Objective
It has been suggested that rheumatoid arthritis (RA) may originate at the oral mucosa. The aim of the present study was to assess the oral microbiome and periodontal condition in patients ...with early RA and individuals at risk of developing RA compared to healthy controls.
Methods
Three groups were recruited (n = 50 participants per group): 1) patients with early RA (meeting the American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 classification criteria), 2) individuals at risk of developing RA (those with arthralgia who were positive for RA‐associated autoantibodies), and 3) healthy controls. A periodontal examination was conducted to assess the presence of bleeding on probing (BOP), pocket probing depth (PPD), and periodontal inflamed surface area (PISA). The microbial composition of subgingival dental plaque, saliva, and tongue coating was assessed using 16S ribosomal DNA amplicon sequencing, and findings were compared between groups with permutational multivariate analysis of variance (PERMANOVA).
Results
There were no significant differences in any of the 3 periodontal variables between patients with early RA, at‐risk individuals, and healthy controls (P = 0.70 for BOP, P = 0.30 for PPD, and P = 0.57 for PISA, by Kruskal‐Wallis test). PERMANOVA analyses comparing microbial composition between the groups showed significant differences in the microbial composition of saliva (F = 2.08, P = 0.0002) and tongue coating (F = 2.04, P = 0.008), but not subgingival dental plaque (F = 0.948, P = 0.51). However, in post hoc tests, no significant differences in microbial composition of the saliva or tongue coating were observed between the early RA group and the at‐risk group (F = 1.12, P = 0.28 for saliva; F = 0.834, P = 0.59 for tongue coating). In assessing microbial diversity based on the number of zero‐radius operational taxonomic units per sample, Prevotella in the saliva and Veillonella in the saliva and tongue coating were each found at a higher relative abundance in samples from patients with early RA and at‐risk individuals compared to healthy controls.
Conclusion
The results show similarities in the oral microbiome between patients with early RA and at‐risk individuals, since in both groups, the oral microbiome was characterized by an increased relative abundance of potentially proinflammatory species when compared to that in healthy controls. These findings suggest a possible association between the oral microbiome and the onset of RA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
We developed a smartphone application for patients with rheumatoid arthritis (RA) that allows them to self‐monitor their disease activity in between clinic visits by answering a weekly ...Routine Assessment of Patient Index Data 3. This study was undertaken to assess the safety (noninferiority in the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate DAS28‐ESR) and efficacy (reduction in number of visits) of patient‐initiated care assisted using a smartphone app, compared to usual care.
Methods
A 12‐month, randomized, noninferiority clinical trial was conducted in RA patients with low disease activity and without treatment changes in the past 6 months. Patients were randomized 1:1 to either app‐supported patient‐initiated care with a scheduled follow‐up consultation after a year (app intervention group) or usual care. The coprimary outcome measures were noninferiority in terms of change in DAS28‐ESR score after 12 months and the ratio of the mean number of consultations with rheumatologists between the groups. The noninferiority limit was 0.5 difference in DAS28‐ESR between the groups.
Results
Of the 103 randomized patients, 102 completed the study. After a year, noninferiority in terms of the DAS28‐ESR score was established, as the 95% confidence interval (95% CI) of the mean ΔDAS28‐ESR between the groups was within the noninferiority limit: −0.04 in favor of the app intervention group (95% CI −0.39, 0.30). The number of rheumatologist consultations was significantly lower in the app intervention group compared to the usual care group (mean ± SD 1.7 ± 1.8 versus 2.8 ± 1.4; visit ratio 0.62 95% CI 0.47, 0.81).
Conclusion
Patient‐initiated care supported by smartphone self‐monitoring was noninferior to usual care in terms of the ΔDAS28‐ESR and led to a 38% reduction in rheumatologist consultations in RA patients with stable low disease activity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest ...clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix 'pre-RA with:' could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites.
Objective
The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti–citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of ...N‐linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages.
Methods
Using liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new‐onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long‐term drug‐free remission (DFR) during up to 16 years follow‐up.
Results
IgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset.
Conclusion
The abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre‐disease phase and contributes to disease development.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
Rheumatoid factors (RFs), which are anti‐IgG autoantibodies strongly associated with rheumatoid arthritis (RA), are also found in other diseases and in healthy individuals. RFs bind to ...various epitopes in the constant (Fc‐) domain of IgG. Therefore, disease‐specific reactivity patterns may exist. This study was undertaken in order to develop a new approach to dissecting RF epitope binding patterns across different diseases.
Methods
We analyzed RF reactivity patterns in serum from patients with seropositive arthralgia, patients with RA, and patients with primary Sjögren’s syndrome (SS) using bioengineered, natively folded IgG‐Fc targets that demonstrated selective RF binding toward several distinct regions of the IgG‐Fc domain.
Results
Rheumatoid factor responses primarily bound the Fc Elbow region, with a smaller number of RFs binding the Fc Tail region, while the Fc receptor binding region was hardly targeted. A restricted reactivity against the IgG‐Fc Tail region was associated with less positivity for anti–citrullinated protein antibodies (ACPAs) and less arthritis development in arthralgia, whereas combined reactivity toward IgG‐Fc Tail and Elbow regions was associated with more arthritis development. Reactivity toward the IgG‐Fc Tail region was observed far more frequently in RA than in primary SS.
Conclusion
Bioengineered IgG targets enable serologic characterization of RF reactivity patterns, and use of this approach appears to reveal patterns associated with ACPA detection and arthritis development in patients with arthralgia. These patterns are able to distinguish RA patients from primary SS patients. This new methodology improves the clinical value of RFs and our understanding of their pathophysiologic processes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
Pain interference and pain behavior are highly relevant outcomes in patients with rheumatoid arthritis (RA). The Patient‐Reported Outcomes Measurement Information System (PROMIS) is a ...universally applicable set of item banks measuring patient‐reported health, and if applied as computerized adaptive tests (CATs), more efficiently and precisely than current instruments. The objective was to study the psychometric properties of the Dutch‐Flemish PROMIS pain interference (PROMIS‐PI) and the PROMIS pain behavior (PROMIS‐PB) item banks in patients with RA.
Methods
A total of 2,029 patients with RA completed the full PROMIS‐PI (version 1.1, 40 items), and 1,554 patients completed the full PROMIS‐PB (version 1.1, 39 items). The following psychometric properties were studied: unidimensionality, local dependence, monotonicity and graded response model (GRM) fit, cross‐cultural validity (differential item functioning DIF for language Dutch versus Flemish), other forms of measurement invariance, construct validity, reliability, and floor and ceiling effects.
Results
The PROMIS‐PI and PROMIS‐PB banks were sufficiently unidimensional (Omega‐hierarchical Omega‐H 0.99, 0.95, and explained common variance 0.95, 0.78, respectively), had negligible local dependence (0.3–1.4% of item pairs), good monotonicity (H 0.75, 0.46), and a good GRM model fit (no misfitting items). Furthermore, both item banks showed good cross‐cultural validity (no DIF for language), measurement invariance (no DIF for age, sex, administration mode, and disease activity), good construct validity (all hypotheses met), high reliability (>0.90 in the range of patients with RA), and an absence of floor and ceiling effects (0% minimum or maximum score, respectively).
Conclusion
Both PROMIS‐PI and PROMIS‐PB banks showed good psychometric properties in patients with RA and can be used as CATs in research and clinical practice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives
Evaluating the cost effectiveness and cost utility of an integrated care intervention and participatory workplace intervention for workers with rheumatoid arthritis (RA) to improve their ...work productivity.
Methods
Twelve month follow‐up economic evaluation alongside a randomized controlled trial (RCT) within specialized rheumatology treatment centers. Adults diagnosed with RA between 18‐64 years, in a paid job for at least eight hours per week, experiencing minor difficulties in work functioning were randomized to the intervention (n = 75) or the care‐as‐usual (CAU) group (n = 75). Effect outcomes were productivity and quality of life (QA‐LYs). Costs associated with healthcare, patient and family, productivity, and intervention were calculated from a societal perspective. Cost effectiveness and cost utility were assessed to indicate the incremental costs and benefits per additional unit of effect. Subgroup and sensitivity analyses evaluated the robustness of the findings.
Results
At‐work productivity loss was about 4.6 hours in the intervention group and 3.5 hours in the care as usual (CAU) group per two weeks. Differences in QALY were negligible; 0.77 for the CAU group and 0.74 for the intervention group. In total, average costs after twelve months follow‐up were highest in the intervention group (€ 7,437.76) compared to the CAU group (€, 758.23). The cost‐effectiveness and cost‐utility analyses show that the intervention was less effective and (often) more expensive when compared to CAU. Sensitivity analyses supported these findings.
Discussion
The integrated care intervention and participatory workplace intervention for workers with RA provides gains neither in productivity at the workplace nor in quality of life. These results do not justify the additional costs.
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CEKLJ, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The typical evolution of rheumatoid arthritis (RA) is that a person with genetic risk factors develops autoantibodies and subclinical inflammation under relevant environmental influences, culminating ...in symptoms and finally clinically detectable arthritis. Because several of these characteristics can be present before the outbreak of clinical arthritis, it is possible to study the at-risk phase (the presence of ≥1 risk factors for RA in an individual) with the aim of quantifying the risk for that individual. As a person progresses through the different phases of disease development, different markers can be used for prediction. In the early asymptomatic phase, genetics, environmental factors, and autoantibodies are relevant, whereas in later phases additional markers, such as symptoms and imaging, come into play, conveying the risk of not only RA but sometimes even of imminent RA. Prediction is of limited use when not coupled with the possibility to intervene and lower the risk of RA. There is a clear need for effective preventive strategies that take the phase of disease development into account. On the other hand, selecting the right persons for preventive treatment according to their stage of disease development requires the improvement of current prediction models and strategies. This commentary presents an overview of risk factors and their combination into prediction models for use in different stages of RA development. Although clear progress has been made and assuming a future with effective options to intervene, there are still several gaps in our knowledge that need to be filled before it is clear who should be tested and when.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to explore symptoms and symptom development during the earliest phases of RA in patients with seropositive arthralgia and patients newly diagnosed with RA.
Interviews were ...conducted with 15 seropositive patients (anti-CCP positive, and often with arthralgia) and 11 newly presenting RA patients classified according to the 2010 ACR/European League Against Rheumatism (EULAR) criteria. Feedback procedures shared the experiences of seropositive arthralgia patients with early RA patients and vice versa. Data were analysed using thematic analysis.
Symptoms common to both groups included joint pain, psychological distress, muscle cramps, abnormal skin sensations, stiffness, loss of motor control, weakness, fatigue and sleeping difficulties. Also, patterns of symptom evolution and the order of symptom development were described. Seropositive arthralgia patients described pain as annoying, while RA patients described how the severity of pain intensified before diagnosis, to the point where symptoms were psychologically distressing. Patients with seropositive arthralgia described reddening of the skin and burning sensations that they felt were indicative of the onset of swelling. Intense pain appeared to precede the onset of swelling for those with RA, which was often palindromic and travelled between joints until it later became persistent.
This study highlights the breadth of symptoms that constitute the earliest phases of RA. Further research is needed to develop measures of symptom patterns and clusters to allow the predictive utility of symptoms to be assessed and to allow the integration of aspects of the patient's history into evidence-based investigative and management algorithms for use in primary and secondary care.
Abstract van Dijk GM, Veenhof C, Spreeuwenberg P, Coene N, Burger BJ, van Schaardenburg D, van den Ende CH, Lankhorst GJ, Dekker J, on behalf of the CARPA Study Group. Prognosis of limitations in ...activities in osteoarthritis of the hip or knee: a 3-year cohort study. Objective To describe the course of limitations in activities in elderly patients with osteoarthritis (OA) of the hip or knee over a follow-up period of 3 years, and to identify prognostic factors of the course of limitations in activities, focusing on body functions, comorbidity, and cognitive functioning. Design A longitudinal cohort study with 3 years of follow-up. Measurements were conducted annually. Statistical analyses included t tests, univariate regression analyses, and multivariate regression analyses. Setting Rehabilitation centers and hospitals (Departments of Orthopedics, Rheumatology, and Rehabilitation) in The Netherlands. Participants Patients (N=237) with hip or knee OA. Interventions Not applicable. Main Outcome Measures Patient-perceived change, self-reported limitations in activities measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and observed limitations in activities (timed walking test). Prognostic factors: demographic data, clinical data, body function (pain, muscle strength, range of motion ROM), comorbidity, and cognitive functioning (cognitive decline, memory, attention). Results Self-reported limitations in activities measured by the WOMAC improved slightly after 3-year follow-up. In knee OA, reduced ROM at 1-year follow-up (β=.120), increased pain at 1-year follow-up (β=−.177), and higher morbidity count (β=−.180) predicted worsening of self-reported limitations in activities. In hip OA, reduced ROM at 1-year follow-up (β=.201 for hip external rotation and β=.144 for knee extension), increased pain at 1-year follow-up (β=−.134), higher morbidity count (β=−.220), or the presence of moderate to severe cardiac disease (β=−.214) and poorer cognitive functioning (β=.181) predicted worsening of self-reported limitations in activities. Performance-based limitations in activities measured by the timed walking test did not change after 3 years of follow-up. In knee OA, decreased muscle strength at 1-year follow-up (β=−.272) and higher morbidity count (β=.199) predicted worsening of performance-based limitations in activities. In hip OA, better ROM (β=.182), higher morbidity count (β=.232), or the presence of moderate to severe cardiac and eye-ear-nose-throat disease (β=.210 and β=.188, respectively) and older age (β=.355) predicted worsening of performance-based limitations in activities. Conclusions Overall, at the group level, limitations in activities of patients with OA of the hip or knee recruited from hospitals and rehabilitation centers seem fairly stable during the first 3 years of follow-up. However, at the level of individual patients, considerable variation occurs. Prognostic factors for worsening of limitations in activities include increased pain, reduced ROM, and decreased muscle strength at 1-year follow-up; higher morbidity count; and to a lesser extent poor cognitive functioning.
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