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OBJECTIVE: To perform a systematic literature review on definitions and instruments used to measure remission, relapse, and disease activity in polymyalgia rheumatica (PMR), to inform an OMERACT project to endorse instruments for these outcomes. METHODS: A search of Pubmed/MEDLINE, EMBASE, CINAHL, Cochrane, and Epistemonikos was performed May 2021 and updated August 2023. Qualitative and quantitative studies published in English were included if they recruited people with isolated PMR regardless of treatment. Study selection and data extraction was performed independently by two investigators and disagreement was resolved through discussion. Data extracted encompassed definitions of disease activity, remission and relapse, and details regarding the instruments used to measure these outcomes. RESULTS: From the 5,718 records, we included 26 articles on disease activity, 36 on remission, and 53 on relapse; 64 studies were observational and 15interventional, and none used qualitative methods. Some heterogeneity was found regarding definitions and instruments encompassing the domains pain, stiffness, fatigue, laboratory markers (mainly acute phase reactants), and patient and physician global assessment of disease activity. However, instruments for clinical signs were often poorly described. Whilst measurement properties of the polymyalgia rheumatica activity score (PMR-AS) have been assessed, data to support its use for measurement of remission and relapse is limited. CONCLUSION: Remission, relapse, and disease activity have been defined heterogeneously in clinical studies. Instruments to measure these disease states still need to be validated. Qualitative research is needed to better understand the concepts of remission and relapse in PMR. REVIEW REGISTRATION: PROSPERO identification: CRD42021255925.
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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.
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BACKGROUND: The REDO trial (REtreatment with Rituximab in RhEmatoid arthritis: Disease Outcome after Dose Optimisation) showed similar disease activity for retreatment with ultralow doses (200 mg and 500 mg per 6 months) compared with standard low-dose rituximab (RTX, 1000 mg per 6 months). We performed an observational extension study of the REDO trial to assess long-term effectiveness. METHODS: Patients from the REDO trial were followed from start of the trial to censoring in April 2021. RTX use was at the discretion of patient and rheumatologist using treat to target. The primary outcome was disease activity (disease activity score in 28 joints C-reactive protein (DAS28-CRP)), analysed using a longitudinal mixed model by original randomisation and time-varying RTX dose. The original DAS28-CRP non-inferiority (NI) margin of 0.6 was used. RTX dose and persistence, safety and radiological outcomes were also assessed. FINDINGS: Data from 126 of 142 REDO patients was collected from 15 December 2016, up to 30 April 2021. Drop-outs continued treatment elsewhere (n=3) or did not consent (n=13).Disease activity did not differ by original randomisation group: 1000 mg mean DAS28-CRP (95% CI) of 2.2 (2.0 to 2.5), 500 mg 2.3 (2.1 to 2.4) and 200 mg 2.4 (2.2 to 2.5). Lower time-varying RTX dose was associated with higher DAS28-CRP (0.22 (95% CI 0.05 to 0.40) higher for 200 mg/6 months compared with 1000 mg/6 months), but remained within the NI-margin. RTX persistence was 93%. Median RTX dose was 978 mg (IQR 684-1413) per year, and no association was found between RTX dose and adverse events or radiological damage. INTERPRETATION: Long-term use of ultralow doses of RTX is effective in patients with rheumatoid arthritis responding to standard dose RTX.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Humans , Rituximab/adverse effects , Antirheumatic Agents/adverse effects , Treatment Outcome , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/drug therapy , RadiographyABSTRACT
OBJECTIVES: To investigate safety and effectiveness of disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis over 10 years. METHODS: Observational long-term extension of a randomised study of participants who completed the 3-year extension of the DRESS-study. After the randomised phase (month 0-18), disease activity-guided dose optimisation was allowed for all. Main outcomes were mean time-weighted DAS28-CRP; biological and targeted synthetic anti-rheumatic drug (b/tsDMARD) use per year as proportion of daily defined dose; proportion of patients reaching discontinuation; durability, effectiveness of subsequent dose reduction attempts; and radiographic progression between 3 and 10 years using the Sharp-van der Heijde score. RESULTS: 170 patients were included of whom 127 completed 10-year follow-up. The mean disease activity remained low (DAS28-CRP 2.13, 95% confidence interval 2.10-2.16), whilst the b/tsDMARD dose reduced from 97% at baseline (95%CI 96% to 99%, n = 170)% to56% at year 10 (49% to 63%, n = 127). 119 of 161 participants (74%) with an optimisation attempt reached discontinuation, with a median duration of 7 months (interquartile range 3-33 months), and 25 participants never had to restart their b/tsDMARD (21%, 14% to 29%). The mean dose reduction after dose optimisation was 48% (n = 159) for the first optimisation attempt and 33% for subsequent attempt (n = 86). 48% (41/86) of participants had radiographic progression exceeding the smallest detectable change (5.7 units), and progression was associated with disease activity, not b/tsDMARD use. CONCLUSION: Long-term disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis, including discontinuation and multiple tapering attempts, remains safe and effective.
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Tocilizumab and sarilumab are IL-6-receptor antagonists registered for rheumatoid arthritis (RA), with equal effectiveness and safety. Switching from tocilizumab to sarilumab could be a strategy to reduce injection burden, in case of drug shortages, and to reduce costs. This study therefore aims to investigate the effectiveness and safety of switching patients with RA with well-controlled disease under tocilizumab treatment to sarilumab. Patients with RA with low Disease Activity Score 28 (DAS28;-CRP < 2.9 or < 3.5 with clinical judgment), on stable dose tocilizumab (> 6 months) were offered to switch to sarilumab. Patients who switched and consented were followed for 6 months. Sarilumab was started at 200 mg and double the last tocilizumab interval. Co-primary outcomes at 6 months were (i) the 90% confidence interval (CI) of DAS28-CRP change from baseline compared with the non-inferiority margin of 0.6 and (ii) the 90% CI of the proportion of patients persisting with sarilumab, compared with a prespecified minimum of 70%. Of 50 invited patients, 25 agreed to switch to sarilumab, and 23 patients switched and were included. One patient was lost to follow-up immediately after inclusion, therefore 22 patients are included in the analyses. At 6 months, mean change in DAS28-CRP was 0.48 (90% CI: 0.11-0.87), compared with the non-inferiority margin of 0.6. Sarilumab persistence was 68% (90% CI: 51-82%, 15 out of 22 patients), compared with the prespecified minimum of 70%. Non-medical switching from tocilizumab to sarilumab in patients doing well on tocilizumab failed to show non-inferiority regarding disease activity and drug persistence.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Humans , Antirheumatic Agents/adverse effects , Treatment Outcome , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/drug therapyABSTRACT
OBJECTIVES: To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. METHODS: An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. RESULTS: In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR >2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing >25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. CONCLUSION: This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.
Subject(s)
General Practitioners , Giant Cell Arteritis , Polymyalgia Rheumatica , Humans , Giant Cell Arteritis/diagnosis , Giant Cell Arteritis/drug therapy , Polymyalgia Rheumatica/diagnosis , Polymyalgia Rheumatica/drug therapy , Rheumatologists , Glucocorticoids/therapeutic use , Prednisolone/therapeutic use , Surveys and QuestionnairesABSTRACT
BACKGROUND: Rituximab was effective for patients with polymyalgia rheumatica in the 21-week BRIDGE-PMR randomised controlled trial. Here, we aimed to assess rates of glucocorticoid-free remission up to 1 year after infusion in an extension of this trial. METHODS: BRIDGE-PMR was a randomised controlled proof-of-concept trial that enrolled participants with polymyalgia rheumatica according to 2012 European League Against Rheumatism-American College of Rheumatology classification criteria at the Sint Maartenskliniek, Nijmegen, Netherlands. Patients were randomly allocated in a 1:1 ratio to receive one intravenous dose of 1000 mg rituximab or placebo, with identical pre-medication and accelerated glucocorticoid tapering over 17 weeks. After the 21-week study, patients were followed in a double-blind extension until 1 year after infusion during which standard-of-care treatment was provided. The primary outcome after 52 weeks was between-group difference in glucocorticoid-free remission (ie, polymyalgia rheumatica activity score [PMR-AS] <10), assessed in all randomly allocated participants, with data imputed using a predictive mean matching model (provided data were missing at random). A sensitivity analysis restricted to patients with complete data (complete case analysis) was also done. This trial is registered with EudraCT (2018-002641-11) and the Dutch trial database (NL7414). FINDINGS: Between Dec 18, 2019 and June 8, 2021, 47 patients enrolled in the BRIDGE-PMR were followed up in this extension study (23 [11 women and 12 men] allocated rituximab and 24 [13 women and 11 men] allocated placebo), of who 38 had recently diagnosed polymyalgia rheumatica and nine had relapsing polymyalgia rheumatica. Mean (SD) age was 64 (10) years in the rituximab group and 66 (9) years in the placebo group. All participants were White. Missing data were imputed for six participants (four rituximab, two placebo); because the data were probably missing at random, a complete case analysis was added as sensitivity analyses. In the imputed analysis, the between-group absolute difference reached statistical significance (12 [52%] of 23 in the rituximab group in glucocorticoid-free remission vs five [21%] of 24 participants in the placebo group; absolute difference 31% [95% CI 5 to 57], RR 2·5 [1·0 to 6·0]; p=0·04). In the complete case analysis, nine (47%) of 19 patients in the rituximab group were in glucocorticoid-free remission 1 year after infusion compared with five (23%) of 22 in the placebo group (absolute difference 25% [95% CI -4 to 53], relative risk (RR) 2·1 [95% CI 0·8 to 5·2]; p=0·12). Eight (33%) patients in the placebo group and six (26%) in the rituximab group had adverse events. INTERPRETATION: After a single dose of rituximab (1000 mg), the proportion of patients with polymyalgia rheumatica in glucocorticoid-free remission remained stable at 1 year after infusion, and a glucocorticoid sparing effect was evident. A larger trial including possibility for retreatment is warranted to confirm these results. FUNDING: Sint Maartenskliniek.
Subject(s)
Giant Cell Arteritis , Polymyalgia Rheumatica , Female , Humans , Male , Middle Aged , Glucocorticoids/therapeutic use , Polymyalgia Rheumatica/diagnosis , Retreatment , Rituximab/therapeutic use , Double-Blind MethodABSTRACT
BACKGROUND: Unintentional changes to patients' medicine regimens and drug non-adherence are discovered by medication reconciliation. High numbers of outpatient visits and medication reconciliation being time-consuming, make it challenging to perform medication reconciliation for all outpatients. Therefore, we aimed to get insight into the proportion of outpatient visits in which information obtained with medication reconciliation led to additional drug-related actions. METHODS: In October and November 2018, we performed a cross-sectional observational study at the rheumatology outpatient clinic. Based on a standardized data collection form, outpatient visits were observed by a pharmacy technician trained to observe and report all drug-related actions made by the rheumatologist. Afterwards, the nine observed rheumatologists and an expert panel, consisting of two rheumatologists and two pharmacists, were individually asked which drug information reported on the drug list composed by medication reconciliation was required to perform the drug-related actions. The four members of the expert panel discussed until consensus was reached about their assessment of the required information. Subsequently, a researcher determined if the required information was available in digital sources: electronic medical record (electronic prescribing system plus physician's medical notes) or Dutch Nationwide Medication Record System. RESULTS: Of the 114 selected patients, 83 (73%) patients were included. If both digital drug sources were available, patient's input during medication reconciliation resulted in additional information to perform drug-related actions according to the rheumatologist in 0% of the visits and according to the expert panel in 14%. If there was only access to the electronic medical record, the proportions were 8 and 29%, respectively. Patient's input was especially required for starting a new drug and discussing drug-related problems. CONCLUSIONS: If rheumatologists only had access to the electronic medical record, in 1 out of 3 visits the patient provided additional information during medication reconciliation which was required to perform a drug-related action. When rheumatologists had access to two digital sources, patient's additional input during medication reconciliation was at most 14%. As the added value of patient's input was highest when rheumatologists prescribe a new drug and/or discuss a drug-related problem, it may be considered that rheumatologists only perform medication reconciliation during the visit when performing one of these actions.
Subject(s)
Medication Reconciliation , Rheumatology , Cross-Sectional Studies , Humans , Medication Reconciliation/methods , Outpatients , PharmacistsABSTRACT
BACKGROUND: To develop and assess a prediction model for polymyalgia rheumatica (PMR) relapse within the first year of glucocorticoid (GC) treatment. METHODS: A retrospective PMR cohort (clinical diagnosis) from a rheumatology department was used. All visits > 30 days after starting GC treatment and with > 2.5 mg/day oral prednisolone were used as potential relapse visits. Often used relapse criteria (1) rheumatologist judgement, (2) treatment intensification-based relapse) were assessed for agreement in this cohort. The proportion of patients with treatment-based relapse within 1 and 2 years of treatment and the relapse incidence rate were used to assess unadjusted associations with candidate predictors using logistic and Poisson regression respectively. After using a multiple imputation method, a multivariable model was developed and assessed to predict the occurrence (yes/no) of relapse within the first year of treatment. RESULTS: Data from 417 patients was used. Relapse occurred at 399 and 321 (of 2422) visits based on the rheumatologist judgement- and treatment-based criteria respectively, with low to moderate agreement between the two (87% (95% CI 0.86-0.88), with κ = 0.49 (95% CI 0.44-0.54)). Treatment-based relapse within the first two years was significantly associated with CRP, ESR, and pre-treatment symptom duration, and incidence rate with only CRP and ESR. A model to predict treatment intensification within the first year of treatment was developed using sex, medical history of cardiovascular disease and malignancies, pre-treatment symptom duration, ESR, and Hb, with an AUC of 0.60-0.65. CONCLUSION: PMR relapse occurs frequently, although commonly used criteria only show moderate agreement, underlining the importance of a uniform definition and criteria of a PMR specific relapse. A model to predict treatment intensification was developed using practical predictors, although its performance was modest.
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BACKGROUND: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease affecting people older than 50, resulting in pain and stiffness of the neck, shoulder, and pelvic girdle. To date, glucocorticoids (GC) remain the cornerstone of treatment, but these have several drawbacks. Firstly, a large proportion of patients do not achieve GC-free remission within either the first (over 70%) or second year of treatment (over 50%). Secondly, GC-related adverse events (AE) occur in up to 65% of patients and can be severe. The current EULAR/ACR guidelines for PMR recommend early introduction of methotrexate (MTX) as a GC sparing agent in patients at risk for worse prognosis. However, earlier trials of low to medium quality only studied MTX dosages of 7.5-10 mg/week with no to modest effect. These doses may be suboptimal as MTX is recommended in higher doses (25 mg/week) for other inflammatory rheumatic diseases. The exact role, timing, and dose of MTX in PMR remain unclear, and therefore, our objective is to study the efficacy of MTX 25 mg/week in recently diagnosed PMR patients. METHODS: We set up a double-blind, randomized, placebo-controlled superiority trial (PMR MODE) to assess the efficacy of MTX 25 mg/week versus placebo in a 1:1 ratio in 100 recently diagnosed PMR patients according to the 2012 EULAR/ACR criteria. All patients will receive prednisolone 15 mg/day, tapered to 0 mg over the course of 24 weeks. In case of primary non-response or disease relapse, prednisolone dose will be temporarily increased. Assessments will take place at baseline, 4, 12, 24, 32, and 52 weeks. The primary outcome is the difference in proportion of patients in GC-free remission at week 52. DISCUSSION: No relapsing PMR patients were chosen, since the possible benefits of MTX may not outweigh the risks at low doses and effect modification may occur. Accelerated tapering was chosen in order to more easily identify a GC-sparing effect if one exists. A composite endpoint of GC-free remission was chosen as a clinically relevant endpoint for both patients and rheumatologist and may reduce second order (treatment) effects. TRIAL REGISTRATION: Dutch Trial Registration, NL8366 . Registered on 10 February 2020.
Subject(s)
Giant Cell Arteritis , Polymyalgia Rheumatica , Giant Cell Arteritis/chemically induced , Giant Cell Arteritis/drug therapy , Glucocorticoids , Humans , Methotrexate , Multicenter Studies as Topic , Polymyalgia Rheumatica/chemically induced , Polymyalgia Rheumatica/diagnosis , Polymyalgia Rheumatica/drug therapy , Prednisolone/therapeutic use , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
OBJECTIVE: To perform a COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN)-based systematic literature review of measurement properties of the Polymyalgia Rheumatica Activity Score (PMR-AS). METHODS: PubMed, EMBASE, and CINAHL were broadly searched. English full-text articles, with (quantitative) data on ≥ 5 patients with PMR using the PMR-AS were selected. Seven hypotheses for construct validity and 3 for responsiveness, concerning associations with erythrocyte sedimentation rate, physical function, quality of life, clinical disease states, ultrasound, and treatment response, were formulated. We assessed the structural validity, internal consistency, reliability, and measurement error, or the hypotheses on construct validity or responsiveness of the PMR-AS based on COSMIN criteria. RESULTS: Out of the identified 26 articles that used the PMR-AS, we were able to use 12 articles. Structural validity, internal consistency, construct validity, and responsiveness were assessed in 1, 2, 8, and 3 articles, respectively. Insufficient evidence was found to confirm structural validity and internal consistency. No data were found on reliability or measurement error. Although 60% and 67% of hypotheses tested for construct validity and responsiveness, respectively, were confirmed, there was insufficient evidence to meet criteria for good measurement properties. CONCLUSION: While there is some promising evidence for construct validity and responsiveness of the PMR-AS, it is lacking for other properties and, overall, falls short of criteria for good measurement properties. Therefore, further research is needed to assess its role in clinical research and care.
Subject(s)
Giant Cell Arteritis , Polymyalgia Rheumatica , Blood Sedimentation , Humans , Polymyalgia Rheumatica/diagnostic imaging , Polymyalgia Rheumatica/drug therapy , Psychometrics , Quality of Life , Reproducibility of ResultsABSTRACT
OBJECTIVES: To investigate the reliability and validity of fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT scanning (FDG-PET) in RA patients with low disease activity tapering TNF inhibitors (TNFis) and its predictive value for successful tapering or discontinuation. METHODS: Patients in the tapering arm of the Dose REduction Strategies of Subcutaneous TNFi study, a randomized controlled trial of TNFi tapering in RA, underwent FDG-PET before tapering (baseline) and after maximal tapering. A total of 48 joints per scan were scored both visually [FDG-avid joint (FAJ), yes/no] and quantitatively [maximal and mean standardized uptake values (SUVmax and SUVmean)]. Interobserver agreement was calculated in 10 patients at baseline. Quantitative and visual FDG-PET scores were investigated for (multilevel) association with clinical parameters both on a joint and patient level and for the predictive value at baseline and the change between baseline and maximal tapering (Δ) for successful tapering and discontinuation at 18 months. RESULTS: A total of 79 patients underwent FDG-PET. For performance of identification of FAJs on PET, Cohen's κ was 0.49 (range 0.35-0.63). For SUVmax and SUVmean, intraclass correlation coefficients were 0.80 (range 0.77-0.83) and 0.96 (0.9-1.0), respectively. On a joint level, swelling was significantly associated with SUVmax and SUVmean [B coefficients 1.0 (95% CI 0.73, 1.35) and 0.2 (0.08, 0.32), respectively]. On a patient level, only correlation with acute phase reactants was found. FDG-PET scores were not predictive of successful tapering or discontinuation. CONCLUSIONS: Quantitative FDG-PET arthritis scoring in RA patients with low disease activity is reliable and has some construct validity. However, no predictive values were found for FDG-PET parameters for successful tapering and/or discontinuation of TNFi.
Subject(s)
Arthritis, Rheumatoid , Fluorodeoxyglucose F18 , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/drug therapy , Humans , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Radiopharmaceuticals , Reproducibility of ResultsABSTRACT
Guidelines on management of polymyalgia rheumatica (PMR) recommend early introduction of methotrexate (MTX), especially in patients with worse prognosis, although evidence on clinical efficacy of MTX in PMR is limited. Our objective was to assess MTX efficacy in real-world PMR care. Retrospective data of newly diagnosed PMR patients who started MTX were compared to control patients in whom MTX was not started at the first flare. Main outcomes were number of flares per year (Poisson regression) and weighted daily glucocorticoid (GC)-dose (linear regression), and flare incidence rate ratio in the MTX group only. 240 patients were selected; 39 patients in the MTX group and 201 in the control group. The yearly incidence rate ratio of flares in the MTX versus control group was 0.80 (95% CI 0.45-1.42). The yearly flare rate was 1.22 before and 0.43 after MTX initiation, resulting in an incidence ratio of 0.35 (95% CI 0.23-0.52). Adjusted time weighted daily GC dose was higher in the MTX versus control group (ratio 1.37, 95% CI 1.04-1.80). No clear effect of MTX on flares was found and time weighted daily GC dose was higher, possibly due to residual confounding by indication. However, the clearly reduced flare rate after MTX start might be suggestive for a beneficial effect of MTX.
Subject(s)
Antirheumatic Agents/administration & dosage , Methotrexate/administration & dosage , Polymyalgia Rheumatica/drug therapy , Symptom Flare Up , Case-Control Studies , Female , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Humans , Male , Retrospective Studies , Treatment OutcomeABSTRACT
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.
Subject(s)
Giant Cell Arteritis , Polymyalgia Rheumatica , Acute-Phase Proteins , Glucocorticoids/therapeutic use , Humans , Polymyalgia Rheumatica/complications , Polymyalgia Rheumatica/diagnosis , Polymyalgia Rheumatica/drug therapy , Retrospective StudiesABSTRACT
BACKGROUND: After adalimumab treatment failure, tumour necrosis factor inhibition (TNFi) and non-TNFi biological disease-modifying anti-rheumatic drugs (bDMARDs) are equally viable options on a group level as subsequent treatment in rheumatoid arthritis (RA) based on the current best evidence synthesis. However, preliminary data suggest that anti-adalimumab antibodies (anti-drug antibodies, ADA) and adalimumab serum levels (ADL) during treatment predict response to a TNFi as subsequent treatment. OBJECTIVE: To validate the association of presence of ADA and/or low ADL with response to a subsequent TNFi bDMARD or non-TNFi bDMARD. Sub-analyses were performed for primary and secondary non-responders. METHODS: A diagnostic test accuracy retrospective cohort study was done in consenting RA patients who discontinued adalimumab after >3 months of treatment due to inefficacy and started another bDMARD. Inclusion criteria included the availability of (random timed) serum samples between ≥8 weeks after start and ≤2 weeks after discontinuation of adalimumab, and clinical outcome measurements Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) between 3 to 6 months after treatment switch. Test characteristics for EULAR (European League Against Rheumatism) good response (DAS28-CRP based) after treatment with the next (non-)TNFi bDMARD were assessed using area under the receiver operating characteristic and sensitivity/specificity. RESULTS: 137 patients were included. ADA presence was not predictive for response in switchers to a TNFi (sensitivity/specificity 18%/75%) or a non-TNFi (sensitivity/specificity 33%/70%). The same was true for ADL levels in patients that switched to a TNFi (sensitivity/specificity 50%/52%) and patients that switched to a non-TNFi (sensitivity/specificity 32%/69%). Predictive value of ADA and ADL were similar for both primary and secondary non-responders to adalimumab. CONCLUSIONS: In contrast to earlier research, we could not find predictive value for response to a second TNFi or non-TNFi for either ADA or random timed ADL.
Subject(s)
Adalimumab/blood , Antibodies/blood , Antirheumatic Agents/blood , Arthritis, Rheumatoid/blood , Drug Monitoring/statistics & numerical data , Adalimumab/immunology , Aged , Antirheumatic Agents/immunology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Drug Monitoring/methods , Drug Substitution , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Severity of Illness Index , Tumor Necrosis Factor Inhibitors/immunologyABSTRACT
BACKGROUND: Tumour necrosis factor inhibitors (TNFi) are effective in the treatment of patients with spondyloarthritis (SpA), including psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). However, these drugs come with some disadvantages such as adverse events, practical burden for patients and high costs. Dose optimisation of TNFi after patients have reached low disease activity (LDA) has been shown feasible and safe in rheumatoid arthritis (RA). However, data on TNFi dose optimisation in PsA and axSpA are scarce, especially pragmatic, randomised strategy studies. METHODS: We developed an investigator-driven, pragmatic, open-label, randomised, controlled, non-inferiority trial (DRESS-PS) to compare the effects of a disease activity-guided treat-to-target strategy with or without a tapering attempt in patients with SpA (PsA and axSpA combined), ≥ 16 years of age, who are being treated with TNFi, and have had at least 6 months of low disease activity. The primary outcome is the percentage of patients in LDA after 12 months of follow up. Patients are assessed at baseline, 3, 6, 9, and 12 months of follow up. Bayesian power analyses with a weakened prior based on a similar study performed in RA resulted in a sample size of 95 patients in total. DISCUSSION: More knowledge on disease activity-guided treatment algorithms would contribute to better treatment choices and cost savings and potentially decrease the risk of side effects. In this article we elucidate some of our design choices on TNFi dose optimisation and its clinical and methodological consequences. TRIAL REGISTRATION: Dutch Trial Register, NL6771. Registered on 27 November 2018 (CMO NL66181.091.18, 23 October 2018).
Subject(s)
Arthritis, Psoriatic/drug therapy , Spondylarthritis/drug therapy , Tumor Necrosis Factor Inhibitors/adverse effects , Tumor Necrosis Factor Inhibitors/therapeutic use , Adalimumab/adverse effects , Adalimumab/economics , Adalimumab/therapeutic use , Adolescent , Adult , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/economics , Antibodies, Monoclonal/therapeutic use , Arthritis, Psoriatic/psychology , Bayes Theorem , Case-Control Studies , Cost-Benefit Analysis , Dose-Response Relationship, Drug , Etanercept/adverse effects , Etanercept/economics , Etanercept/therapeutic use , Follow-Up Studies , Humans , Infliximab/adverse effects , Infliximab/economics , Infliximab/therapeutic use , Netherlands/epidemiology , Quality of Life , Research Design , Severity of Illness Index , Spondylarthritis/psychology , Tumor Necrosis Factor Inhibitors/economics , Young AdultABSTRACT
BACKGROUND: Anti-tumour necrosis factor (TNF) agents are effective in treating people with rheumatoid arthritis (RA), but are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. This is an update of a Cochrane Review published in 2014. OBJECTIVES: To evaluate the benefits and harms of down-titration (dose reduction, discontinuation, or disease activity-guided dose tapering) of anti-TNF agents on disease activity, functioning, costs, safety, and radiographic damage compared with usual care in people with RA and low disease activity. SEARCH METHODS: We searched MEDLINE, Embase, Web of Science and CENTRAL (29 March 2018) and four trial registries (11 April 2018) together with reference checking, citation searching, and contact with study authors to identify additional studies. We screened conference proceedings (American College of Rheumatology and European League Against Rheumatism 2005-2017). SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in people with RA and low disease activity. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: One previously included trial was excluded retrospectively in this update because it was not an RCT/CCT. We included eight additional trials, for a total of 14 studies (13 RCTs and one CCT, 3315 participants in total) reporting anti-TNF down-titration. Six studies (1148 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Eight studies (2111 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (three studies assessed both anti-TNF discontinuation and dose reduction), and three studies assessed disease activity-guided anti-TNF dose tapering (365 participants). These studies included data on all anti-TNF agents, but primarily adalimumab and etanercept. Thirteen studies were available in full text, one was available as abstract. We assessed the included studies generally at low to moderate risk of bias; our main concerns were bias due to open-label treatment and unblinded outcome assessment. Clinical heterogeneity between the trials was high. The included studies were performed at clinical centres around the world and included people with early as well as established RA, the majority of whom were female with mean ages between 47 and 60. Study durations ranged from 6 months to 3.5 years.We found that anti-TNF dose reduction leads to little or no difference in mean disease activity score (DAS28) after 26 to 52 weeks (high-certainty evidence, mean difference (MD) 0.06, 95% confidence interval (CI) -0.11 to 0.24, absolute risk difference (ARD) 1%) compared with continuation. Also, anti-TNF dose reduction does not result in an important deterioration in function after 26 to 52 weeks (Health Assessment Questionnaire Disability Index (HAQ-DI)) (high-certainty evidence, MD 0.09, 95% CI 0.00 to 0.19, ARD 3%). Next to this, anti-TNF dose reduction may slightly reduce the proportion of participants switched to another biologic (low-certainty evidence), but probably slightly increases the proportion of participants with minimal radiographic progression after 52 weeks (moderate-certainty evidence, risk ratio (RR) 1.22, 95% CI 0.76 to 1.95, ARD 2% higher). Anti-TNF dose reduction may cause little or no difference in serious adverse events, withdrawals due to adverse events and proportion of participants with persistent remission (low-certainty evidence).Results show that anti-TNF discontinuation probably slightly increases the mean disease activity score (DAS28) after 28 to 52 weeks (moderate-certainty evidence, MD 0.96, 95% CI 0.67 to 1.25, ARD 14%), and that the RR of persistent remission lies between 0.16 and 0.77 (low-certainty evidence). Anti-TNF discontinuation increases the proportion participants with minimal radiographic progression after 52 weeks (high-certainty evidence, RR 1.69, 95% CI 1.10 to 2.59, ARD 7%) and may lead to a slight deterioration in function (HAQ-DI) (low-certainty evidence). It is uncertain whether anti-TNF discontinuation influences the number of serious adverse events (due to very low-certainty evidence) and the number of withdrawals due to adverse events after 28 to 52 weeks probably increases slightly (moderate-certainty evidence, RR 1.46, 95% CI 0.75 to 2.84, ARD 1% higher).Anti-TNF disease activity-guided dose tapering may result in little or no difference in mean disease activity score (DAS28) after 72 to 78 weeks (low-certainty evidence). Furthermore, anti-TNF disease activity-guided dose tapering results in little or no difference in the proportion of participants with persistent remission after 18 months (high-certainty evidence, RR 0.89, 95% CI 0.75 to 1.06, ARD -9%) and may result in little or no difference in switching to another biologic (low-certainty evidence). Anti-TNF disease activity-guided dose tapering may slightly increase proportion of participants with minimal radiographic progression (low-certainty evidence) and probably leads to a slight deterioration of function after 18 months (moderate-certainty evidence, MD 0.2 higher, 0.02 lower to 0.42 higher, ARD 7% higher), It is uncertain whether anti-TNF disease activity-guided dose tapering influences the number of serious adverse events due to very low-certainty evidence. AUTHORS' CONCLUSIONS: We found that fixed-dose reduction of anti-TNF, after at least three to 12 months of low disease activity, is comparable to continuation of the standard dose regarding disease activity and function, and may be comparable with regards to the proportion of participants with persistent remission. Discontinuation (also without disease activity-guided adaptation) of anti-TNF is probably inferior to continuation of treatment with respect to disease activity, the proportion of participants with persistent remission, function, and minimal radiographic damage. Disease activity-guided dose tapering of anti-TNF is comparable to continuation of treatment with respect to the proportion of participants with persistent remission and may be comparable regarding disease activity.Caveats of this review are that available data are mainly limited to etanercept and adalimumab, the heterogeneity between studies, and the use of superiority instead of non-inferiority designs.Future research should focus on the anti-TNF agents infliximab and golimumab; assessment of disease activity, function, and radiographic outcomes after longer follow-up; and assessment of long-term safety, cost-effectiveness, and predictors for successful down-titration. Also, use of a validated flare criterion, non-inferiority designs, and disease activity-guided tapering instead of fixed-dose reduction or discontinuation would allow researchers to better interpret study findings and generalise to clinical practice.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Receptors, Tumor Necrosis Factor/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Antibodies, Monoclonal, Humanized , Female , Humans , Male , Middle Aged , Randomized Controlled Trials as Topic , Recurrence , Remission InductionSubject(s)
Antirheumatic Agents/economics , Arthritis, Rheumatoid/economics , Clinical Protocols , Deprescriptions , Adult , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Cost-Benefit Analysis , Female , Humans , Male , Middle Aged , Quality-Adjusted Life Years , Randomized Controlled Trials as TopicABSTRACT
OBJECTIVES: As data on disease-activity-guided dose optimization of abatacept and tocilizumab are scarce, we explored the feasibility, effectiveness and safety of dose optimization of these biological DMARDs in RA patients in daily practice. METHODS: RA patients who had been treated with abatacept or tocilizumab for ≥6 months, with DAS28 <3.2, were included. Four groups were identified: abatacept dose reduction (DR) and usual care (UC), and tocilizumab DR and UC. Successful DR and discontinuation entailed being on a lower dose than at baseline or having discontinued abatacept or tocilizumab, while maintaining disease activity score with ESR using 28 joint count (DAS28) <3.2. Proportions of patients with successful DR or discontinuation at 12 months were described. Maintenance of DR was investigated using Kaplan-Meier curves. Between-group differences in mean DAS28 and Health assessment questionnaire disability index (HAQ-DI) change (Δ) over 6 and 12 months were estimated. RESULTS: One hundred and nineteen patients were included. DR was attempted in 13 of 28 (46%; 95% CI: 28, 66%) abatacept and 64 of 91 (70%; 95% CI: 60, 79%) tocilizumab patients. At 12 months, 3 of 11 (27%; 95% CI: 6, 61%) abatacept and 20 of 48 (42%; 95% CI: 28, 57%) tocilizumab patients were successfully tapered. One of 11 (9%; 95% CI: 0, 41%) abatacept and 5 of 48 (10%; 95% CI: 3, 23%) tocilizumab patients were successfully discontinued. Mean ΔDAS28 and ΔHAQ-DI at months 6 and 12 were not significantly different between DR and UC. For tocilizumab, DAS28 was significantly higher in the DR compared with the UC group at 6 months. Adverse events were comparable between groups. CONCLUSION: Abatacept and tocilizumab DR appears to be feasible and safe in clinical practice. No benefits in terms of fewer adverse events in the DR group were observed. Furthermore, DR was suboptimal, because all patients were eligible for DR, but in a substantial number of patients no DR was attempted.