Filgotinib for Moderate to Severe Rheumatoid Arthritis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Gilead) of filgotinib (JyselecaTM), as part of the single technology appraisal process, to submit evidence for its clinical and cost effectiveness for the treatment of patients with moderate to severe rheumatoid arthritis (RA). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical- and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee. The evidence for filgotinib was based on two good-quality international randomised controlled trials. In FINCH 1, filgotinib was compared with placebo, and in FINCH 2, filgotinib was compared with adalimumab and placebo. As there was no head-to-head evidence with most active comparators, the company performed two separate network meta-analyses (NMAs), one for the conventional disease-modifying antirheumatic drugs-inadequate response population and one for the biological disease-modifying antirheumatic drugs-inadequate response population. The outcomes analysed were American College of Rheumatology response criteria at weeks 12 and 24, and European League Against Rheumatism response criteria at 24 weeks. The statistical methods used to perform the NMAs were valid and were in line with previous NICE appraisals. Results of the NMAs are confidential and cannot be reported here, but they were uncertain due to heterogeneity of the included studies. The economic analysis of the patient population with moderate RA suffered from limited evidence on the progression from moderate to severe health states. For the moderate RA population, the final analyses comparing filgotinib, with or without methotrexate, against standard of care resulted in incremental cost-effectiveness ratios of around £20,000 per quality-adjusted life-year gained in the company's and ERG's base-case and scenario analyses. NICE recommended filgotinib in combination with methotrexate or as monotherapy when methotrexate is contraindicated, or if people cannot tolerate it, for patients with moderate RA whose disease had responded inadequately to two or more conventional disease-modifying antirheumatic drugs (DMARDs). For the severe RA population, in view of the higher or similar net health benefits that filgotinib provided versus its comparators, NICE recommended filgotinib with or without methotrexate for patients whose disease had responded inadequately to two or more conventional DMARDs, who had been treated with one or more biological DMARDs, if rituximab was not an option, or after treatment with rituximab.

Drivers of patient global assessment in patients with rheumatoid arthritis who are close to remission: an analysis of 1588 patients.

Objectives: ACR/EULAR Boolean remission in RA is frequently not obtained solely due to a patient global assessment (PGA) >1/10 (a condition often designated as near-remission). This study aimed to assess which domains of impact could explain an elevated PGA in near-remission patients. Methods: We performed an ancillary analysis of data from three cross-sectional studies in patients with established RA. Three disease activity states were defined: remission (tender and swollen joint counts, CRP and PGA all ⩽1), near-remission (tender and swollen joint counts, and CRP are all ≤1 but PGA >1) and non-remission. Physical and psychological domains were assessed using the RA Impact of Disease 0-10 (numeric rating scale) as explanatory factors of PGA. Univariable and multivariable linear regression analyses were performed to explain PGA. Results: A total of 1588 patients (79.1% females) were analysed. The mean disease duration was 13.0 years (s.d. 9.8) and the 28-joint DAS with four variables was 3.2 (s.d. 1.4). Near-remission [mean PGA 3.6 (s.d. 1.9)] was more frequent (19.1%) than remission (12.3%). Scores of RA Impact of Disease domains were similar in near-remission and non-remission patients. In near-remission, PGA was explained (R2adjusted = 0.55) by pain (ß = 0.29), function (ß = 0.23), physical well-being (ß = 0.19) and fatigue (ß = 0.15). Conclusion: Near-remission was more frequent than remission. These patients, despite having no signs of significant inflammation, report an impact of disease similar to the non-remission patients. PGA in near-remission seems to be driven by physical rather than psychological domains. Selecting the best therapy for these patients requires a better understanding of the meaning of PGA, both globally and in individual patients.

"You Obviously Just Have to Put on a Brave Face": A Qualitative Study of the Experiences and Coping Styles of Men With Rheumatoid Arthritis.

OBJECTIVE: To explore the experiences, coping styles, and support preferences of male rheumatoid arthritis (RA) patients. METHODS: Six focus groups comprised 22 men with RA. Transcripts were analyzed using inductive thematic analysis. RESULTS: Three overarching themes describe the experiences, coping styles, and support preferences of men with RA. In "challenges to masculinity," the men described a "reduction in strength and abilities," which can lead to loss of independence, "challenges to masculine identity and role," and "loss of power and control." Coping by "getting through life with RA" meant dealing with RA by "just getting on with it," "information seeking," engaging in "destructive behaviors," and "withdrawing socially." Preferred "sources of support" tended not to include friends, as they were perceived to lack understanding or support. For acceptable support the men reported a preference for information-giving sessions rather than a discussion group, but there was no agreement on whether these should be mixed-sex or men only, or who should run the sessions. CONCLUSION: Male patients reported a range of coping styles and support preferences to address their experiences of living with RA, many of which may not be shared with women. Further research is needed to investigate whether these findings exist in a larger sample and whether the support preferences of men with RA are broadly different from those of women with RA to decide whether there is a clinical need to design a service for the potentially different needs of men.

Identifying different typologies of experiences and coping strategies in men with rheumatoid arthritis: a Q-methodology study.

OBJECTIVE: To identify typologies of experiences and coping strategies of men with rheumatoid arthritis (RA). DESIGN: Q-methodology (a qualitative and quantitative approach to grouping people according to their subjective opinion). Men with RA sorted 64 statements relating to their experience of living with RA according to level of agreement across a normal distribution grid. Data were examined using Q-factor analysis. SETTING: Rheumatology outpatient departments in the UK. PARTICIPANTS: 30 of 65 invited men with RA participated in this study (46%). RESULTS: All participants ranked highly the need to be well informed about their medication and the importance of keeping a positive attitude. 2 factors describing the experiences and coping strategies of male patients living with RA were identified: factor A: 'acknowledge, accept and adapt' (n=14) take a proactive approach to managing the impact of RA and find different ways of doing things; while factor B: 'trying to match up to a macho ideal' (n=8) are determined to continue with their pre-RA lives, and therefore push themselves to carry on even if this causes them pain. They are frustrated and angry due to the impact of RA but they internalise this rather than directing it at others. CONCLUSIONS: While some men adapt to their RA by renegotiating their masculine identity, others struggle to relinquish their traditional masculine roles. Further research is needed to identify whether the finding that there are 2 distinct groups of men with RA can be generalised, and if so whether the differences can be explained by clinical, social or psychological factors, which may inform different therapeutic approaches.

Updating the OMERACT filter: implications of filter 2.0 to select outcome instruments through assessment of "truth": content, face, and construct validity.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The "Truth" section of the OMERACT Filter requires that criteria be met to demonstrate that the outcome instrument meets the criteria for content, face, and construct validity. METHODS: Discussion groups critically reviewed a variety of ways in which case studies of current OMERACT Working Groups complied with the Truth component of the Filter and what issues remained to be resolved. RESULTS: The case studies showed that there is broad agreement on criteria for meeting the Truth criteria through demonstration of content, face, and construct validity; however, several issues were identified that the Filter Working Group will need to address. CONCLUSION: These issues will require resolution to reach consensus on how Truth will be assessed for the proposed Filter 2.0 framework, for instruments to be endorsed by OMERACT.

OMERACT 10 Patient Perspective Virtual Campus: valuing health; measuring outcomes in rheumatoid arthritis fatigue, RA sleep, arthroplasty, and systemic sclerosis; and clinical significance of changes in health.

This workshop reviewed progress in a number of areas related to patient perspective outcomes that were not specifically included within other areas of the program. A substantial review of the work of the valuing health outcomes group (the "QALY" working group) with participation and feedback from the plenary audience resulted in guidance to refocus on the use of patient preferences in the elaboration of more robust outcome measures for patient-reported outcomes and life impact measures. Progress and developments in the areas of fatigue and sleep in rheumatoid arthritis, outcome measures in hip and knee arthroplasty clinical trials, and scleroderma were outlined, and the challenge of truly understanding the nature of clinically important improvement was reviewed.

Progress on incorporating the patient perspective in outcome assessment in rheumatology and the emergence of life impact measures at OMERACT 9.

The Patient Perspective Workshop included over 100 researchers and 18 patient participants from 8 countries. Following preconference reading and short plenary presentations, breakout groups considered work undertaken on measurement of sleep, assessing interventions to develop the effective consumer, and assessing psychological and educational interventions. The workshop explored the best way to identify other outcome domains (and instruments) that should be measured in observational or interventional studies with broader intentions than simply altering outcomes captured in the traditional "core set" plus fatigue. Four sleep questionnaires showed promise and will be the subject of further study. The Effective Consumer scale (EC-17) was reviewed and the concept Effective Consumer was well received. Participants thought it worthwhile to measure the skills and attributes of an effective consumer and develop an intervention that would include education in all of the scale's categories. Assessment of educational and psychological interventions requires a wider set of instruments than is currently used; these should relate to the purpose of the intervention. This principle was extended to include wider measures of the impact of disease on life, as indicated in the International Classification of Functioning, Disability and Health. Life impact measure sets covering domains appropriate to different rheumatic conditions and focused on different interventions might be defined by future OMERACT consensus. Measurement instruments within these domains that are valid for use in rheumatic conditions can then be identified and, in the case of psychological and educational interventions, chosen to fit with the purpose of the intervention.

Progress since OMERACT 6 on including patient perspective in rheumatoid arthritis outcome assessment.

The first OMERACT Patient Perspective Workshop took place at OMERACT 6 in 2002. Through a series of meetings and discussion sessions a research agenda emerged and this report outlines progress made on this agenda. Work on identifying novel outcomes, instruments, and methods has shown similarities across European countries in the importance patients with rheumatoid arthritis (RA) attach to specific outcomes, in particular fatigue. Validation of an appropriate instrument to measure fatigue in patients with RA is currently being investigated. Frequent or repeated real-time assessment of symptoms such as pain and fatigue is becoming possible using electronic systems. An OMERACT Patient Panel has been established, and has produced a glossary for patients involved in supporting clinical research. In some centers, efforts are being made to provide Patient Research Partners with knowledge and skills that will enhance their contribution, and some of these approaches will be incorporated into OMERACT 7. The research agenda that was developed during the first Patient Perspective Workshop has stimulated new work in several areas. In addition, international attention has been drawn to the need to make sure that the patient's perspective is not lost among the technical expertise of rheumatology.

Incorporating the patient perspective into outcome assessment in rheumatoid arthritis--progress at OMERACT 7.

The Patient Perspective Workshop at OMERACT 7 addressed the question of assessing the outcomes of intervention in rheumatoid arthritis (RA) from the perspective of those who experience the disease. A particular emphasis at this workshop was placed on fatigue, but other areas included well-being, real-time assessment, patient priorities, and needs in early and late disease. Through a series of overview presentations, discussion groups, and plenary sessions, workshop participants (who included 19 patients) clarified what is known and what are the outstanding issues for future research. The importance of further work on clarifying the validity of fatigue measurements in RA has been confirmed, and with at least one suitable instrument available there will be strong pressure to include fatigue in a redefined core set of outcome measures in RA. In the other 4 areas covered there are important issues that can be addressed by enquiry and experiment and that together provide a challenging research agenda. At the final plenary session the OMERACT conference endorsed, by a large majority, the proposal that fatigue may warrant consideration for inclusion in the OMERACT core set for RA.

Standardized assessment of adverse events in rheumatology clinical trials: summary of the OMERACT 7 drug safety module update.

A presentation, demonstration, and discussion of recently developed adverse event instruments were the topics for the OMERACT 7 Drug Safety Module. The module began with a plenary introducing the needs and challenges of adverse event ascertainment. It was followed by a review of module work from previous OMERACT meetings on a prototype coding instrument (Rheumatology Common Toxicity Criteria), then a brief description of the process behind the recently developed patient self-report and investigator report adverse event instruments. These current instruments are designed for use in controlled trials although they could be used in other settings. The instruments rely primarily on patient self-reporting using a checklist, which the investigator then folds into a parallel structured but more medically sophisticated instrument. In pilot testing, this innovative dual-use system has shown reliability and acceptability, while preserving validity. A "stakeholder panel" of representatives from 8 sectors followed--patient, nurse investigator, regulator, clinician scientist, industry, OMERACT, global public health/WHO, and Cochrane Collaboration--for their perspectives on the needs, challenges, and potential ways forward for adverse event ascertainment and reporting in clinical trials. At the breakout session small focus groups participated in hands-on interactive testing of one of 3 versions of the instruments, which differ in degree of comprehensiveness. Each focus group had a participatory patient with rheumatoid arthritis. At a second plenary there was group feedback by rapporteurs and presentation of results from pilot studies of iterative testing of validity, reliability, and feasibility of the instruments. During plenary discussion a frequent suggestion for improvement was to refine the process so that event ascertainment could be done entirely using the patient instrument with minimal input from the investigator at the visit, if patient-investigator agreement was high. Most found the patient checklist attractive, particularly if the patient instrument was shown to be reliable and valid. Finally, a future research agenda was discussed.

General practitioners' knowledge of functional and social factors in patients with rheumatoid arthritis.

The care of people with chronic physical disease is an important part of the work of general practitioners (GPs). Knowledge of social and functional factors, and good teamwork with other health and social care professionals, are necessary to provide high quality general practice care. This study investigated functional disability, social situation and the involvement of health and social care professionals in patients with rheumatoid arthritis, and their GPs' knowledge of these factors. Questionnaires were sent to all patients aged 15-74 with rheumatoid arthritis in two general practices, and similar questionnaires were given to their GPs. Functional disability was assessed using the health assessment questionnaire (HAQ), on a scale of 0-3. The GP consultation rate for patients with rheumatoid arthritis in the previous year was 6.9 compared to 3.7 for all patients in the practices, and increased with increasing disability. Sixty-five per cent of patients had a moderate (HAQ > 1 but 2) disabiltiy. There was an average difference between patient and GP scores for functional disability on the HAQ of 0.49 (95% confidence interval 0.36-0.62), with GPs scoring lower than patients and the difference increased with increasing disability. Seventy-one per cent of patients had seen a rheumatologist or orthopaedic surgeon in the previous year, but there was little involvement by other members of the primary health care team (PHCT). General practitioners had good levels of knowledge of their patients' employment status and who they lived with, but poor knowledge of most of the welfare benefits they were receiving, and of other health and social care professionals involved. It is concluded that GPs see their patients with rheumatoid arthritis frequently, but are often lacking the knowledge about their patients to provide high quality care. They often only know about aspects of their patients' care in which they are directly involved. Ways are suggested for how this situation could be improved.