Changes in Health Assessment Questionnaire (HAQ) scores in four...

The Biologic IRL201805 Alters Immune Tolerance Leading to Prolonged Pharmacodynamics and Efficacy in Rheumatoid Arthritis Patients

Article

Full-text available

Apr 2024
INT J MOL SCI

A homologue of binding immunoglobulin protein/BiP—IRL201805 alters the function of immune cells in pre-clinical in vivo and in vitro studies. The aim of the study was to select biomarkers that clearly delineate between RA patients who respond to IRL201805 and placebo patients and reveal the immunological mode of action of IRL201805 driving the extended pharmacodynamics observed in responding patients. Biomarkers that distinguished between responding patients and placebo patients included downregulation of serum interferon-γ and IL-1β; upregulation of anti-inflammatory mediators, serum soluble CTLA-4, and intracellular monocyte expression of IDO; and sustained increased CD39 expression on CD3+CD4+CD25hi CD127lo regulatory T cells. In the responding patients, selected biomarkers verified that the therapeutic effect could be continuous for at least 12 weeks post-infusion. In secondary co-culture, pre-infusion PBMCs cultured 1:1 with autologous PBMCs, isolated at later time-points during the trial, showed significantly inhibited IL-6 and IL-1β production upon anti-CD3/CD28 stimulation demonstrating IRL201805 alters the function of immune cells leading to prolonged pharmacodynamics confirmed by biomarker differences. IRL201805 may be the first of a new class of biologic drug providing long-term drug-free therapy in RA.

Long-term effectiveness of a lifestyle intervention for rheumatoid arthritis and osteoarthritis: 1-year follow-up of the ‘Plants for Joints’ randomised clinical trial

Article

Full-text available

Feb 2024

Objectives In two randomised controlled trials, the Plants for Joints (PFJ) multidisciplinary lifestyle intervention reduced signs and symptoms of rheumatoid arthritis (RA), or metabolic syndrome-associated hip or knee osteoarthritis (MSOA) compared with usual care. The current study investigated long-term outcomes. Methods After completion of two 16-week trials in people with (1) RA or (2) MSOA, control groups switched to the active PFJ intervention. At the end of the intervention, all participants were followed up in a 1-year observational extension study. Primary outcomes were 28-joint Disease Activity Score (DAS28) (RA) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (MSOA). Secondary outcomes included body composition, metabolic outcomes, medication changes and intervention adherence. An intention-to-treat analysis with a linear mixed model was used to analyse within-group changes. Results 65 (84%) of 77 RA participants and 49 (77%) of 64 MSOA participants completed the extension study. The effects of the PFJ intervention were replicated in the original control groups and sustained within the RA group a year after intervention completion (mean DAS28 –0.9 points; p<0.001), while in the MSOA group mean WOMAC increased towards but remained well under the starting value (–7.8 points, p<0.001). Improvements in C-reactive protein, waist circumference (RA and MSOA); low-density lipoprotein cholesterol (RA); and weight, haemoglobin A1c, blood pressure (MSOA) were also sustained. Participants had a net decrease of medication, and intervention adherence was largely sustained. Conclusions A year after the PFJ lifestyle intervention, improvements of disease activity and metabolic outcomes within RA and MSOA groups were largely sustained and related to sustained adherence, with a net decrease of medication. Trial registration numbers NL7800, NL7801.

A multidisciplinary lifestyle program for rheumatoid arthritis: the “Plants for Joints” randomized controlled trial

Article

Full-text available

Jan 2023
Br J Rheumatol

Objective To determine the effect of a multidisciplinary lifestyle program in patients with RA with low-moderate disease activity. Methods In the “Plants for Joints” (PFJ) parallel-arm, assessor-blind randomized controlled trial, patients with RA and 28-joint Disease Activity Score [DAS28] ≥ 2.6 and ≤ 5.1 were randomized to the PFJ or control group. The PFJ group followed a 16-week lifestyle program based on a whole food plant-based diet, physical activity, and stress management. The control group received usual care. Medication was kept stable three months before and during the trial whenever possible. We hypothesized that PFJ would lower disease activity (DAS28). Secondary outcomes included anthropometric, metabolic, and patient-reported measures. An intention-to-treat analysis with a linear mixed model adjusted for baseline values was used to analyse between-group differences. Results Of the 83 people randomized, 77 completed the study. Participants were 92% female with mean (SD) age of 55 (12), BMI of 26 (4) kg/m2 and mean DAS28 of 3.8 (0.7). After 16 weeks the PFJ group had a mean 0.9-point greater improvement of DAS28 vs the control group (95% CI 0.4–1.3; p < 0.0001). The PFJ intervention led to greater decreases in body weight (difference –3.9 kg), fat mass (–2.8 kg), waist circumference (–3 cm), HbA1c (–1.3 mmol/mol) and LDL (–0.32 mmol/l), whereas patient-reported outcome measures, blood pressure, glucose and other lipids did not change. Conclusion The 16-week PFJ multidisciplinary lifestyle program substantially decreased disease activity and improved metabolic status in people with RA with low-moderate disease activity. Trial Registration International Clinical Trials Registry Platform; https://www.who.int/clinical-trials-registry-platform; NL7800

Intensive therapy for moderate established rheumatoid arthritis: the TITRATE research programme

Article

Full-text available

Aug 2021

Background Rheumatoid arthritis is a major inflammatory disorder and causes substantial disability. Treatment goals span minimising disease activity, achieving remission and decreasing disability. In active rheumatoid arthritis, intensive management achieves these goals. As many patients with established rheumatoid arthritis have moderate disease activity, the TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis ThErapy) programme assessed the benefits of intensive management. Objectives To (1) define how to deliver intensive therapy in moderate established rheumatoid arthritis; (2) establish its clinical effectiveness and cost-effectiveness in a trial; and (3) evaluate evidence supporting intensive management in observational studies and completed trials. Design Observational studies, secondary analyses of completed trials and systematic reviews assessed existing evidence about intensive management. Qualitative research, patient workshops and systematic reviews defined how to deliver it. The trial assessed its clinical effectiveness and cost-effectiveness in moderate established rheumatoid arthritis. Setting Observational studies (in three London centres) involved 3167 patients. These were supplemented by secondary analyses of three previously completed trials (in centres across all English regions), involving 668 patients. Qualitative studies assessed expectations (nine patients in four London centres) and experiences of intensive management (15 patients in 10 centres across England). The main clinical trial enrolled 335 patients with diverse socioeconomic deprivation and ethnicity (in 39 centres across all English regions). Participants Patients with established moderately active rheumatoid arthritis receiving conventional disease-modifying drugs. Interventions Intensive management used combinations of conventional disease-modifying drugs, biologics (particularly tumour necrosis factor inhibitors) and depot steroid injections; nurses saw patients monthly, adjusted treatment and provided supportive person-centred psychoeducation. Control patients received standard care. Main outcome measures Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)-categorised patients (active to remission). Remission (DAS28-ESR < 2.60) was the treatment target. Other outcomes included fatigue (measured on a 100-mm visual analogue scale), disability (as measured on the Health Assessment Questionnaire), harms and resource use for economic assessments. Results Evaluation of existing evidence for intensive rheumatoid arthritis management showed the following. First, in observational studies, DAS28-ESR scores decreased over 10–20 years, whereas remissions and treatment intensities increased. Second, in systematic reviews of published trials, all intensive management strategies increased remissions. Finally, patients with high disability scores had fewer remissions. Qualitative studies of rheumatoid arthritis patients, workshops and systematic reviews helped develop an intensive management pathway. A 2-day training session for rheumatology practitioners explained its use, including motivational interviewing techniques and patient handbooks. The trial screened 459 patients and randomised 335 patients (168 patients received intensive management and 167 patients received standard care). A total of 303 patients provided 12-month outcome data. Intention-to-treat analysis showed intensive management increased DAS28-ESR 12-month remissions, compared with standard care (32% vs. 18%, odds ratio 2.17, 95% confidence interval 1.28 to 3.68; p = 0.004), and reduced fatigue [mean difference –18, 95% confidence interval –24 to –11 (scale 0–100); p < 0.001]. Disability (as measured on the Health Assessment Questionnaire) decreased when intensive management patients achieved remission (difference –0.40, 95% confidence interval –0.57 to –0.22) and these differences were considered clinically relevant. However, in all intensive management patients reductions in the Health Assessment Questionnaire scores were less marked (difference –0.1, 95% confidence interval –0.2 to 0.0). The numbers of serious adverse events (intensive management n = 15 vs. standard care n = 11) and other adverse events (intensive management n = 114 vs. standard care n = 151) were similar. Economic analysis showed that the base-case incremental cost-effectiveness ratio was £43,972 from NHS and Personal Social Services cost perspectives. The probability of meeting a willingness-to-pay threshold of £30,000 was 17%. The incremental cost-effectiveness ratio decreased to £29,363 after including patients’ personal costs and lost working time, corresponding to a 50% probability that intensive management is cost-effective at English willingness-to-pay thresholds. Analysing trial baseline predictors showed that remission predictors comprised baseline DAS28-ESR, disability scores and body mass index. A 6-month extension study (involving 95 intensive management patients) showed fewer remissions by 18 months, although more sustained remissions were more likley to persist. Qualitative research in trial completers showed that intensive management was acceptable and treatment support from specialist nurses was beneficial. Limitations The main limitations comprised (1) using single time point remissions rather than sustained responses, (2) uncertainty about benefits of different aspects of intensive management and differences in its delivery across centres, (3) doubts about optimal treatment of patients unresponsive to intensive management and (4) the lack of formal international definitions of ‘intensive management’. Conclusion The benefits of intensive management need to be set against its additional costs. These were relatively high. Not all patients benefited. Patients with high pretreatment physical disability or who were substantially overweight usually did not achieve remission. Future work Further research should (1) identify the most effective components of the intervention, (2) consider its most cost-effective delivery and (3) identify alternative strategies for patients not responding to intensive management. Trial registration Current Controlled Trials ISRCTN70160382. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research ; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.

The Use of Oral Analgesics and Pain Self-Efficacy Are Independent Predictors of the Quality of Life of Individuals with Rheumatoid Arthritis

Article

Full-text available

Jul 2020
Pain Res Manag

Objectives: This study investigated the relationship between quality of life (QOL) and several factors, including pain assessments, in patients with rheumatoid arthritis (RA). Methods: This cross-sectional, single-center study enrolled 85 patients with RA. The variables investigated included demographic characteristics, the 28-joint disease activity score with C-reactive protein (DAS28-CRP), painDETECT questionnaire (PDQ), pain self-efficacy questionnaire (PSEQ), and pain catastrophizing scale (PCS). QOL was measured using the Japanese validated version of the European Quality of Life questionnaire with five dimensions and five levels (EQ-5D-5L). Results: The use of oral steroids and oral analgesics was significantly associated with low EQ-5D-5L scores (P < 0.05). EQ-5D-5L score had a significant positive association with PSEQ (r = 0.414) and significant negative association with age, disease duration, DAS28-CRP, PDQ, and PCS (r = -0.217, -0.343, -0.217, -0.277, and -0.384, respectively). Multiple regression analysis showed that the use of oral analgesics and PSEQ were independent predictors of EQ-5D-5L score (β = -0.248, P < 0.05 and β = 0.233, P < 0.05). Conclusions: The use of oral analgesics by RA patients may influence their QOL, which, in turn, may affect their feelings of self-efficacy. Various pain management strategies, including surgical treatment, may be explored for the treatment of RA. Furthermore, the PSEQ may be a prominent part of the patient's overall assessment.

Validity and reliability of EQ-5D-5L among patients with axial spondyloarthritis in Singapore

Article

Full-text available

May 2020

Objective: This study aims to evaluate the reliability and validity of EuroQOL-5 Dimensions-5 Levels (EQ-5D-5L) among patients with axial spondyloarthritis (SpA) in Singapore. Methods: A cross-sectional study was conducted involving patients with axial SpA in an Asian tertiary hospital from 2017 to 2018. This study followed the COnsensus-based Standards for selection of health Measurement Instruments framework. Construct validity was evaluated by testing 22 a priori hypotheses with other patient-reported outcomes measures. Cronbach's alpha was used to estimate the internal consistency of the EQ-5D-5L, while its test-retest reliability was assessed using weighted kappa and the intraclass correlation coefficient (ICC). The measurement error was assessed by analyzing minimal detectable change (MDC). Results: The median age of included patients (n=118) was 35 years (interquartile range: 28, 49). Ninety-six (81.4%) patients were male, while 112 (94.9%) patients were of Chinese ethnicity. The EQ-5D-5L demonstrated good internal consistency with a Cronbach’s alpha of 0.79. The test-retest reliability of the EQ-5D-5L was good with a weighted kappa of ≥0.61 for mobility, self-care, usual activities, and anxiety/depression; the ICC was 0.92 and 0.99 for the EQ-5D-5L index and visual analog scale (VAS) scores, respectively. The weighted kappa for the EQ-5D-5L pain/discomfort was moderate [0.53, 95% confidence interval: 0.41-0.60]. The MDC for EQ-5D-5L index and VAS scores was 0.06 and 4.5, respectively. Convergent validity was supported as all hypotheses were confirmed in the results. Conclusion: This study supports EQ-5D-5L as a valid and reliable instrument for assessing health-related quality of life among patients with axial SpA in Singapore.

Clinico-epidemiological profile and treatment outcome (DAS28-ESR) in Adult Rheumatoid Arthritis: Early results of intensive treatment in a tertiary care institute from North-East India

Article

Full-text available

Apr 2020

Introduction: Although Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis that can lead to chronic disability and deformities, the overall benefit of intensive treatment strategies in rheumatoid arthritis remains uncertain. RA often causes pain and swelling in the wrist and small joints of the hand and feet. DAS28 score in RA of greater than 5.1 implies active disease, less than 3.2 low disease activities, and less than 2.6 remissions. Adequate treatment not only controls the symptoms but also may prevent joint damage and deformities. Objective/Aim: To understand clinic-epidemiology of RA and value of applying DAS28-ESR scores in monitoring disease activity in a “treat to target” strategy before, during and after treatment for making timely treatment decisions. Materials and Method: We longitudinally studied confirmed cases of Adult RA (n = 44) in a tertiary care teaching hospital located in the North-eastern region of India ACR/EULAR (2010) classification criteria were used for case definition. Patients with advanced stage disease were excluded. Baseline DAS28- ESR score was calculated. The target was to achieve and maintain a target DAS28-ESR of 3.2 or improve score by at least 1.2 within 3-6 Months. Patient-centric physiotherapy and occupation therapy were added to the regime. After six months of intensive treatment targets with DMARDs and symptom modifying agents, final endpoint DAS28-ESR data were compared to baseline scores to measure treatment outcomes. Results: The cohort was dominated by females between 30-55 years of age with M/F ratio 1.17: 4. Nearly 85% were seropositive RA. The average baseline DAS28-ESR score was 5 indicating aggressive RA cohort. The change in the average score by 2.27 after intensive treatments with DAS28-ESR targets was impressive for further treatment decisions. Thirty out of 44 had DAS28 <3.2. Indicating low disease activity and 27/44 had score <2.6 indicating remission. Conclusion: Intensive treatment in RA with a treat to target strategy to bring objective change in DAS28 score was generally well-tolerated and it complemented well with the concept of early intensive treatment according to inverted pyramid model for timely optimization of appropriate regime and lower likelihood of joint damage and disease progression. Keywords: Rheumatoid arthritis (RA), DAS28 (Disease activity score), ESR (Erythrocyte sedimentation rate), DMARDs (Disease modifying anti-rheumatoid drugs)

Defining response to TNF-inhibitors in rheumatoid arthritis: the negative impact of anti-TNF cycling and the need for a personalized medicine approach to identify primary non-responders

Article

Full-text available

Sep 2019
CLIN RHEUMATOL

Current guidelines recommend treating rheumatoid arthritis (RA) patients to reach low disease activity or remission, however, most biologic-naive RA patients fail to reach treatment targets on their first biologic therapy. Approximately 90% of biologic-naive RA patients receive a tumor necrosis factor alpha inhibitor (anti-TNF) as their first biologic treatment, even though several alternative mechanism of action (MOA) therapies are approved as first-line options. After 3 months of therapy, patients may remain on anti-TNF therapy even if they fail to achieve the treatment target, mainly due to formulary structures. This means patients have to endure a second and even a third ineffective anti-TNF—called anti-TNF cycling—before changing MOA. This significantly delays patients from reaching their treatment targets. All anti-TNF drugs target the same molecular and inflammatory pathways; thus, it is not surprising that most patients who are primary non-responders to their initial anti-TNF therapy fail to achieve their treatment targets when cycled through alternative anti-TNFs. This suggests that primary non-responders should be switched to an alternative MOA therapy rather than enduring anti-TNF cycling. Avoiding anti-TNF cycling would prevent disease progression and improve quality of life for RA patients who are primary non-responders to anti-TNFs. The development of a personalized medicine approach to identify primary non-responders to anti-TNFs prior to treatment would allow significantly more patients to reach their treatment target by treating them with alternative MOA therapies as first-line therapies.

Patients’ conceptions of their own influence on good treatment response to biological therapy in chronic inflammatory arthritis

Article

Full-text available

Jun 2017

Ingrid Larsson

Background Biological therapies are common in the treatment of patients with chronic inflammatory arthritis (CIA). However, despite the fact that many patients respond well to their biological therapies, there are still a number of nonresponders. In order to design the best care for patients, it is important to understand how they conceive their own role in their treatment response. Objective To explore how patients with CIA conceive their own influence on a good treatment response to biological therapy. Methods This study had an exploratory and descriptive design with a phenomenographic approach. Interviews were conducted with 25 patients (11 women and 14 men) aged 17–79 years, with CIA who were undergoing biological therapy and who had low disease activity or were in remission. Results Patients with CIA undergoing biological therapy conceived their own influence on good treatment response in terms of adherence, physical activity, mental attitude, social support, and self-awareness. Adherence was described as the foundation for the patients’ own influence on good treatment response. Physical activity, mental attitude, and social support reflected three essential ways of understanding patients’ influence on good treatment response where the patients spoke about physical strength, mental strength, and social strength. Self-awareness reflected a comprehensive way of influencing good treatment response in which patients balanced their physical, mental, and social resources in partnership with health care professionals. Conclusion Patients conceived that they had a responsibility for adhering to the treatment as well as achieving balance in life in order to ensure good treatment response. Self-awareness was essential for maintaining a good treatment response, and this reflected the patients’ awareness of the complexity of living their lives with a chronic illness.

Clinico-epidemiological profile and treatment outcome (DAS28-ESR) in Adult Rheumatoid Arthritis: Early results of intensive treatment in a tertiary care institute from North-East India

Article

Full-text available

Jun 2017

Introduction: Although Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis that can lead to chronic disability and deformities, the overall benefit of intensive treatment strategies in rheumatoid arthritis remains uncertain. RA often causes pain and swelling in the wrist and small joints of the hand and feet. DAS28 score in RA of greater than 5.1 implies active disease, less than 3.2 low disease activities, and less than 2.6 remissions. Adequate treatment not only controls the symptoms but also may prevent joint damage and deformities. Objective/Aim: To understand clinic-epidemiology of RA and value of applying DAS28-ESR scores in monitoring disease activity in a “treat to target” strategy before, during and after treatment for making timely treatment decisions. Materials and Method: We longitudinally studied confirmed cases of Adult RA (n = 44) in a tertiary care teaching hospital located in the North-eastern region of India ACR/EULAR (2010) classification criteria were used for case definition. Patients with advanced stage disease were excluded. Baseline DAS28- ESR score was calculated. The target was to achieve and maintain a target DAS28-ESR of 3.2 or improve score by at least 1.2 within 3-6 Months. Patient-centric physiotherapy and occupation therapy were added to the regime. After six months of intensive treatment targets with DMARDs and symptom modifying agents, final endpoint DAS28-ESR data were compared to baseline scores to measure treatment outcomes. Results: The cohort was dominated by females between 30-55 years of age with M/F ratio 1.17: 4. Nearly 85% were seropositive RA. The average baseline DAS28-ESR score was 5 indicating aggressive RA cohort. The change in the average score by 2.27 after intensive treatments with DAS28-ESR targets was impressive for further treatment decisions. Thirty out of 44 had DAS28 <3.2. Indicating low disease activity and 27/44 had score <2.6 indicating remission. Conclusion: Intensive treatment in RA with a treat to target strategy to bring objective change in DAS28 score was generally well-tolerated and it complemented well with the concept of early intensive treatment according to inverted pyramid model for timely optimization of appropriate regime and lower likelihood of joint damage and disease progression.

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