Rituximab for the treatment of rheumatoid arthritis
Co-authored with Bagust, A. Boland, A. Hockenhull, J. Greenhalgh, J. Dundar, Y. Proudlove, C. Kennedy, T. Moots, R. Williamson, P. Dickson, R.
This paper presents a summary of the evidence review group's critical review of the evidence for the clinical... more This paper presents a summary of the evidence review group's critical review of the evidence for the clinical effectiveness and cost-effectiveness of rituximab for the treatment of severe rheumatoid arthritis (RA) following failure of previous therapy, including one or more tumour necrosis factor-alpha inhibitors (TNFi), compared with current standards of care, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's clinical evidence came from one randomised, placebo-controlled, double-blind trial (REFLEX--Random Evaluation of Long-term Efficacy of Rituximab in Rheumatoid Arthritis) comparing rituximab plus methotrexate (MTX) with placebo plus MTX in 517 patients with long-standing refractory RA. Rituximab plus MTX was more effective than placebo plus MTX across a range of primary and secondary outcome measures, e.g. American College of Rheumatology (ACR) responses, Health Assessment Questionnaire (HAQ). However, this evidence cannot be used directly to address the manufacturer's analysis of the decision problem because, in the REFLEX trial, rituximab was not compared with a relevant comparator (e.g. leflunomide or second or third TNFi). Long-term efficacy data for retreatment with rituximab are favourable, with an estimated mean time to retreatment of 307 days (n = 164). Evidence from a further five trials is presented as the basis for indirect comparisons with other disease-modifying antirheumatic drugs (DMARDs); however, it is not clear that all relevant clinical studies have been included in the indirect comparison exercise, the rationale for the choice of indirect comparison method adopted is unclear and the indirect comparison method used to adjust the ACR responses only uses a single value for the reference placebo. The submitted microsimulation Markov model was based upon the REFLEX trial. For the 'NICE-recommended' scenario and the 'sequential TNFi' scenario, the original submission reports incremental cost-effectiveness ratios (ICERs) of 14,690 pounds and 11,601 pounds per quality-adjusted life-year (QALY) gained respectively. After model assumptions were adjusted to more realistic estimates by the ERG, the ICERs for the NICE-recommended scenario and the sequential use of TNFi range from 37,002 pounds to 80,198 pounds per QALY gained and from 28,553 pounds to 65,558 pounds per QALY gained respectively. The guidance issued by NICE in August 2007 states that rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other DMARDs including treatment with at least one TNFi therapy.
Illness perceptions account for variation in positive outlook as well as psychological distress in Rheumatoid Arthritis
by Sam Norton
S. van Os, S. Norton, L. D. Hughes, & J. Chilcot (2011). Psychology, Health & Medicine, in press
Psychological distress in rheumatoid arthritis (RA) is associated with adverse clinical outcomes, and appears highly... more Psychological distress in rheumatoid arthritis (RA) is associated with adverse clinical outcomes, and appears highly related to patient’s illness perceptions. This study aimed to investigate the association between illness perceptions, psychological distress, positive outlook, and physical outcomes in RA. 230 patients aged > 18 years and prescribed at least one DMARD were recruited from outpatient clinics across Hertfordshire (England). Patients completed a questionnaire that assessed psychological distress and positive outlook (DAPOS), illness perceptions (IPQ-R), and functional disability (HAQ). Information regarding prescribed medication and disease activity (DAS28) was collected from medical notes. Psychological distress, but not positive outlook, was associated with functional disability and DAS28. After controlling for sex, age and DAS28, perceptions of greater symptomatology (identity) and lesser understanding of RA (coherence) were significantly associated with increased psychological distress. Perceptions of greater treatment control were associated with greater positive outlook, but only for those with low DAS28. Coherence was also associated with positive outlook. These findings indicate that illness perceptions may influence psychological distress and positive outlook in RA patients, and may therefore be a useful basis for future psychological interventions.
Computational analysis of rheumatoid arthritis disease using XAMPP server
Abstract: When advancement in software and hardware technology takes place, there is an evolution of new computational... more
Abstract: When advancement in software and hardware technology takes place, there is an evolution of new computational approach for the analysis of biological data such as analysis of sequence of protein or nucleic acid. Bioinformatics is the application of computer technology to the management of biological information. Computers are used to gather and analyze biological information, which can then be applied to drug discovery and development. There is a huge input of data for rheumatoid arthritis everyday. The data may be protein or nucleic acid sequence. This system includes development of integrated system in order to do all in one analysis of rheumatoid arthritis. In this system doing both protein and genomic analysis is done with the help of tools like Clustal x and Tree view. In this system software’s like XAMPP server and scripting languages like Hypertext Preprocessor and Perl are used. This system takes all sequences related to rheumatoid arthritis and does phylogenetic analysis. Results will be in the form of alignments and scores. Results of this system will be useful for research communities like doctors and pharmacists.
Key words: In silico, Rheumatoid arthritis, Phylogenetic analysis, Perl, Hypertext Preprocessor.
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Qualitative Research Ethics: Enhancing Evidence-Based Practice in Physical Therapy
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http://ptjournal.apta.org/content/90/4/615.full
Background. Increasing challenges to health care systems and the prominence of patient-centered care and... more
Background. Increasing challenges to health care systems and the prominence of patient-centered care and evidence-based practice have fostered the application of qualitative approaches in health care settings, prompting discussions of associated ethical issues in a range of disciplines.
Objectives. The purposes of this work were to identify and describe the application and value of qualitative health research for physical therapy and to identify ethical considerations in a qualitative research study.
Design. This was a qualitative interview study with telephone follow-ups.
Methods. Forty-six participants were interviewed about their early experiences with rheumatoid arthritis. They also were asked what motivated them to volunteer for the study. To inform the discussion of ethics in qualitative health research, this study drew on the in-depth interviews, took a descriptive approach to the data, and applied the traditional ethical principles of autonomy, justice, and beneficence to the
study process.
Results. Ethical issues emerged in this qualitative health research study that were both similar to and different from those that exist in a positivist paradigm (eg, clinical
research). With flexibility and latitude, the traditional principle approach can be applied usefully to qualitative health research.
Conclusions. These findings build on previous research and discussion in physical therapy and other disciplines that urge a flexible approach to qualitative research ethics and recognize that ethics are embedded in an unfolding research process
involving the role of the subjective researcher and an active participant. We suggest reflexivity as a way to recognize ethical moments throughout qualitative research and
to help build methodological and ethical rigor in research relevant to physical therapist practice.
Synthesis and Characterization of Gold@Gold(I)-Thiomalate Core@Shell Nanoparticles
G. Corthey, L. J. Giovanetti, J. M. Ramallo-López, E. Zelaya, A. A. Rubert, G. A. Benitez, F. G. Requejo, M. H. Fonticelli, R. C. Salvarezza.
ACS Nano 4 3413-3421 (2010)
In this paper, the synthesis of gold@gold(I)−thiolate core@shell nanoparticles is described for the first time. The... more In this paper, the synthesis of gold@gold(I)−thiolate core@shell nanoparticles is described for the first time. The chemical nature and structure of these nanoparticles were characterized by a multi-technique approach. The prepared particles consist of gold metallic cores, about 1 nm in size, surrounded by stable gold(I)−thiomalate shells (Au@Au(I)−TM). These nanoparticles could be useful in medicine due to the interesting properties that gold(I)−thiomalate has against rheumatoid arthritis. Furthermore, the described results give new insights in the synthesis and characterization of metallic and core@shell nanoparticles.
The CO-releasing molecule CORM-3 protects against articular degradation in the K/BxN serum transfer arthritis model
EUROPEAN JOURNAL OF PHARMACOLOGY
Nuria MAICAS, Maria Luisa FERRANDIZ, Isabel DEVESA, Roberto MOTTERLINI, Marije I. KOENDERS, Wim B. VAN DEN BERG, Maria José ALCARAZ
Carbon monoxide-releasing molecules can counteract inflammatory responses. The aim of this study was to investigate... more Carbon monoxide-releasing molecules can counteract inflammatory responses. The aim of this study was to investigate whether tricarbonylchloro(glycinate)ruthenium (II) (CORM-3) is able to control the effector phase of experimental arthritis. Arthritis was induced in C57Black-6 mice by an intraperitoneal injection of serum from arthritic K/BxN mice. CORM-3 was administered intraperitoneally at 10 mg/kg/day (5 mg/kg twice a day) from days 0 to 10 and animals were sacrificed on day 11. Serum levels of osteocalcin and prostanoids were measured by enzyme-linked immunosorbent assay and radioimmunoassay. Gene expression was determined by real-time PCR. Histological analysis was performed and protein expression was examined by immunohistochemistry. Treatment with CORM-3 reduced the macroscopic score in hind paws, the migration of inflammatory cells and erosion of cartilage and bone. CORM-3 increased the levels of osteocalcin in the serum and reduced PGD2 levels, whereas PGE2 and 6-ketoPGF1alpha were not affected. In synovial tissues, we also observed a significant reduction in gene expression of interleukin-1beta, receptor activator of nuclear factor kappaB ligand (RANKL), matrix metalloproteinase (MMP)-9 and MMP-13. CORM-3 induced HO-1 expression in joint tissues but inhibited high mobility group box 1 (HMGB1), hematopoietic-prostaglandin D2 synthase (H-PGDS) and lipocalin-type prostaglandin D2 synthase (L-PGDS), as well as RANKL and intercellular adhesion molecule-1. COX-2 expression was not affected by CORM-3 treatment. We have shown that CORM-3 decreases the inflammatory response and protects against the degradation of cartilage and bone in the arthritic mice. Pharmacological CO delivery represents a novel strategy to regulate the effector phase of arthritis.
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Autoantibodies and Diagnosis of Rheumatoid Arthritis
by Tracy Rodman
Authors; Huizinga Tom WJ, Oswald J Erik
Published in Touch European Musculoskeletal Review, 2008;3(1):27-8
Sustained clinical remission in rheumatoid arthritis: prevalence and prognostic factors in an inception cohort of patients treated with conventional DMARDs
by Sam Norton
Jayakumar, K., Norton, S., Dixey, J., James, D., Gough, A., Williams, P., Prouse, P., Young, A. (2012). Rheumatology 51 (1): 169-175.
Objective: Clinical remission is now a realistic goal in managing rheumatoid arthritis (RA) following the introduction... more
Objective: Clinical remission is now a realistic goal in managing rheumatoid arthritis (RA) following the introduction of biologic agents. As there is limited data on sustained remission in conventionally treated RA, this study examines prevalence and predictive factors of sustained remission in a pre-biologic inception cohort of RA.
Methods: Patients with recent onset RA and prior to use of disease modifying anti rheumatic drugs (DMARDs) were recruited from nine centres. Standard clinical and radiological assessments were recorded at baseline and yearly. Point remission was defined by disease activity scores (DAS) of <1.6, and sustained remission if DAS was <1.6 at all 3, 4 and 5yr follow ups. Sustained remission was compared to baseline features and to mortality, and to radiological and functional progression in 704 patients.
Results: Point remission at 3, 4 and 5yrs was 25%, 26% and 22% respectively. 11% (n=78) had sustained remission. Male sex, short duration of symptoms and less tender joints at baseline were independent predictors of sustained remission. These patients had less DMARD therapies and less radiographic progression by 5yrs. Mean HAQ decreased from 0.79 to 0.13 (p<0.001) in sustained remission, compared to an increase from 0.92 to 1.1 (p<0.001) in the non-remission group.
Conclusion: Sustained clinical remission by 5yrs with conventional DMARDs was 11%, half as likely as point remission. Prognostic factors were similar to comparable studies and simple to measure. Patients in sustained clinical remission showed less structural damage and better functional outcomes.
Distinct psychological distress trajectories in rheumatoid arthritis: findings from an inception cohort
by Sam Norton
Norton, S., Sacker. A., Young, A., & Done, J. (2011). Journal of Psychosomatic Research, 71(5):290-295.
Objective: As with other chronic physical illness, rates of depressive disorder are high in rheumatoid arthritis (RA).... more
Objective: As with other chronic physical illness, rates of depressive disorder are high in rheumatoid arthritis (RA). The aim of the current study was to identify distinct trajectories of psychological distress over 10-years in a cohort of RA patients recruited very early in the course of the disease.
Methods: Psychological distress as measured by the Hospital Anxiety and Depression Scale total score was assessed annually in a subgroup of 784 patients enrolled in a multi-centre RA inception cohort (Early RA Study). A latent growth mixture modelling (GMM) approach was used to identify distinct psychological distress patterns.
Results: Four distinct psychological distress trajectories were observed: low-stable (68%), high-stable (12%), high-decreasing (9%) and low-increasing (11%). Symptoms of pain, stiffness and functional impairment were significantly associated with levels of psychological distress at the time of diagnosis and after 3-years; serological markers of disease activity (ESR and CRP) were not.
Conclusions: Although the majority of individuals developing RA experience little or no impact of the effects of the disease on their psychological well-being, a significant proportion experience high levels of distress at some point which may be related to their subjective appraisal of RA. Assessment and treatment of psychological distress should occur synchronously with somatic symptoms.
Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort
by Sam Norton
Koduri, G., Norton, S., Young, A. et al. (2010). Rheumatology 49(8):1483-1489
Objectives. Pulmonary complications of RA are well described. Although some are benign, interstitial lung disease... more
Objectives. Pulmonary complications of RA are well described. Although some are benign, interstitial lung disease (ILD) has a poor prognosis. Few RA inception cohorts have reported the natural history of ILD related to RA (RA-ILD). We examine its incidence, outcome and prognostic indicators.
Methods. Extra-articular features and comorbidity have been recorded yearly in a well-established inception cohort of RA with a 20-year follow-up. Standard clinical, laboratory and radiological measures of RA were recorded at baseline and yearly. Details of deaths were provided by a national central register.
Results. Out of 1460 patients, 52 developed RA-ILD, half either at baseline or within 3 years of onset. The annualized incidence was 4.1/1000 (95% CI 3.0, 5.4) and the 15-year cumulative incidence 62.9/1000 (95% CI 43.0, 91.7). Incidence of RA-ILD was associated with older age, raised baseline ESR and HAQ. Evidence to implicate any drug effect (e.g. MTX) was lacking. Of these patients, 39 died, attributed to RA-ILD in 28. Median survival following diagnosis of RA-ILD was 3 years.
Conclusions. RA-ILD is an important and early feature of RA. It is related to disease activity and has a poor prognosis. Further studies are required to determine whether screening for pulmonary disease would identify these patients at an earlier stage.
Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis
by Sam Norton
Young, A., Koduri, G., Batley, M. et al. (2007). Rheumatology 46(2):350-357
Objective. To examine the cause of death in a large UK inception cohort of rheumatoid arthritis (RA), and whether this... more
Objective. To examine the cause of death in a large UK inception cohort of rheumatoid arthritis (RA), and whether this was related to disease duration and severity, treatment effects or extra-articular features and complications of RA.
Methods. Standard clinical, laboratory, radiological and socio-economic measures were recorded at baseline and yearly in an inception cohort started in nine centres in 1986. Date and the cause of death were based on death certificates and the comparisons made with age and sex matched population figures. Risk factors for mortality were identified from baseline measures of disease.
Results. There were 459 deaths (32%) in 1429 patients followed for up to 18 yrs. Standard mortality ratio was 1.27. Survival was significantly lower in the first 7 yrs of RA. Excess mortality was seen in cardiovascular disease (31%), pulmonary fibrosis (4%) and lymphoma (2.3%). Baseline predictors for mortality were men, older age, poor function, lower socio-economic status, extra-articular features, comorbidity, rheumatoid factor, X-ray erosions, high-ESR and low-haemoglobin.
Conclusion. There was a modest increase in mortality in RA, mainly in the first 7 yrs. Deaths from cardiovascular disease and pulmonary fibrosis were higher than expected, but treatment-related deaths were low. Risk factors included less favourable socio-economic status, markers of disease severity and diminished function within the first year.