Efficacy of methylprednisolone in very early systemic sclerosis: results of the "Hit hard and early'' randomized controlled trial.

OBJECTIVE: We hypothesized that glucocorticoids would induce remission in very early Systemic Sclerosis patients by inhibition of inflammation driving the disease. We examined the efficacy and safety of methylprednisolone in very early Systemic Sclerosis. METHODS: In this trial adults with puffy fingers for less than three years, specific auto-antibodies and meeting the Very Early Diagnosis of Systemic Sclerosis criteria were randomly assigned (2:1) to methylprednisolone 1000 mg intravenously or placebo for 3 consecutive days 3 times with monthly intervals. The primary end point was nailfold capillary density at week 12. Capillary density at 52 weeks, number of megacapillaries, and patient-reported outcomes were secondary outcomes. In addition, we assessed disease progression and lung function decline over 52 weeks. We used linear regression analyses adjusted for baseline values and stratification variables to estimate differences between groups. RESULTS: Between February 2017 and February 2021, 87 patients were screened, of whom 30 (70% female, median (IQR) age 52·9 (40·8-60·8) years, median (IQR) disease duration 11.4 (4.6-18.6) months) were randomly assigned to methylprednisolone (n = 21) or placebo (n = 9). We found no difference in nailfold capillary density at 12 weeks: -0.5 (95% CI 1.1, 0.2) nor in any of the secondary outcomes. Eleven (37%) patients showed disease progression during 1 year follow up, 7 (23%) patients had a relevant pulmonary function decline. No serious adverse events were reported. CONCLUSIONS: No clinically relevant effect of short-term methylprednisolone in patients with very early Systemic Sclerosis was observed. A substantial proportion of patients showed disease progression.

Effect of using the Simple Erosion Narrowing Score or Sharp/van der Heijde score on power of rheumatoid arthritis clinical trials to detect differences in radiographic progression.

OBJECTIVES: The Simple Erosion Narrowing Score (SENS) is a simplification of the Sharp/van der Heijde score (SHS). Previous studies found SENS and SHS to have very similar measurement properties, but suggest that SENS has a lower discriminative ability that may result in reduced power. Therefore, we aimed to quantify the effect of using SENS rather than SHS on the power to show between-group differences in radiographic progression. METHODS: Using data from two clinical trials in rheumatoid arthritis (DRESS and BeSt), SENS was derived from the SHS. Criterion validity of the SENS in relation to the SHS was assessed by calculating the Spearman correlation. The power of both scores to show a difference between groups was compared using bootstrapping to generate 10.000 replications of each study. Then, the number of replications with a significant difference in progression (using ANCOVA adjusted for baseline scores) were compared. RESULTS: Correlations between SENS and SHS were all >0.9, indicating high criterion validity of SENS compared with SHS as a reference standard. There was one exception, the DRESS study showed a somewhat lower correlation for the change score at 18 months (0.787). The loss in power of SENS over SHS was limited to at most 19% (BeSt year 5). In addition, the difference in power between SENS and SHS is smaller at higher levels of power. CONCLUSION: SENS appears to be a reasonable alternative to SHS, with only a limited loss of power to show between-group differences in radiographic progression.

Development of a New Referral Tool to Identify Psoriasis Patients with Concomitant Psoriatic Arthritis: Results of the Prospective DAPPER Cohort.

Patients with psoriasis are at risk of developing psoriatic arthritis, which can lead to joint damage. While screening questionnaires have been developed, their performance varies. The objective of this study was to develop a referral tool for dermatologists to identify psoriasis patients with concomitant psoriatic arthritis for rheumatological referral. This study used data from the DAPPER study, in which psoriasis patients were screened by a rheumatologist for the presence of concomitant psoriatic arthritis. Multivariable regression analysis was used to identify predictive variables for the presence of concomitant psoriatic arthritis: treatment history with conventional systemic drugs (odds ratio (OR) 2.97, 95% confidence interval (95% CI) 1.01-8.74, p = 0.04), treatment history with biologicals/small molecule inhibitors (OR 2.90, 95% CI 1.52-5.53, p = 0.01), patient-reported history of joint pain not caused by trauma (OR 4.23, 95% CI 1.21-14.79, p = 0.01), patient-reported history of swollen joints (OR 4.25, 95% CI 2.17-8.32, p < 0.001), and patient-reported history of sausage-like swollen digits (OR 2.38, 95% CI 1.25-4.55, p = 0.01). Based on these variables, a referral tool was created with an area under the curve of 0.82. This referral tool could be used to aid dermatologists to identify psoriasis patients with concomitant psoriatic arthritis, who may benefit from rheumatological referral.

Tumour necrosis factor inhibitor dose adaptation in psoriatic arthritis and axial spondyloarthritis (TAPAS): a retrospective cohort study.

OBJECTIVES: We investigated the effect of disease activity-guided dose optimization (DAGDO) of TNF inhibitor (TNFi) on disease activity and TNFi dose in PsA and axial spondyloarthritis (axSpA) patients with low disease activity (LDA). METHODS: A retrospective cohort study was conducted in PsA and axSpA patients doing well on TNFi and eligible for TNFi DAGDO. Three different treatment periods were defined: (i) full dose continuation period, (ii) TNFi DAGDO period, and (iii) period with stable TNFi dose after DAGDO. A mixed-model analysis was used to estimate mean Disease Activity Score 28-joint count CRP (DAS28-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) during these periods, and a mean percentage of the daily defined dose (%DDD) was calculated as secondary outcome. RESULTS: Three hundred and twenty-four patients (153 PsA and 171 axSpA) were included, with a mean of 6.5 DAS28-CRP and 6.4 BASDAI measurements and a median follow-up duration of 46 and 44 months, respectively. A corrected difference of 0.06 (95% CI: -0.09, 0.21) in mean DAS28-CRP was found for the TNFi DAGDO period and 0.03 (95% CI: -0.14, 0.20) for the period with stable TNFi dose, compared with full dose continuation period. Differences for BASDAI were 0.03 (95% CI: -0.21, 0.27) and 0.05 (95% CI: -0.24, 0.34), respectively. The mean %DDD for the three treatment periods was for PsA 108%, 62% and 78%, and for axSpA 108%, 62% and 72%, respectively. CONCLUSION: DAGDO of TNFi reduces drug exposure and has no negative effects on disease activity in PsA and axSpA patients compared with full dose continuation.

Evidence and consensus-based recommendations for non-pharmacological treatment of fatigue, hand function loss, Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis.

OBJECTIVE: SSc is a complex CTD affecting mental and physical health. Fatigue, hand function loss, and RP are the most prevalent disease-specific symptoms of systemic sclerosis. This study aimed to develop consensus and evidence-based recommendations for non-pharmacological treatment of these symptoms. METHODS: A multidisciplinary task force was installed comprising 20 Dutch experts. After agreeing on the method for formulating the recommendations, clinically relevant questions about patient education and treatments were inventoried. During a face-to-face task force meeting, draft recommendations were generated through a systematically structured discussion, following the nominal group technique. To support the recommendations, an extensive literature search was conducted in MEDLINE and six other databases until September 2020, and 20 key systematic reviews, randomized controlled trials, and published recommendations were selected. Moreover, 13 Dutch medical specialists were consulted on non-pharmacological advice regarding RP and digital ulcers. For each recommendation, the level of evidence and the level of agreement was determined. RESULTS: Forty-one evidence and consensus-based recommendations were developed, and 34, concerning treatments and patient education of fatigue, hand function loss, and RP/digital ulcers-related problems, were approved by the task force. CONCLUSIONS: These 34 recommendations provide guidance on non-pharmacological treatment of three of the most frequently described symptoms in patients with systemic sclerosis. The proposed recommendations can guide referrals to health professionals, inform the content of non-pharmacological interventions, and can be used in the development of national and international postgraduate educational offerings.

Discovery of Psoriatic Arthritis in Psoriasis Patients for Early Rheumatological Referral (DAPPER) Study: A Prospective Observational Cohort.

Patients with psoriasis are at risk of developing psoriatic arthritis, which can lead to irreversible joint damage. However, a proportion of patients with psoriasis and concomitant psoriatic arthritis remain undiscovered in practice. The aims of this study were: to prospectively determine prevalence, characteristics, and disease burden of psoriatic arthritis in a psoriasis population; and to determine the prevalence and characteristics of patients with active psoriatic arthritis, who were not under rheumatological care. Patients with psoriasis were screened by a rheumatologist at the dermatology outpatient clinic for psoriatic arthritis. Patients with suspected active psoriatic arthritis who were not seeing a rheumatologist were referred to a rheumatologist for confirmation. The total prevalence of psoriatic arthritis in this observational, prospective cohort (n = 303) was 24%. Patients with psoriasis with concomitant psoriatic arthritis had longer duration of skin disease and more often a treatment history with systemic therapies. In this academic, specialized, setting, 2.3% of patients (n = 7), were not receiving rheumatological care despite having active psoriatic arthritis. These patients were characterized by a combination of low (perceived) disease burden and low yield of screening questionnaires, making it difficult for dermatologists to discover psoriatic arthritis in these patients. Thus, screening for more subtle active arthritis in patients with psoriasis in a dermatology setting could be improved.

Measuring disease activity in psoriatic arthritis: PASDAS implementation in a tightly monitored cohort reveals residual disease burden.

OBJECTIVES: We aimed to investigate the disease activity and overall disease burden of (subgroups of) patients with PsA using the Psoriatic Arthritis Disease Activity Score (PASDAS) in an already tightly monitored cohort. METHODS: This is a cross-sectional study evaluating data from the first visit of 855 PsA patients after implementation of the PASDAS in our tightly monitored cohort [e.g. DAS 28 (DAS28) was provided as an anchor]. Differences in clinical outcomes between subgroups of patients using established cut-offs for disease activity status [i.e. very low (VLDA), low (LDA), moderate (MDA), and high disease activity (HDA)] were examined. RESULTS: Based on the PASDAS, 53.1% of patients were in VLDA/LDA. 29.5% of patients had ≥1 swollen joint, 20.6% had ≥1 enthesitis index point and 3.0% had active dactylitis. Based on DAS28, 77.5% of the patients were in VLDA/LDA. Patients reaching both DAS28 VLDA/LDA status and PASDAS VLDA/LDA status [N = 445 (52.0%)] were compared with patients reaching only DAS28 VLDA/LDA status [N = 218 (25.5%)]. For these latter patients, significantly worse scores on separate parameters were found in measures used for PASDAS/DAS28 calculation (e.g. swollen and tender joint count and patient's visual analogue scale global disease activity) as well as other disease measures (e.g. function and inflammatory back pain). This result remained, even when the stricter VLDA cut-off was used for the DAS28. CONCLUSION: PASDAS implementation uncovered relevant residual disease activity in a quarter of patients previously assessed as being in DAS28 VLDA/LDA, underscoring the potential value of PASDAS measurements in PsA clinical care.

Polymyalgia rheumatica patients with and without elevated baseline acute phase reactants: distinct subgroups of polymyalgia rheumatica?

OBJECTIVES: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease characterised by pain and stiffness of neck, shoulder- and hipgirdle, typically with elevated acute phase reactants (APR). However, patients may present with normal APR. Our aim was to explore whether normal APR were due to 1) 'caught early in the disease', 2) misdiagnosis, or 3) a distinct subset of PMR with different clinical presentation and prognosis. METHODS: This was a retrospective cohort study on patients with clinical PMR diagnosis visiting the rheumatologists of the Sint Maartenskliniek from April 2008 to September 2017. RESULTS: Of 454 patients, 62 patients had normal, and 392 elevated APR. Normal APR patients had longer symptom duration before diagnosis (13 vs. 10 weeks; p=0.02), however, during follow-up 31% developed elevated APR. In elevated APR patients with previous APR data available while already symptomatic, 58% had earlier normal APR. Fewer normal APR patients had peripheral arthritis (2% vs. 9%;p=0.04), and anaemia (17% vs. 43%; p=0.001). More often they had a previous PMR diagnosis (16% vs. 8%; p=0.057) and a shorter median time to glucocorticoid-free remission (552 vs. 693 days; n=36 vs. 160; p=0.02). Route of GC administration differed between groups (p=0.026). Fewer patients received methotrexate; 3 vs. 12%; p=0.046). No difference in alternative diagnosis was observed. CONCLUSIONS: PMR patients with long-term normal APR seem to be a milder subset of PMR in clinical presentation and prognosis. Additionally, our data also suggest there is a subgroup with normal APR who are caught early in the disease. Misdiagnosis does not appear to play a role.

Opening the black box of non-pharmacological care in systemic sclerosis: a cross-sectional online survey of Dutch health professionals.

The objective is to describe the spectrum of the health professional (HP) treatment approach for systemic sclerosis (SSc) from the perspective of Dutch HPs, including alignment of treatment goals set by HPs with self-reported referral reasons, coverage of patient-reported unmet care needs, and quality of communication between HPs and rheumatologists. Dutch HPs were invited through their patients with SSc to complete an anonymous online survey. The survey covered referral reasons, treatment goals, and interventions of the last patient treated, as well as the perceived quality of communication between HPs and rheumatologists. Referral reasons and treatment targets were linked to the International Classification of Functioning, Disability and Health following the refined ICF Linking Rules. Seventy-nine HPs from 8 professions (including 58 physiotherapists, 73%) completed the survey. One hundred and thirty-three different referral reasons were reported, yielding 58 different ICF codes, with 41 (70.7%) being linked to the ICF domain "body structures and functions." The reported interventions focused on body functions/structures (27.9%), training of daily activities (25.6%), education and advice (26.3%), and psychosocial interventions (20.2%). The quality of communication between HPs and rheumatologists was perceived as low. Our findings revealed numerous treatment options offered by Dutch HPs addressing the unmet care needs of patients with SSc. There is an overlap in the content of the various HP disciplines, and HP treatment goals are not sufficiently aligned with referrals of rheumatologists. HP treatment offer seemed inefficiently organized, possibly precluding rheumatologists from making targeted referrals. Communication between rheumatologists and HPs should be improved.

Use and usability of the dr. Bart app and its relation with health care utilisation and clinical outcomes in people with knee and/or hip osteoarthritis.

BACKGROUND: Self-management is of paramount importance in the non-surgical treatment of knee/hip osteoarthritis (OA). Modern technologies offer the possibility of 24/7 self-management support. We developed an e-self-management application (dr. Bart app) for people with knee/hip OA. The aim of this study was to document the use and usability of the dr. Bart app and its relation with health care utilisation and clinical outcomes in people with knee/hip OA. METHODS: For this study we used backend data for the first 26 weeks of use by the intervention group (N = 214) of an RCT examining the effectiveness of the dr. Bart app. A central element of the dr. Bart app is that it proposes a selection of 72 preformulated goals for health behaviours based on the 'tiny habits method' (e.g. after lunch I rise 12 times from my chair to train my leg muscles). The usability of the app was measured using the System Usability Scale questionnaire (SUS), on a scale of 0-100. To assess the association between the intensity of use of the app and health care utilisation (i.e., consultations in primary or secondary health care) and clinical outcomes (i.e., self-management behaviour, physical activity, health-related quality of life, illness perceptions, symptoms, pain, activities of daily living) we calculated Spearman rank correlation coefficients. RESULTS: Of the 214 participants, 171 (80%) logged in at least once with 151 (71%) choosing at least one goal and 114 (53%) completing at least one goal during the 26 weeks. Of those who chose at least one goal, 56 participants (37%) continued to log in for up to 26 weeks, 12 (8%) continued to select new goals from the offered goals and 37 (25%) continued to complete goals. Preformulated goals in the themes of physical activity (e.g., performing an exercise from the exercises library in the app) and nutrition (e.g., 'eat two pieces of fruit today') were found to be most popular with users. The mean usability scores (standard deviation) at the three and six month follow-ups were 65.9 (16.9) and 64.5 (17.5), respectively. The vast majority of associations between the intensity of use of the dr. Bart app and target outcomes were weak at ρ < (-) 0.25. CONCLUSIONS: More than one-third of people with knee/hip OA who started using the app, continued to use it up to 26 weeks, though usability could be improved. Patients appear to have preferences for goals related to physical activity and nutrition, rather than for goals related to vitality and education. We found weak/no associations between the intensity of use of the dr. Bart app and health care utilisation and clinical outcomes. TRIAL REGISTRATION: (21 September 2017): Dutch Trial Register (Trial Number NTR6693/NL6505 ).

Blood-Based Immune Profiling Combined with Machine Learning Discriminates Psoriatic Arthritis from Psoriasis Patients.

Psoriasis (Pso) is a chronic inflammatory skin disease, and up to 30% of Pso patients develop psoriatic arthritis (PsA), which can lead to irreversible joint damage. Early detection of PsA in Pso patients is crucial for timely treatment but difficult for dermatologists to implement. We, therefore, aimed to find disease-specific immune profiles, discriminating Pso from PsA patients, possibly facilitating the correct identification of Pso patients in need of referral to a rheumatology clinic. The phenotypes of peripheral blood immune cells of consecutive Pso and PsA patients were analyzed, and disease-specific immune profiles were identified via a machine learning approach. This approach resulted in a random forest classification model capable of distinguishing PsA from Pso (mean AUC = 0.95). Key PsA-classifying cell subsets selected included increased proportions of differentiated CD4+CD196+CD183-CD194+ and CD4+CD196-CD183-CD194+ T-cells and reduced proportions of CD196+ and CD197+ monocytes, memory CD4+ and CD8+ T-cell subsets and CD4+ regulatory T-cells. Within PsA, joint scores showed an association with memory CD8+CD45RA-CD197- effector T-cells and CD197+ monocytes. To conclude, through the integration of in-depth flow cytometry and machine learning, we identified an immune cell profile discriminating PsA from Pso. This immune profile may aid in timely diagnosing PsA in Pso.

Treatment with cyclophosphamide i.v. pulse therapy is an option for effective treatment of skin fibrosis in patients with early systemic sclerosis.

OBJECTIVES: SSc is a autoimmune disease characterized by fibrosis of the skin and internal organs. There is a lack of evidence for the efficacy of i.v. CYC pulse therapy on skin thickening. We aimed to examine the response of i.v. CYC pulse therapy on skin thickening in our cohort of SSc patients and analysed factors that predict this response. METHODS: We retrospectively evaluated the data for 143 patients with SSc from baseline to 12, 24 and 36 months. All patients were treated with at least 6 i.v. CYC pulses (750 mg/m2/month). We applied the modified Rodnan Skin Score (mRSS) to assess skin thickening. A clinically relevant response was defined as a decrease in mRSS of 5 points and 25% from baseline. Different baseline variables for predicting response on month 12 were tested in logistic regression analyses. RESULTS: Baseline characteristics of the patients with dcSSc and lcSSc were collected. Forty-three percent (n = 42) of dcSSc patients had a clinically relevant response on month 12. Non-responding on month 6 predicts non-response on month 12 (odds ratio 37.1; 95% CI 4.5, 306.4). CONCLUSION: We concluded that i.v. CYC pulse therapy should be considered as an effective treatment option for skin thickening in dcSSc patients, because 43% of this group of patients were found to have a clinically relevant response. Of the dcSSC patients who did not respond by month 6, only 29% had a response by month 12. This finding can help the physician and patient in shared decision making about whether or not to continue therapy.

Comparison of physical activity among different subsets of patients with knee or hip osteoarthritis and the general population.

To compare the amount of physical activity (PA) among patients with different subsets of knee or hip osteoarthritis (OA) and the general population. Secondary analyses of data of subjects ≥ 50 years from four studies: a study on the effectiveness of an educational program for OA patients in primary care (n = 110), a RCT on the effectiveness of a multidisciplinary self-management program for patients with generalized OA in secondary care (n = 131), a survey among patients who underwent total joint arthroplasty (TJA) for end-stage OA (n = 510), and a survey among the general population in the Netherlands (n = 3374). The Short QUestionnaire to ASssess Health-enhancing physical activity (SQUASH) was used to assess PA in all 4 studies. Differences in PA were analysed by multivariable linear regression analyses, adjusted for age, body mass index and sex. In all groups, at least one-third of total time spent on PA was of at least moderate-intensity. Unadjusted mean duration (hours/week) of at least moderate-intensity PA was 15.3, 12.3, 18.1 and 17.8 for patients in primary, secondary care, post TJA, and the general population, respectively. Adjusted analyses showed that patients post TJA spent 5.6 h [95% CI: 1.5; 9.7] more time on PA of at least moderate-intensity than patients in secondary care. The reported amount of PA of at least moderate-intensity was high in different subsets of OA and the general population. Regarding the amount of PA in patients with different subsets of OA, there was a substantial difference between patients in secondary care and post TJA patients.

Preparing for an orthopedic consultation using an eHealth tool: a randomized controlled trial in patients with hip and knee osteoarthritis.

BACKGROUND: To evaluate the effect of a stand-alone mobile and web-based educational intervention (eHealth tool) compared to usual preparation of a first orthopedic consultation of patients with hip or knee osteoarthritis (OA) on patients' satisfaction. METHODS: A two-armed randomized controlled trial involving 286 patients with (suspicion of) hip or knee OA, randomly allocated to either receiving an educational eHealth tool to prepare their upcoming consultation (n = 144) or usual care (n = 142). Satisfaction with the consultation on three subscales (range 1-4) of the Consumer Quality Index (CQI - primary outcome) and knowledge (assessed using 22 statements on OA, range 0-22), treatment beliefs (assessed by the Treatment beliefs in OsteoArthritis questionnaire, range 1-5), assessment of patient's involvement in consultation by the surgeon (assessed on a 5-point Likert scale) and patient satisfaction with the outcome of the consultation (numeric rating scale), were assessed. RESULTS: No differences between groups were observed on the 3 subscales of the CQI (group difference (95% CI): communication 0.009 (- 0.10, 0.12), conduct - 0.02 (- 0.12, 0.07) and information provision 0.02 (- 0.18, 0.21)). Between group differences (95% CI) were in favor of the intervention group for knowledge (1.4 (0.6, 2.2)), negative beliefs regarding physical activities (- 0.19 (- 0.37, - 0.002) and pain medication (- 0.30 (- 0.49, - 0.01)). We found no differences on other secondary outcomes. CONCLUSIONS: An educational eHealth tool to prepare a first orthopedic consultation for hip or knee OA does not result in higher patient satisfaction with the consultation, but it does influence cognitions about osteoarthritis. TRIAL REGISTRATION: Dutch Trial Register (trial number NTR6262). Registered 30 January 2017.

Effectiveness of low-dose radiation therapy on symptoms in patients with knee osteoarthritis: a randomised, double-blinded, sham-controlled trial.

OBJECTIVES: Low-dose radiation therapy (LDRT) for benign disorders such as knee osteoarthritis (OA) is widely used in some parts of the world, despite absence of controlled studies. We evaluated the effect of LDRT on symptoms and inflammation in patients with knee OA. METHODS: In this randomised, double-blinded, sham-controlled clinical trial (RCT), we recruited patients with knee OA (clinical ACR criteria) in the Netherlands, aged ≥50 years, pain score ≥5/10 and non-responding to analgesics and exercise therapy. Patients were randomised 1:1 to receive LDRT (1 Gray per fraction) or sham intervention six times in 2 weeks, stratified by pain (<8 versus ≥8/10). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months postintervention. Secondary outcomes included pain, function and inflammatory signs assessed by ultrasound, MRI and serum inflammatory markers. RESULTS: We randomly assigned 55 patients: 27 (49%) to LDRT and 28 (51%) to sham. At 3 months postintervention, 12/27 patients (44%; 95% CI 26% to 63%) in the LDRT vs 12/28 patients (43%; 95% CI 25% to 61%) in the sham group responded; difference 2% (95% CI 25% to 28%), OR adjusted for the stratifying variable was 1.1 (95% CI 0.4 to 3.2). Also, for clinical and any of the inflammatory signs, no differences were observed. CONCLUSIONS: We found no substantial beneficial effect on symptoms and inflammatory signs of LDRT in patients knee OA, compared with sham treatment. Therefore, based on this RCT and the absence of other high-quality evidence, we advise against the use of LDRT as treatment for knee OA. TRIAL REGISTRATION NUMBER: NTR4574.

Predictive value of ex-vivo drug-inhibited cytokine production for clinical response to biologic DMARD therapy in rheumatoid arthritis.

OBJECTIVES: To investigate ex-vivo drug-inhibited cytokine production before the start of a biological DMARD (bDMARD) as predictor of treatment response in rheumatoid arthritis (RA). METHODS: In a prospective RA cohort study [BIO-TOP], blood samples were obtained from patients before the start of a bDMARD (abatacept, adalimumab, etanercept, rituximab or tocilizumab). Peripheral blood mononuclear cells were pre-incubated for 1 hour with the therapeutic in-vivo concentration of the bDMARD and stimulated for 24 hours with heat-killed Candida albicans or Pam3Cys. Concentrations of IL-1ß, IL-6, TNFα, IL-17 and IFNγ were determined by ELISA. EULAR response (good vs. moderate/no) was assessed at month 6. Area under the receiver operating characteristic curves (AUCs) were generated to evaluate the predictive value of baseline characteristics and ex-vivo cytokine production (including stimulated cytokine concentrations and absolute changes after inhibition by a bDMARD). Logistic prediction models were created to assess the added value of potential cytokine predictors. RESULTS: 277 RA patients were included with 330 blood samples. Good response was reached in 39% of the cases. DAS28-CRP was predictive for response to adalimumab (AUC 0.70, 95%CI 0.57-0.83), etanercept (AUC 0.68, 95%CI 0.58-0.78) and rituximab (AUC 0.76, 95%CI 0.65-0.86). ACPA was modestly predictive for response to abatacept (AUC 0.63, 95%CI 0.52-0.75). In the ex-vivo analysis, 4 of 64 (6%) tests showed some predictive value but these had no added value to clinical factors routinely measured in RA, such as DAS28-CRP. CONCLUSIONS: Ex-vivo inhibition of cytokine production by bDMARDs is unable to help prediction of treatment response to bDMARDs in RA.

Short-term clinical worsening is a clear predictor for worsening at 2 years in established knee and hip osteoarthritis.

OBJECTIVES: Our aim was to estimate the proportion of knee and hip OA patients showing worsening at 2 years, and to examine the additional predictive value of failure of optimised non-surgical treatment during 3 months for worsening at 2 years. METHODS: Data of patients participating in the longitudinal CONTROL-PRO study (patients fulfilling clinical ACR criteria for knee or hip OA) were used. Measurements of pain, functioning and patient global assessments were performed at baseline, 3 months and 2 years. Worsening at 2 years was defined as fulfilling the recently validated clinical worsening criteria for knee and hip OA, or total joint replacement (TJR). Logistic regression was performed with worsening at 2 years as the dependent variable. RESULTS: The 297 included patients were predominantly women (66%) with a mean age of 55 years. At 2 years, 61% showed worsening (knee 59%; hip 71%) and 24% had undergone a TJR (knee 19%; hip 51%). Clinical worsening at 3 months appeared to be a clear independent predictor for worsening at 2 years (OR 2.8 95% CI 1.5-5.2) with a moderate discriminative ability (AUC 0.68 95% CI 0.57-0.70). Similar results were obtained when only TJR at 2 years was used as the outcome measure (OR 4.1 95% CI 2.0-8.4) with good AUC (0.82 95% CI 0.76-0.87). CONCLUSIONS: Our findings suggest that re-assessment of symptoms after optimised non-surgical treatment could be meaningful in clinical decision making for TJR. Furthermore, this information could be used to identify subgroups of patients potentially eligible for novel and advanced treatment options.

Development and evaluation of a tailored e-self-management intervention (dr. Bart app) for knee and/or hip osteoarthritis: study protocol.

BACKGROUND: This paper describes (the development of) an eHealth tool (dr. Bart app) to enhance self-management and to optimize non-surgical health care utilization in patients with knee and/or hip osteoarthritis (OA) and presents a study aiming 1) to study the effectiveness of the dr. Bart app on health care use 2) to explore differences in use, usability and the clinical outcomes of the dr. Bart app between the Netherlands and Germany. METHODS: The dr. Bart app is a fully automated eHealth application and is based on the Fogg model for behavioural change, augmented with reminders, rewards and self-monitoring to reinforce app engagement and health behaviour. The dr. Bart app propose goals to a healthier lifestyle based on machine learning techniques fed by data collected in a personal profile and choosing behaviour of the app user. Patients ≥50 years with self-reported knee and/or hip OA will be eligible to participate. Participants will be recruited in the community through advertisements in local newspapers and campaigns on social media. This protocol presents a study with three arms, aiming to include 161 patients in each arm. In the Netherlands, patients are randomly allocated to usual care or dr. Bart app and in Germany all patients receive the dr. Bart app. The primary outcome of the first research question is the number of self-reported consultations in secondary health care. The primary outcome of the second research question (comparison between the Netherlands and Germany) is self-management behaviour assessed by the patient activation measure (PAM-13) questionnaire. Secondary outcomes are costs, health-related quality of life, physical functioning and activity, pain, use and usability of the dr. Bart app. Data will be collected through three online questionnaires (at baseline and after 3 and 6 months after inclusion). DISCUSSION: This study will gain insight into the effectiveness of the dr. Bart app in the (conservative) treatment of patients with knee and/or hip OA and differences in the use and usability of the dr. Bart app between the Netherlands and Germany. TRIAL REGISTRATION: Dutch Trial Register (Trial Number NTR6693 / NL6505 ). Registration date: 4 September 2017.

The patient perspective on biologic DMARD dose reduction in rheumatoid arthritis: a mixed methods study.

Objectives: The aim of this study was to identify the factors that play a role for patients with RA when considering dose reduction (i.e. gradual tapering until discontinuation) of biological DMARDs (bDMARDs), and to determine their relative importance. Methods: A mixed methods design was used in which we identified influencing factors by performing semi-structured interviews and ranked these factors using a Maximum Difference Scaling questionnaire. Also, we looked at the influence of several patient characteristics on this ranking. Results: For sub study 1 and 2, 22 and 192 patients with RA were included, respectively, in the analyses. Thirty factors were identified from the interviews-characterized into nine themes-and appraised in the questionnaire. Most respondents had a positive attitude towards bDMARD dose reduction. The study showed that patients are concerned that dose reduction will lead to a disease flare that affects their daily life (pain, function). It is important for them to know that it is possible to increase the dose if (further) reduction fails and that the bDMARD will be effective again. Patients value the opinion of their rheumatologist, and being involved in the decision to start tapering is highly ranked as well. The most important factors were consistent between different groups of patients. Conclusion: The results from this study facilitate implementation of bDMARD dose reduction; they inform care providers on what is important for patients and provide a basis for shared decision making.

Ex vivo inhibited cytokine profiling may explain inferior treatment response to golimumab after adalimumab failure in rheumatoid arthritis.

OBJECTIVES: Clinical data suggest that the response of rheumatoid arthritis patients to treatment with golimumab is much lower among those who switched from adalimumab than among those who switched from etanercept. To elucidate the mechanism behind this difference in response to sequential biologic treatment, we examined the effect of TNF inhibitors on ex vivo cytokine production profiling. METHODS: In a prospective cohort study, blood samples were obtained from patients before the start of a biologic. Peripheral blood mononuclear cells were pre-incubated for 1 hour with the therapeutic in vivo concentration of adalimumab, etanercept or golimumab and stimulated for 24 hours with heat killed Candida albicans or Pam3Cys. Cytokine concentrations of IL-1ß, IL-6 and TNFα were determined by ELISA. RESULTS: Ex vivo cytokine profiling was performed in 71 patients. Golimumab, adalimumab and etanercept significantly (p<0.01) decreased Candida albicans-induced IL-1ß and IL-6 production and Pam3Cys-induced IL-6 production. In contrast to etanercept, golimumab and adalimumab decreased the concentration of TNFα below the detection limit. Absolute changes in cytokine levels after inhibition by golimumab or adalimumab were all significantly correlated (Spearman rank rs: 0.52-0.99, p<0.001). These correlations were much lower or non-significant between etanercept and either golimumab or adalimumab. CONCLUSIONS: High similarity between ex vivo inhibited cytokine profiling by golimumab and adalimumab, compared to etanercept, may explain the previously found inferior treatment response to golimumab after adalimumab failure. This suggests that patients who are non-responsive to adalimumab should preferably not switch to golimumab and vice versa.