developed ad hoc, with little regard to considerations of scaling, reliability, validity, and responsiveness to change, because this will severely limit their ability to confidently assess treatment efficacy and prognostic indicators.