ObjectivesAlthough current treatment guidelines for rheumatoid arthritis (RA) suggest tapering disease-modifying anti-rheumatic drugs (DMARDs), it is unclear whether DMARD-free remission (DFR) is an achievable and sustainable outcome. Therefore, we systematically reviewed the literature to determine the prevalence and sustainability of DFR and evaluated potential predictors for DFR.MethodsA systematic literature search was performed in March 2019 in multiple databases. All clinical trials and observational studies reporting on discontinuation of DMARDs in RA patients in remission were included. Our quality assessment included a general assessment and assessment of the description of DFR. Prevalence of DFR and its sustainability and flares during tapering and after DMARD stop were summarised. Also, potential predictors for achieving DFR were reviewed.ResultsFrom 631 articles, 51 were included, comprising 14 clinical trials and 5 observational studies. DFR definition differed, especially for the duration of DMARD-free state. Considering only high- and moderate-quality studies, DFR was achieved in 5.0%–24.3% and sustained DFR (duration>12 months) in 11.6%–19.4% (both relative to the number of patients eligible for tapering). Flares occurred frequently during DMARD tapering (41.8%–75.0%) and in the first year after achieving DFR (10.4%–11.8%), while late flares, >1 year after DMARD-stop, were infrequent (0.3%–3.5%). Many patient characteristics lacked association with DFR. Absence of autoantibodies and shared epitope alleles increased the chance of achieving DFR.ConclusionsDFR is achievable in RA and is sustainable in ~10%–20% of patients. DFR can become an important outcome measure for clinical trials and requires consistency in the definition. Considering the high rate of flares in the first year after DMARD stop, a DMARD-free follow-up of >12 months is advisable to evaluate sustainability.
ObjectivesThe human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis.MethodsWe performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA).ResultsMeta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not.ConclusionsHLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.
Objectives International guidelines stress timely DMARD-initiation in early-arthritis, also when classification-criteria are not yet fulfilled. Consequently, undifferentiated arthritis (UA)-patients may be increasingly treated with DMARDs. Since UA is a diagnosis per exclusionem, the introduction of the 2010-classification-criteria presumably decreased the UA-population as former UA-patients became regarded as RA. The contemporary definition of UA has therefore become: not fulfilling the 1987- nor 2010-criteria. Importantly, placebo-controlled trials on DMARD-efficacy in contemporary UA are absent. We aimed to study whether enhanced treatment-strategies across 25-years improved outcomes in contemporary UA, whereby inclusion-period was an instrumental variable for DMARD-treatment. Methods UA was defined, retrospectively, as clinical arthritis (joint-swelling at physical-examination) neither fulfilling the 1987 nor 2010-RA-criteria, nor any other clinical diagnosis. In total, 1132 UA-patients, consecutively included in the Leiden-EAC between 1993–2019, were studied, divided into 5 inclusion-periods; 1993–1997, 1998–2005, 2006–2010, 2011–2014, 2015–2019. Frequency of DMARD-initiation was compared across the inclusion-periods, as were the following outcomes: DAS28CRP and disability (HAQ-DI) during follow-up, prevalence of DMARD-free-status within 10-years (DFS; spontaneous remission or sustained remission after DMARD-stop) and progression to RA (according 1987/2010-criteria). Results The contemporary UA-population is mainly autoantibody-negative, with median SJC = 2, TJC = 3 and HAQ = 0.6. These characteristics were similar across the inclusion-periods. DMARD-treatment increased from 17% (1993–1997) up-to 52% (2015–2019), methotrexate became more common. DAS28CRP during follow-up improved from 2011 onwards (-0.18,-0.25DAS-units/p< 0.05). Disability-scores during follow-up did not significantly improve. DFS-prevalence also remained similar: 58%, 57%, 61% (1993–1997/1998–2005/2006–2010; p= 0.77). Likewise, the percentages RA-development did not decrease (14%/21%/26%/18%/27%). Conclusion Although intensified DMARD-treatment slightly improved disease-activity-scores, physical-functioning and long-term outcomes did not improve. This suggests overtreatment in the contemporary UA-population and underlines the importance to develop stratification-methods suitable for this population.
In the majority of patients the change of urinary albumin excretion was small, but the range was wide. A weak non-significant relationship between microalbuminuria and all-cause mortality and cardiovascular morbidity was observed.
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