Results of a 6-week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hand osteoarthritis is a prevalent joint condition that has a high burden of disease and an unmet medical need for effective therapeutic options. Since local inflammation is recognised as contributing to osteoarthritic complaints, the Hand Osteoarthritis Prednisolone Efficacy (HOPE) study aimed to investigate the efficacy and safety of short-term prednisolone in patients with painful hand osteoarthritis and synovial inflammation. METHODS: The HOPE study is a double-blind, randomised, placebo-controlled trial. We recruited eligible adults from rheumatology outpatient clinics at two sites in the Netherlands. Patients were considered eligible if they had symptomatic hand osteoarthritis and signs of inflammation in their distal and proximal interphalangeal (DIP/PIP) joints. For inclusion, patients were required to have four or more DIP/PIP joints with osteoarthritic nodes; at least one DIP/PIP joint with soft swelling or erythema; at least one DIP/PIP joint with a positive power Doppler signal or synovial thickening of at least grade 2 on ultrasound; and finger pain of at least 30 mm on a 100-mm visual analogue scale (VAS) that flared up during a 48-h non-steroidal anti-inflammatory drug (NSAID) washout (defined as worsening of finger pain by at least 20 mm on the VAS). Eligible patients were randomly assigned (1:1) to receive 10 mg prednisolone or placebo orally once daily for 6 weeks, followed by a 2-week tapering scheme, and a 6-week follow-up without study medication. The patients and study team were masked to treatment assignment. The primary endpoint was finger pain, assessed on a VAS, at 6 weeks in participants who had been randomly assigned to groups and attended the baseline visit. This study is registered with the Netherlands Trial Registry, number NTR5263. FINDINGS: We screened patients for enrolment between Dec 3, 2015, and May 31, 2018. Patients completed baseline visits and started treatment between Dec 14, 2015, and July 2, 2018, and the last study visit of the last patient was Oct 4, 2018. Of 149 patients assessed for eligibility, 57 (38%) patients were excluded (predominantly because they did not meet one or several inclusion criteria, most often because of an absence of synovial inflammation or of flare-ups after NSAID washout) and 92 (62%) patients were eligible for inclusion. We randomly assigned 46 (50%) patients to receive prednisolone and 46 (50%) patients to receive placebo, all of whom were included in the modified intention-to-treat analysis of the primary endpoint. 42 (91%) patients in the prednisolone group and 42 (91%) in the placebo group completed the 14-week study. The mean change between baseline and week 6 on VAS-reported finger pain was -21·5 (SD 21·7) in the prednisolone group and -5·2 (24·3) in the placebo group, with a mean between-group difference (of prednisolone vs placebo) of -16·5 (95% CI -26·1 to -6·9; p=0·0007). The number of non-serious adverse events was similar between the groups. Five serious adverse events were reported during our study: one serious adverse event in the prednisolone group (a myocardial infarction) and four serious adverse events in the placebo group (an infected traumatic leg haematoma that required surgery, bowel surgery, atrial fibrillation that required a pacemaker implantation, and symptomatic uterine myomas that required a hysterectomy). Four (4%) patients discontinued the study because of an adverse event: one (2%) patient receiving prednisolone (for a myocardial infarction) and three (7%) patients receiving placebo (for surgery of the bowel and for an infected leg haematoma and for Lyme disease arthritis of the knee). INTERPRETATION: Treatment with 10 mg prednisolone for 6 weeks is efficacious and safe for the treatment of patients with painful hand osteoarthritis and signs of inflammation. The results of our study provide clinicians with a new short-term treatment option for patients with hand osteoarthritis who report a flare-up of their disease. FUNDING: Dutch Arthritis Society.

Validation of two frailty questionnaires in older patients with rheumatoid arthritis: a cross-sectional study.

OBJECTIVES: Several questionnaires exist to assess frailty, a geriatric syndrome. None of these has been validated in older patients with rheumatoid arthritis (RA). Our objective was to assess aspects of validity of two frailty questionnaires: Groningen Frailty Indicator (GFI) and Geriatric 8 (G8) among RA patients. METHODS: In a cross-sectional study among patients ≥65 years information was collected on socio-demographics, disease characteristics including comorbidities and physical function and on frailty using the GFI and G8. Content validity was assessed by linking items of the GFI and G8 to the International Classification of Functioning, Disability and Health (ICF). Classic psychometric methods were used to test hypotheses on construct validity and interpretability. RESULTS: Eighty patients (74.6 years (SD 5.9); 66% female) participated. The GFI has more items on social and mental functions; the G8 more on functions of the digestive system (e.g. nutritional status). As hypothesised, correlations (r) with physical function (RGFI=0.54; RG8=0.56) and disease activity (RGFI=0.24; RG8=0.36) were moderate to weak. However, correlations with age (RGFI=0.20; RG8=0.11) or comorbidities (RGFI=0.30; RG8=0.16) were lower than expected. Instrument-specific thresholds classified 43 (54%) of participants as frail on the GFI and 44 (55%) on the G8; 33 (41%) were frail on both instruments. CONCLUSIONS: The GFI and G8 differ in content with more emphasis on nutritional status for the G8. Both instruments are insensitive to age and comorbidities. Before deciding on their usefulness in RA, their predictive validity for mortality and resource utilisation independent of disease activity and physical function should be further evaluated.

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial.

BACKGROUND: For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS: We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS: Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION: For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING: Roche Nederland BV.

Rheumatologists' Views and Experiences in Managing Rheumatoid Arthritis in Elderly Patients: A Qualitative Study.

OBJECTIVE: In this qualitative study we analyzed the (1) influence of age, comorbidity, and frailty on management goals in elderly patients with RA; (2) experiences of rheumatologists regarding the use of the Disease Activity Score at 28 joints (DAS28) to monitor disease activity; and (3) differences in management strategies in elderly patients with RA compared to their younger counterparts. METHODS: Rheumatologists were purposively sampled for a semistructured interview. Two readers independently read and coded the interview transcripts. Important concepts were taxonomically categorized and combined in overarching themes by using NVivo 11 software. RESULTS: Seventeen rheumatologists (mean age 44.8 yrs, SD 7.7 yrs; 29% male) from 9 medical centers were interviewed. Preserving an acceptable level of functioning was the most important management goal in patients ≥ 80 years and in patients with high levels of comorbidity and frailty. The DAS28 score less frequently steered the management strategy, because rheumatologists commented that comorbidity and an age-related erythrocyte sedimentation rate elevation might distort the DAS28 score. Instead, management of elderly patients highly depended on comorbidity, frailty, and their subsequent effects such as cognitive and physical decline, dependency, and polypharmacy. Presence of 1 or more of these factors frequently resulted in a less future-oriented management approach with less emphasis on the maximal prevention of joint erosions. CONCLUSION: The treat-to-target model is not automatically adopted in the elderly patient population. Future evidence-based RA management recommendations for elderly patients with RA are needed and should account for factors such as comorbidity and frailty.

Disease and management beliefs of elderly patients with rheumatoid arthritis and comorbidity: a qualitative study.

To explore in elderly patients with rheumatoid arthritis (RA) and comorbidity (1) in which order and why patients prioritize their morbidities with regard to functioning and health, (2) their beliefs about common (age-related) musculoskeletal complaints, and (3) experiences about the influence of comorbidity on medication treatment of RA. Patients between 50 and 85 years with RA and ≥ 1 comorbidity or lifestyle risk factor were invited for a semi-structured interview. Two readers coded the transcripts of the interviews, by using NVivo11 software. Fifteen patients (14 women; mean age 67 years (range 51-83 years); mean disease duration 14 years (range 1-39 years)) were interviewed. Only 3 (20%) out of 15 patients prioritized RA over their comorbidity; these patients often experienced severe functional limitations. The level of current or (perceived) future disability, risk of dependency, and the perceived lethality of a condition were considered by participants when prioritizing morbidities. Most participants had misconceptions about common age-related musculoskeletal complaints. Consequently, these participants attributed all joint complaints or even all physical complaints to RA, disregarding degenerative joint disease and physiological aging as alternative diagnoses. Half of the participants ever had to change RA medication because of comorbidity. Most of these patients had prioritized the comorbidity, sometimes even over treatment of RA disease activity. Most elderly RA patients with comorbidity prioritize the importance and treatment of comorbidity over RA. Better understanding of patients' beliefs on RA and comorbidity is essential when managing chronic conditions in elderly patients.