Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention acquisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX). DATA SOURCES: The following databases were searched: MEDLINE from 1948 to July 2013; EMBASE from 1980 to July 2013; Cochrane Database of Systematic Reviews from 1996 to May 2013; Cochrane Central Register of Controlled Trials from 1898 to May 2013; Health Technology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cumulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Studies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheumatoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs. METHODS: Network meta-analyses (NMAs) were undertaken for patients who were cDMARD naive and for those who were cDMARD experienced. These were undertaken separately for EULAR and ACR data. Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient. A mathematical model was constructed to simulate the experiences of hypothetical patients. The model was based on EULAR response as this is commonly used in clinical practice in England. Observational databases, published literature and NMA results were used to populate the model. The outcome measure was cost per quality-adjusted life-year (QALY) gained. RESULTS: Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncertainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analysis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for individuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX. CONCLUSIONS: bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the relationship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission). STUDY REGISTRATION: This study is registered as PROSPERO CRD42012003386. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Growth factor expression in breast tissue

We have studied mRNA levels for a variety of growth factors in biopsy specimens from malignant, benign and normal breast tissue. We found TGFb mRNA in all breast cancers and neoplastic breast tissues but the level of the TGFb mRNA were found to be higher in breast cancer (P = 0.01). TGFa mRNA was detected in a similar proportion of cancers as in neoplastic breast tissues but the TGFa receptor EGFR mRNA was detected in only 55% of breast cancers but in all non-neoplastic breast tissue tested. The presence of EGFR mRNA was inverted related to oestrogen receptor status and coexpression of TGFa and EGFR was observed in 28% of carcinomas, and significantly more commonly in ER negative tumours (P = 0.01). PDGF a and b chain transcripts coexisted in all normal and malignant breast tissue. Insulin-like growth factor II mRNA was present in all 15 samples of non-malignant breast tissue but in only 11 of 21 (52%) of carcinomas

Transcripts for transforming growth factors in human breast cancer: clinical correlates

The levels of mRNA for transforming growth factors (TGF alpha and beta) and the epidermal growth factor receptor (EGFR) were determined in 69 human breast carcinomas and 20 biopsies of non-neoplastic breast tissue by dot blot hybridisation analysis. TGF alpha mRNA was detected in 42% of cancers and 44% of non-neoplastic breast tissue at low levels. TGF beta mRNA was found in all breast cancers and non-neoplastic breast tissues, but the levels of TGF beta mRNA were found to be higher in breast cancers (P = 0.01). EGFR mRNA was detected in 55% of breast cancers and in all non-neoplastic breast tissue tested. The presence of EGFR mRNA was inversely related to oestrogen receptor (ER) status (P = 0.0001). Coexpression of TGF alpha and EGFR was observed in 28% of the carcinomas, and significantly more commonly in ER negative tumours (P = 0.01). No significant relationship was found between histological grade, tumour cellularity or tumour desmoplasia and expression of either the TGFs or of EGFR mRNA. High levels of TGF beta were, however, associated with the absence of lymph node metastases at presentation (P = 0.05). Levels of TGF alpha and beta and EGFR mRNA were analysed in relationship to the relapse-free and overall survival of patients with breast cancer, but none was found to predict significantly the outcome in these patients. Longer clinical follow-up and larger numbers of patients are required to determine whether TGFs will prove a useful marker for prognosis in breast cancer patients

OFF AXIS INCLINATION MEASUREMENT OF DRILLING SHAFTS

The inclination of drilling shafts from vertical axis poses some problems to workers in the oil exploration fields. A simple device is developed and tested at KFUPM to give the exact angle of the shaft axis off the vertical. Further, the design is capable of determining the direction of the shaft in the horizontal plane. The device is based on a laser beam source placed at the center of a hemisphere with light sensors distributed over its inner surface. The laser beam is held fixed in space through frictionless hinge and a pendulum attachment. As the shaft inclines an angle θ off the vertical, the hemisphere, being attached to the shaft, will have its axis making the same angle with the vertical and the laser beam will fall on a prescribed sensor indicating both the vertical and the horizontal angles of inclinations. The device is reliable since it has no moving parts, robust and quite accurate. Some results of a crude prototype are presented