Disentangling heterogeneity in contemporary undifferentiated arthritis - A large cohort study using latent class analysis.

OBJECTIVES: Undifferentiated arthritis(UA) is clinically heterogeneous and differs in outcomes ranging from spontaneous resolution to RA-development. Therefore, we hypothesized that subgroups exist within UA and we aimed to identify homogeneous groups based on clinical features, and thereafter to relate these groups to the outcomes spontaneous resolution and RA-development. These outcomes can only be studied in UA-patients in which DMARD-treatment does not influence the natural disease course; these cohorts are scarce. METHODS: We studied autoantibody-negative UA-patients (not fulfilling 1987/2010 RA-criteria, no alternate diagnosis), included in the Leiden Early Arthritis Clinic between 1993 and 2006, when early DMARD-treatment in UA was infrequent. Latent class analysis was used to identify subgroups based on combinations of clinical features. Within these subgroups, test-characteristics were assessed for spontaneous resolution of arthritis and RA-development within 1 year. RESULTS: 310 consecutive UA-patients were studied. Five classes were identified: location and number of swollen joints were most distinguishing. Classes were characterized by: 1) polyarthritis, often symmetric; 2) oligoarthritis, frequently with subacute onset; 3) wrist-monoarthritis, often with subacute onset, increased BMI and without morning stiffness; 4) small-joint monoarthritis, often without increased acute phase reactants, and 5) large-joint monoarthritis, often with subacute onset. Studying the classes in relation to the outcomes revealed that patients without spontaneous resolution (thus having persistent disease) were nearly absent in the classes characterized by monoarthritis (specificity >90%). Additionally, patients who developed RA were infrequent in monoarthritis classes (sensitivity <7%). CONCLUSION: Using a data-driven unsupervised approach, five subgroups within contemporary UA were identified. These have differences in the natural course of disease.

Unraveling heterogeneity within ACPA-negative rheumatoid arthritis: the subgroup of patients with a strong clinical and serological response to initiation of DMARD treatment favor disease resolution.

BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes. This applies especially to anti-citrullinated protein antibodies (ACPA)-negative RA, where a proportion achieves sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD cessation). Differentiation of RA patients who will achieve SDFR can guide personalized treatment/tapering strategies. Although this subgroup remains scarcely discerned, previous research demonstrated that these RA patients are characterized by an early clinical response (DAS remission after 4 months) after DMARD start. We studied whether, in addition to this clinical response, a specific biomarker response can further distinguish the subgroup of RA patients most likely to achieve SDFR. METHODS: In 266 RA patients, levels of 12 biomarkers (SAA/CRP/MMP-1/MMP-3/resistin/leptin/IL-6/TNF-R1/YKL-40/EGF/VEGF/VCAM-1), in the first 2 years after diagnosis, were studied in relation to SDFR, stratified for ACPA status. Subsequently, biomarkers associated with SDFR development were combined with early DAS remission to study its additional value in defining subgroups. Since most biomarker levels are not routinely measured in clinical practice, we explored how this subgroup can be clinically recognized. RESULTS: ACPA-negative RA patients achieving SDFR were characterized by high baseline levels and stronger decline in MMP-1/MMP-3/SAA/CRP after DMARD-start, respectively 1.30×/1.44×/2.12×/2.24× stronger. This effect was absent in ACPA-positive RA. In ACPA-negative RA, a strong biomarker decline is associated with early DAS remission. The combination of both declines (clinical, biomarker) was present in a subgroup of ACPA-negative RA patients achieving SDFR. This subgroup can be clinically recognized by the combination of high baseline CRP levels (≥ 3 times ULN), and early DAS remission (DAS4 months < 1.6). This latter was replicated in independent ACPA-negative RA patients. CONCLUSIONS: ACPA-negative RA patients with early DAS remission and a strong biomarker response (or baseline CRP levels ≥ 3× ULN) are most likely to achieve SDFR later on. This could guide personalized decisions on DMARD tapering/cessation in ACPA-negative RA.

Comparison between 1.5T and 3.0T MRI: both field strengths sensitively detect subclinical inflammation of hand and forefoot in patients with arthralgia.

OBJECTIVE: Magnetic resonance imaging (MRI) of small joints sensitively detects inflammation. This inflammation, and tenosynovitis in particular, has been shown to predict rheumatoid arthritis (RA) development in arthralgia patients. These data have predominantly been acquired on 1.0-1.5 T MRI. However, 3.0 T is now commonly used in practice. Evidence on the comparability of these field strengths is scarce and has never included subtle inflammation in arthralgia patients or tenosynovitis. Therefore, we assessed the comparability of 1.5 T and 3.0 T in detecting subclinical inflammation in arthralgia patients. METHOD: A total of 2968 locations (joints, bones, tendon sheaths) in the hands and forefeet of 28 patients with small-joint arthralgia, at risk for RA, were imaged on both 1.5 and 3.0 T MRI. Two blinded readers independently scored erosions, osteitis, synovitis, and tenosynovitis, in line with the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS). Features were summed into inflammation (osteitis, synovitis, tenosynovitis) and RAMRIS (inflammation and erosions). Agreement was assessed with intraclass correlation coefficients (ICCs) for continuous scores and after dichotomization into presence or absence of inflammation, on patient and location levels. RESULTS: Interreader ICCs were excellent (> 0.90). Comparing 1.5 and 3.0 T revealed an ICC of 0.90 for inflammation and RAMRIS. ICCs for individual inflammation features were: tenosynovitis 0.87 (95% confidence interval 0.74-0.94), synovitis 0.65 (0.24-0.84), and osteitis 0.96 (0.91-0.98). Agreement was 83% for inflammation and 89% for RAMRIS. Analyses on the location level showed similar results. CONCLUSION: Agreement on subclinical inflammation between 1.5 T and 3.0 T was excellent. Although synovitis scores were slightly different, synovitis often occurs simultaneously with other inflammatory signs, suggesting that scientific results on the predictive value of MRI-detected inflammation for RA, obtained on 1.5 T MRI, can be generalized to 3.0 T MRI.

Early DAS response after DMARD-start increases probability of achieving sustained DMARD-free remission in rheumatoid arthritis.

BACKGROUND: Sustained DMARD-free remission (SDFR) is increasingly achievable. The pathogenesis underlying SDFR development is unknown and patient characteristics at diagnosis poorly explain whether SDFR will be achieved. To increase the understanding, we studied the course of disease activity scores (DAS) over time in relation to SDFR development. Subsequently, we explored whether DAS course could be helpful identifying RA patients likely to achieve SDFR. METHODS: 772 consecutive RA patients, promptly treated with csDMARDs (mostly methotrexate and treat-to-target treatment adjustments), were studied for SDFR development (absence of synovitis, persisting minimally 12 months after DMARD stop). The course of disease activity scores (DAS) was compared between RA patients with and without SDFR development within 7 years, using linear mixed models, stratified for ACPA. The relation between 4-month DAS and the probability of SDFR development was studied with logistic regression. Cumulative incidence of SDFR within DAS categories (< 1.6, 1.6-2.4, 2.4-3.6, ≥ 3.6) at 4 months was visualized using Kaplan-Meier curves. RESULTS: In ACPA-negative RA patients, those achieving SDFR showed a remarkably stronger DAS decline within the first 4 months, compared to RA patients without SDFR; - 1.73 units (95%CI, 1.28-2.18) versus - 1.07 units (95%CI, 0.90-1.23) (p < 0.001). In APCA-positive RA patients, such an effect was not observed, yet SDFR prevalence in this group was low. In ACPA-negative RA, DAS decline in the first 4 months and absolute DAS levels at 4 months (DAS4 months) were equally predictive for SDFR development. Incidence of SDFR in ACPA-negative RA patients was high (70.2%) when DAS4 months was < 1.6, whilst SDFR was rare (7.1%) when DAS4 months was ≥ 3.6. CONCLUSIONS: In ACPA-negative RA, an early response to treatment, i.e., a strong DAS decline within the first 4 months, is associated with a higher probability of SDFR development. DAS values at 4 months could be useful for later decisions to stop DMARDs.

DMARD-free remission as novel treatment target in rheumatoid arthritis: A systematic literature review of achievability and sustainability.

OBJECTIVES: Although 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. METHODS: A 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. RESULTS: From 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. CONCLUSIONS: DFR 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.

Glued intraocular lens implantation: A three-year retrospective analysis at two hospitals in Brussels, Belgium.

PURPOSE: To analyze the outcomes and refraction of cases receiving fibrin glue-assisted posterior chamber intraocular lens implantation (Glued IOL) from December 2014 to December 2017 at Saint-Pierre Hospital and Saint-Anne Hospital in Brussels. METHODS: Multicenter retrospective descriptive observational study of consecutive cases that underwent glued intraocular lens implantation from December 2014 to December 2017 at Saint-Pierre Hospital and Saint-Anne Hospital in Brussels. The purpose is to analyze the results preoperatively and 3months postoperatively, the postoperative intraocular pressure, the reasons that led us to use this surgical technique, the immediate and late complications and finally the astigmatism and refraction before and after the surgery. RESULTS: A total of 33 eyes were evaluated. Among the indications, 42.42% were intraoperative posterior capsular rupture, 33.3% were dislocated IOL and 12% were (sub) luxated cataract. The mean preoperative and postoperative intraocular pressure was 17.1mmHg and 16.3mmHg, respectively. There were no intraoperative complications, but there were 5 postoperative complications, one macular cystoid edema, one hyphema, one retinal detachment and 2 haptic extrusions. The mean corneal astigmatism pre- and postoperatively was 1.43 and 1.49 diopters, respectively. The postoperative spherical equivalent refractions were between -0.75 and +0.75 D.

[A man with oral ulcers caused by hypereosinophilic syndrome and a good response to the tyrosine-kinase inhibitor imatinib]. / Een man met orale ulcera door hypereosinofiel syndroom en met een goede respons op de tyrosinekinaseremmer imatinib.

For the last 2 years, a 55-year-old man had painful, recurrent oral ulcers. Histological examination showed non-specific inflammation. Eosinophilia in the blood and bone marrow raised the suspicion of hypereosinophilic syndrome. No other specific organ involvement was observed. The diagnosis was confirmed by detection of the fusion gene 'FIP1-like-1-platelet-derived growth factor receptor alpha' (FIP1L1-PDGFRA) in the peripheral blood and bone marrow. Treatment with the tyrosine-kinase inhibitor imatinib resulted in a rapid response that has been maintained for more than 2 years. Hypereosinophilic syndrome is a rare haematological disorder. Until recently diagnosis was made by exclusion, and the course of disease was often fatal. Fusion of the FIP1L1 gene to the PDGFRA gene was identified recently in some patients with hypereosinophilic syndrome. The fusion results in a novel tyrosine kinase that is constitutively activated and may induce proliferation ofhaematopoietic cells. Treatment with imatinib targets this tyrosine kinase. These advances in our understanding of the molecular biology of the disease will lead to a new classification of hypereosinophilic syndrome with specific therapeutic options.

Microalbuminuria in patients with Type 2 diabetes mellitus from general practice: course and predictive value.

AIMS: To assess the course of microalbuminuria in patients with Type 2 diabetes mellitus in general practice and the predictive value of urinary albumin concentration on all-cause mortality, cardiovascular mortality and cardiovascular morbidity. METHODS: Cohort study in Type 2 diabetic patients tested for microalbuminuria in 1992, and re-tested in 1998. During follow-up all cardiovascular morbidity and mortality were recorded. RESULTS: Of the original sample of 317 patients, 163 patients were re-tested. The mean change in urinary albumin concentration was +16.2 mg/l (range -122.0 to +602 mg/l). Seventy-five per cent of the patients without microalbuminuria in 1992 still had no microalbuminuria in 1998 and 40% of those with microalbuminuria in 1992 reverted to normoalbuminuria in 1998. Cox survival analysis, stratified for age, showed that microalbuminuria at baseline resulted in a risk ratio of all-cause mortality of 1.4 (95% confidence interval 0.8-2.7), of cardiovascular mortality of 1.2 (0.5-2.8) and of new cardiovascular events (including cardiovascular mortality) of 1.4 (0.8-2.3). CONCLUSIONS: 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.

Terrestrial locomotion in the black-billed magpie: kinematic analysis of walking, running and out-of-phase hopping.

The inter-limb kinematic patterns of walking, running and out-of-phase hopping in black-billed magpies (Pica pica) were studied using high-speed video recordings. The flexion/extension patterns of the joints were similar between the gait types, suggesting that the within-leg control of the angular excursions is similar. This result is further supported by the fact that running and hopping are alternative gaits at speeds higher than walking; however, magpies show a preference for hopping. Moreover, only small differences occur between the kinematic patterns of the two limbs during out-of-phase hopping, during which the legs are believed to have different functions. The hindlimb kinematic patterns of magpies are like those of other flying and more terrestrial bird species; however, striking differences are found in comparison with humans at the level of the internal angles. This is probably due to the differences in the morphology and configuration of their legs.

Terrestrial locomotion in the black-billed magpie. I. Spatio-temporal gait characteristics.

Spatio-temporal gait characteristics are determined for walking, running, and out of phase hopping magpies, at velocities ranging from 0.4 to 4 m/s. Below 1 m/s, magpies walk. At higher velocities they either run or hop, the latter being preferred. Stride length and frequency during walking and running relate to speed in an identical way. It is suggested that the control of walking and running, despite the abrupt drop in duty factor and step length at the transition from walking to either running or hopping, is represented by one single intrinsic pattern. Swing phase duration is independent of speed and similar of the three gaits, pointing to a passive, mechanical control. Stride frequencies during hopping barely change with velocity, while its stride length relates to velocity in a way highly comparable to that of walking and running. Hopping step length and duty factor are indifferent from those of running. These facts, combined with the similar spatio-temporal behavior of both legs in hopping suggest fairly comparable intra-limb coordination for running and hopping, and a simple phase-shift in inter-limb coordination to transform a run into a hop.