Occurrence and Prediction of Flare After Tapering of Tumor Necrosis Factor Inhibitors in Patients With Axial Spondyloarthritis.

OBJECTIVE: Patients with axial spondyloarthritis (axSpA) in clinical remission tapered tumor necrosis factor inhibitor (TNFi) therapy according to a clinical guideline. Over a 2-year follow-up period, we aimed to investigate flare frequency, dose at which flare occurred, type of flare, and predictors thereof. METHODS: Patients in clinical remission (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] < 40, physician global score < 40, and without disease activity the previous year) tapered TNFi to two-thirds the standard dose at baseline, half at week 16, one-third at week 32, and discontinued at week 48. Flares were defined as BASDAI flare (BASDAI ≥ 40 and change ≥ 20 since inclusion), and/or clinical flare (development of inflammatory back pain, musculoskeletal or extraarticular manifestations, and/or Ankylosing Spondylitis Disease Activity Score [ASDAS] ≥ 0.9), and/or magnetic resonance imaging (MRI) flare (≥ 2 new or worsened inflammatory lesions). RESULTS: Of 108 patients, 106 (99%) flared before 2-year follow-up: 29 patients (27%) at two-thirds standard dose, 21 (20%) at half dose, 29 (27%) at one-third dose, and 27 (25%) after discontinuation. Regarding type of flare, 105 (99%) had clinical flares, 25 (24%) had BASDAI flares, and 23 (29% of patients with MRI at flare available) had MRI flares. Forty-one patients (41%) fulfilled the Assessment of SpondyloArthritis international Society (ASAS) definition of clinically important worsening (≥ 0.9 increase since baseline). Higher baseline physician global score was an independent predictor of flare after tapering to two-thirds (OR 1.19, 95% CI 1.04-1.41, P = 0.01). Changes in clinical and/or imaging variables in the 16 weeks prior to tapering did not predict flare. CONCLUSION: Almost all (99%) patients with axSpA in clinical remission experienced flare during tapering to discontinuation, but in over half of these patients, flare did not occur before receiving one-third dose or less. Higher physician global score was an independent predictor of flare.

The effect of group-based cognitive behavioural therapy for insomnia in patients with rheumatoid arthritis: a randomized controlled trial.

OBJECTIVES: The primary objective was to compare the effect of cognitive behavioural therapy for insomnia (CBT-I) to usual care on sleep efficiency, measured by polysomnography (PSG) immediately after the intervention at week 7. Secondary objectives included comparing the longer-term effect on sleep- and RA-related outcomes at week 26. METHODS: In a randomized controlled trial using a parallel group design, the experimental intervention was 6 weeks' nurse-led group-based CBT-I; the comparator was usual care. Analyses were based on the intention-to-treat (ITT) principle; missing data were statistically modelled using repeated-measures linear mixed effects models adjusted for the level at baseline. RESULTS: The ITT population consisted of 62 patients (89% women), with an average age of 58 years and an average sleep efficiency of 83.1%. At primary end point, sleep efficiency was 88.7% in the CBT-I group, compared with 83.7% in the control group (difference: 5.03 [95% CI -0.37, 10.43]; P = 0.068) measured by PSG at week 7. Key secondary outcomes measured with PSG had not improved at week 26. However, for all the patient-reported key secondary sleep- and RA-related outcomes, there were statistically highly significant differences between CBT-I and usual care (P < 0.0001), e.g. insomnia (Insomnia Severity Index: -9.85 [95% CI -11.77, -7.92]) and the RA impact of disease (RAID: -1.36 [95% CI -1.92, -0.80]) at week 26. CONCLUSION: Nurse-led group-based CBT-I did not lead to an effect on sleep efficiency objectively measured with PSG. However, CBT-I showed improvement on all patient-reported key secondary sleep- and RA-related outcomes measured at week 26. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03766100.

Flare during tapering of biological DMARDs in patients with rheumatoid arthritis in routine care: characteristics and predictors.

OBJECTIVE: To identify predictors of flare in a 2-year follow-up study of patients with rheumatoid arthritis (RA) in sustained clinical remission tapering towards withdrawal of biological disease-modifying anti-rheumatic drugs (bDMARDs). METHODS: Sustained clinical remission was defined as Disease Activity Score for 28 joints (DAS28)-C reactive protein (CRP) ≤2.6 without radiographic progression for >1 year. bDMARDs were tapered according to a mandatory clinical guideline to two-thirds of standard dose at baseline, half of dose at week 16 and discontinuation at week 32. Prospective assessments for 2 years included clinical evaluation, conventional radiography, ultrasound and MRI for signs of inflammation and bone changes. Flare was defined as DAS28-CRP ≥2.6 with ∆DAS28-CRP ≥1.2 from baseline. Baseline predictors of flare were assessed by logistic regression analyses. RESULTS: Of 142 included patients, 121 (85%) flared during follow-up of which 86% regained remission within 24 weeks after flare. Patients that flared were more often rheumatoid factor positive, had tried more bDMARDs and had higher baseline ultrasound synovitis sum scores than those not flaring. For patients on standard dose, predictors of flare within 16 weeks after reduction to two-thirds of standard dose were baseline MRI-osteitis (OR 1.16; 95% CI 1.03 to 1.33; p=0.014), gender (female) (OR 6.71; 95% CI 1.68 to 46.12; p=0.005) and disease duration (OR 1.06; 95% CI 1.01 to 1.11; p=0.020). Baseline predictors for flare within 2 years were ultrasound grey scale synovitis sum score (OR 1.19; 95% CI 1.02 to 1.44; p=0.020) and number of previous bDMARDs (OR 4.07; 95% CI 1.35 to 24.72; p=0.007). CONCLUSION: The majority of real-world patients with RA tapering bDMARDs flared during tapering, with the majority regaining remission after stepwise dose increase. Demographic and imaging parameters (MR-osteitis/ultrasound greyscale synovitis) were independent predictors of immediate flare and flare overall and may be of importance for clinical decision-making in patients eligible for tapering.

Tapering of TNF inhibitors in axial spondyloarthritis in routine care - 2-year clinical and MRI outcomes and predictors of successful tapering.

OBJECTIVES: In a 2-year follow-up study of patients with axial spondyloarthritis (axSpA) in clinical remission who tapered TNF inhibitor (TNFi) treatment according to a clinical guideline, we aimed to investigate the proportion who successfully tapered/discontinued therapy and baseline predictors thereof. The proportion regaining clinical remission after flare and the progression on MRI/radiography were also assessed. METHODS: One-hundred-and-nine patients (78 [72%]/31 [28%] receiving standard and reduced dose, respectively) in clinical remission (BASDAI < 40, physician global score < 40) and no signs of disease activity the previous year tapered TNFi as follows: to two-thirds of standard dose at baseline, half at week 16, one-third at week 32 and discontinuation at week 48. Patients experiencing clinical, BASDAI or MRI flare (predefined criteria) stopped tapering and escalated to previous dose. Prediction analyses were performed by multivariable regression. RESULTS: One hundred and six patients (97%) completed 2 years' follow-up; 55 patients (52%) had successfully tapered: 23 (22%) receiving two-thirds, 15 (14%) half, 16 (15%) one-third dose and 1 (1%) discontinued. In patients at standard dose at baseline (n = 78), lower physician global score was the only independent predictor of successful tapering (odds ratio [OR] = 0.79 [95% CI: 0.64, 0.93]; P = 0.003). In the entire patient group lower physician global score (OR = 0.86 [0.75, 0.98]; P = 0.017), lower Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Erosion score (OR = 0.78 [0.57, 0.98]; P = 0.029) and current smoker (OR = 3.28 [1.15, 10.57]; P = 0.026) were independent predictors of successful tapering. At 2 years, 97% of patients were in clinical remission. Minimal changes in imaging findings were observed. CONCLUSION: After 2 years following a clinical guideline, 52% of patients with axSpA in clinical remission had successfully tapered TNFi, only 1% discontinued. Baseline physician global score was an independent predictor of successful tapering.

Doppler ultrasound predicts successful discontinuation of biological DMARDs in rheumatoid arthritis patients in clinical remission.

OBJECTIVE: To assess the ability of ultrasound to predict successful tapering and successful discontinuation of biological DMARDs (bDMARDs) at the 2-year follow-up in RA patients in sustained remission. METHODS: Patients in sustained remission (DAS28-CRP ≤ 2.6) and with no radiographic progression the previous year tapered bDMARDs according to a standardized regime. A total of 119 of these patients were included in this ultrasound substudy. At baseline, clinical assessment, MRI, X-ray and ultrasound of 24 joints were performed. Ultrasound-detected synovitis was defined and scored 0-3 using the OMERACT scoring system at the joint level for both grey-scale and Doppler activity. Sum scores for each ultrasound modality were calculated for 24 joints at the patient level. The final state of treatment was assessed after 2 years. The predictive value of ultrasound measures for successful tapering and discontinuation at the 2-year follow-up was assessed via logistic regression analyses. RESULTS: Negative IgM-RF [odds ratio (OR) = 0.29, 95% CI: 0.10-0.85; P = 0.024] and lower Doppler sum score of 24 joints (OR = 0.44, 95% CI: 0.15, 0.87; P = 0.014) were independent predictors for successful discontinuation of bDMARDs at the 2-year follow-up. The predictive value of the Doppler sum score was independent of MRI findings. Previous numbers of bDMARDs were predictive of successful tapering (OR = 0.58, 95% CI: 0.35, 0.91; P = 0.018), whereas ultrasound was not. Clinical parameters were not predictive of successful tapering/discontinuation. CONCLUSION: Doppler sum score was an independent predictor for successful discontinuation of bDMARDs at the 2-year follow-up-the odds for achieving successful discontinuation decreased by 56% per one-unit increase in Doppler sum score. Ultrasound could not predict successful tapering.

Association between MRI findings and patient-reported outcomes in patients with rheumatoid arthritis in clinical remission and at relapse.

OBJECTIVE: To investigate whether magnetic resonance imaging (MRI) pathologies in the wrist/hand of rheumatoid arthritis (RA) patients are associated with patient-reported outcomes (PROs) at clinical remission and relapse. METHODS: Wrist/hand MRIs and wrists/hands/feet radiographs were obtained in 114 established RA patients in clinical remission, before tapering their biologic disease-modifying antirheumatic drugs. MRIs were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI score (RAMRIS) for inflammation (synovitis/tenosynovitis/bone marrow edema) and damage (bone erosion/joint space narrowing) at baseline (ie remission) and in case of a relapse (n = 70). Radiographs were assessed according to the Sharp/van der Heijde (SvH) method at baseline. These scores were assessed for associations with health assessment questionnaires (HAQ), visual analog scales (VAS global/pain), EuroQol-5 dimensions and Short-Form 36 physical and mental component summary (SF-36 PCS/MCS) using Spearman correlations, univariate/multivariable linear regression analyses and generalized estimating equations. Furthermore, MRI pathologies were assessed for association with specific hand-related HAQ items using Jonckheere trend tests. RESULTS: Magnetic resonance imaging-assessed damage was associated with impaired HAQ and SF-36 PCS at remission and relapse (P < .01), independent of clinical and radiographic measures, and was also associated with most of the hand-related HAQ items (P < .03). In multivariate models including MRI, SvH scores were not associated with PROs. MRI-assessed inflammation was not associated with PROs at remission or relapse. CONCLUSION: Magnetic resonance imaging-assessed wrist/hand damage, but not inflammation, in patients with established RA is associated with patient-reported physical impairment at remission and relapse. The amount of damage in the wrist/hand is associated with reduced hand function.

Patients with Rheumatoid Arthritis Acquire Sustainable Skills for Home Monitoring: A Prospective Dual-country Cohort Study (ELECTOR Clinical Trial I).

OBJECTIVE: In an eHealth setting, to investigate intra- and interrater reliability and agreement of joint assessments and Disease Activity Score using C-reactive protein (DAS28-CRP) in patients with rheumatoid arthritis (RA) and test the effect of repeated joint assessment training. METHODS: Patients with DAS28-CRP ≤ 5.1 were included in a prospective cohort study (clinicaltrials.gov: NCT02317939). Intrarater reliability and agreement of patient-performed joint counts were assessed through completion of 5 joint assessments over a 2-month period. All patients received training on joint assessment at baseline; only half of the patients received repeated training. A subset of patients was included in an appraisal of interrater reliability and agreement comparing joint assessments completed by patients, healthcare professionals (HCP), and ultrasonography. Cohen's κ coefficients and intraclass correlation coefficients (ICC) were used for quantifying of reliability of joint assessments and DAS28-CRP. Agreement was assessed using Bland-Altman plots. RESULTS: Intrarater reliability was excellent with ICC of 0.87 (95% CI 0.83-0.90) and minimal detectable change of 1.13. ICC for interrater reliability ranged between 0.69 and 0.90 (good to excellent). Patients tended to rate DAS28-CRP slightly higher than HCP. In patients receiving repeated training, a mean difference in DAS28-CRP of -0.08 was observed (limits of agreements of -1.06 and 0.90). After 2 months, reliability between patients and HCP was similar between groups receiving single or repeated training. CONCLUSION: Patient-performed assessments of joints and DAS28-CRP in an eHealth home-monitoring solution were reliable and comparable with HCP. Patients can acquire the necessary skills to conduct a correct joint assessment after initial and thorough training. [clinicaltrials.gov (NCT02317939)].

Dose tapering and discontinuation of biological therapy in rheumatoid arthritis patients in routine care - 2-year outcomes and predictors.

Objectives: A cohort of routine care RA patients in sustained remission had biological DMARD (bDMARDs) tapered according to a treatment guideline. We studied: the proportion of patients whose bDMARD could be successfully tapered or discontinued; unwanted consequences of tapering/discontinuation; and potential baseline predictors of successful tapering and discontinuation. Methods: One-hundred-and-forty-three patients (91% receiving TNF inhibitor and 9% a non-TNF inhibitor) with sustained disease activity score (DAS28-CRP)⩽2.6 and no radiographic progression the previous year were included. bDMARD was reduced to two-thirds of standard dose at baseline, half after 16 weeks, and discontinued after 32 weeks. Patients who flared (defined as either DAS28-CRP ⩾ 2.6 and ΔDAS28-CRP ⩾ 1.2 from baseline, or erosive progression on X-ray and/or MRI) stopped tapering and were escalated to the previous dose level. Results: One-hundred-and-forty-one patients completed 2-year follow-up. At 2 years, 87 patients (62%) had successfully tapered bDMARDs, with 26 (18%) receiving two-thirds of standard dose, 39 (28%) half dose and 22 (16%) having discontinued; and 54 patients (38%) were receiving full dose. ΔDAS28-CRP0-2yrs was 0.1((-0.2)-0.4) (median (interquartile range)) and mean ΔTotal-Sharp-Score0-2yrs was 0.01(1.15)(mean(s.d.)). Radiographic progression was observed in nine patients (7%). Successful tapering was independently predicted by: ⩽1 previous bDMARD, male gender, low baseline MRI combined inflammation score or combined damage score. Negative IgM-RF predicted successful discontinuation. Conclusion: By implementing a clinical guideline, 62% of RA patients in sustained remission in routine care were successfully tapered, including 16% successfully discontinued at 2 years. Radiographic progression was rare. Maximum one bDMARDs, male gender, and low baseline MRI combined inflammation and combined damage scores were independent predictors for successful tapering.

Protocol for evaluating and implementing a pragmatic value-based healthcare management model for patients with inflammatory arthritis: a Danish population-based regional cohort and qualitative implementation study.

INTRODUCTION: The provision of healthcare for patients with inflammatory arthritis occurs in the context of somewhat conflicting targets, values and drivers. Therefore, there is a need for introducing 'value-based healthcare' defined as the value of patient relevant health outcomes in relation to costs. This term is a central part of tomorrow's healthcare sector, especially for rheumatic diseases, yet the transition is a huge challenge, as it will impact the development, delivery and assessment of healthcare. AIMS: The aim of this study is to compare medical and patient evaluated impact of the traditional settlement and financing production (DAGS) controlled healthcare setting with a value-based and patient-centred adjunctive to standard care. METHODS AND ANALYSIS: Patients with inflammatory arthritis receiving treatment in routine care at the outpatient clinics in the Capital Region of Denmark will prospectively and consecutively be enrolled in a Non-Intervention-Study framework providing a pragmatic value-based management model. A Danish reference cohort, used for comparison will be collected as part of routine clinical care. The enrolment period will be from 1 June 2018 until 31December 2023. Baseline and follow-up visits will be according to routine clinical care. Registry data will be obtained directly from patients and include personal, clinical and outcomes information. The study results will be reported in accordance with the STROBE statement. ETHICS AND DISSEMINATION: The study has been notified to the Danish Data Protection Agency and granted authorisation for the period June 2018 to January 2025 (pending). Informed consent will be obtained from all patients before enrolment in the study. The study is approved by the ethics committee, Capital Region of Denmark (H-18013158). Results of the study will be disseminated through publication in international peer-reviewed journals.

Feasibility of a standardized ultrasound examination in patients with rheumatoid arthritis: a quality improvement among rheumatologists cohort.

BACKGROUND: Quality improvement is important to facilitate valid patient outcomes. Standardized examination procedures may improve the validity of US.The aim of this study was to investigate the learning progress for rheumatologists during training of US examination of the hand in patients with rheumatoid arthritis (RA). METHODS: Rheumatologists with varying degrees of experience in US were instructed by skilled tutors. The program consisted of two days with hands-on training followed by personal US examinations performed in their individual clinics. Examinations were sent to the tutors for quality control. The US examinations were evaluated according to a scoring sheet containing 144 items. An acceptable examination was defined as > 80% correct scores. RESULTS: Thirteen rheumatologists participated in the study. They included a total of 104 patients with RA. Only few of the initial examinations were scored below 80%, and as experience increased, the scores improved (p = 0.0004). A few participants displayed decreasing scores.The mean time spent performing the standardized examination procedure decreased from 34 min to less than 10 minutes (p = 0.0001). CONCLUSION: With systematic hands-on training, a rheumatologist can achieve a high level of proficiency in the conduction of US examinations of the joints of the hand in patients with RA. With experience, examination time decreases, while the level of correctness is maintained. The results indicate that US may be applied as a valid measurement tool suitable for clinical practice and in both single- and multi-centre trials.

Motor competence and physical activity in 8-year-old school children with generalized joint hypermobility.

OBJECTIVE: Because the criteria used for diagnosing between generalized joint hypermobility (GJH) and musculoskeletal complaints, as well as relations between GJH and an insufficient motor development and/or a reduced physical activity level differ, the prevalence of GJH varies considerably. The aim of this study was to survey the prevalence of GJH defined by a Beighton score at >or=4, >or=5, or >or=6 positive tests of 9 and benign joint hypermobility syndrome (BJHS) in Danish primary school children at 8 years of age. A second aim was to compare children with and without GJH and BJHS regarding motor competence, self-reported physical activity, and incidence of musculoskeletal pain and injuries. METHODS: A cross-sectional study of 524 children in the second grade from 10 public schools was performed. A positive response rate was obtained for 416 (79.4%) children, and 411 (78.4%) children were clinically examined and tested for motor competence, whereas questionnaire response to items comprising musculoskeletal pain and injuries, in addition to daily level and duration of physical activity, corresponded to 377 (71.9%) children. RESULTS: In total, 29% of the children had GJH4, 19% had GJH5, 10% had GJH6, and 9% had BJHS, with no gender difference. There was no difference in daily level and duration of physical activity and in frequency of musculoskeletal pain and injuries between those with and without GJH. Children with >or=GJH5 as well as with >or=GJH6 performed better in the motor competence tests. CONCLUSION: Motor competence and physical activity are not reduced in primary school children at 8 years of age with GJH or BJHS. It is recommended that a potential negative influence on the musculoskeletal system over time, as a result of GJH, be investigated by longitudinal studies.

Clinical outcome and imaging changes after intraarticular (IA) application of etanercept or methylprednisolone in rheumatoid arthritis: magnetic resonance imaging and ultrasound-Doppler show no effect of IA injections in the wrist after 4 weeks.

OBJECTIVE: To assess the magnetic resonance imaging (MRI) and ultrasound (US) changes in the wrist of patients with rheumatoid arthritis (RA) 4 weeks after an US guided intraarticular (IA) injection. METHODS: Contrast enhanced MRI and US-Doppler were performed at baseline and 4 weeks after IA injection of either 40 mg methylprednisolone (n = 12) or 25 mg etanercept (n = 13) in 25 patients with RA taking disease modifying antirheumatic drugs with a therapy-resistant wrist joint. All injections were US guided. RESULTS: There was an improvement in swollen target joint score (p < 0.001), tender target joint score (p < 0.002), and physician visual analog scale score (p < 0.001) after 4 weeks. Baseline MRI synovitis score was mean 5.08 (range 3-9) and was unchanged at followup in the whole group (p = 0.52) and between treatment groups (p = 0.43). MRI edema score (mean 4.46, range 0-29) in the total group was unchanged after 4 weeks (p = 0.13), whereas MRI erosion score increased in the total group from baseline, 17.88 (range 7-40), to 4 weeks, 18.25 (range 7-40) (p < 0.001). Neither US-Doppler color fraction (0.07) nor Resistive Index (RI) (p = 0.36) changed from baseline to 4 week followup. CONCLUSION: In contrast to the clinical evaluation, imaging measures of relevance for the estimation of inflammation, US-Doppler, US RI, MRI synovitis, and bone-marrow edema did not change 4 weeks after a single IA injection of either methylprednisolone or etanercept in the wrist. Within the same period, erosive progression in some patients suggested that joints with active disease may deteriorate within as little as 1 month, and that this development is not arrested by 1 injection. Given the small sample size of our study further studies are required to confirm our results.

Posturographic description of the regaining of postural stability following stroke.

BACKGROUND: Failing balance and increased liability to falling are common complaints among hemiplegic subjects. During rehabilitation much effort is put into regaining postural stability. PURPOSE: To describe the regaining of postural stability during rehabilitation for the first year following stroke in hemiplegic patients MATERIALS AND METHODS: Twenty-six patients were included within 5 days of suffering a stroke resulting from a CT-verified clearly defined thromboembolic lesion, localized in the vascular bed of middle cerebral artery on either side. Posturographic evaluation of sway was performed on a commercially available force plate system (Balance Master Pro). Measured parameters included per cent maximum stability (PMS), per cent ankle strategy (AST), and average angular velocity (AVE). An additional parameter was derived by calculating the slope (SLP) of the linear relationship between stability and ankle strategy. SLP reflects the predisposition of the stroke patient to keep using ankle strategy when faced with increasingly difficult balance tasks. The presence of familiarization to the measurement method was examined by including a preliminary measurement not otherwise included in the analysis of changes during the first year of follow-up. The temporal evolvement of sway was described by measuring sway parameters 1, 2, 4, 8 and 52 weeks following stroke. The proportions of the variation in sway caused by measurement error and between patients were compared. RESULTS: All parameters improved over time, as demonstrated by significant improvements from each of week 1, 2, 4 and 8 to week 52. There was evidence of familiarisation for PMS, AST and AVE, but not for SLP. Estimation of variance components showed that between patient variation accounts for between two-thirds and four-fifths of the total variation. A considerable part of this variation was caused by individual differences in the temporal improvement of sway over time. Patients considered the evaluation of postural sway demanding and time consuming resulting in a relatively large loss to follow-up: 15 patients completed the 8-week visit while seven completed the 1 year visit. CONCLUSION: Postural stability increases for the first year following stroke. There is evidence of familiarization towards the measurements process for the traditional posturographic parameters PMS, AST and AVE, but not for the derived parameter SLP, which might make the latter a candidate for a sway parameter reflecting basic mechanisms of upholding upright stance in hemiplegic patients. The estimated variance components stress the considerable between-patient variation and question the ability of the force plate method to monitor individual sway performance of such patients during the rehabilitation process.