Long-standing Rheumatoid Arthritis Research Articles

Chronic inflammation-induced senescence impairs immunomodulatory properties of synovial fluid mesenchymal stem cells in rheumatoid arthritis

BackgroundAlthough the immunomodulatory properties of mesenchymal stem cells (MSCs) have been highlighted as a new therapy for autoimmune diseases, including rheumatoid arthritis (RA), the disease-specific characteristics of MSCs derived from elderly RA patients are not well understood.MethodsWe established MSCs derived from synovial fluid (SF) from age-matched early (average duration of the disease: 1.7 years) and long-standing (average duration of the disease: 13.8 years) RA patients (E-/L-SF-MSCs) and then analyzed the MSC characteristics such as stemness, proliferation, cellular senescence, in vitro differentiation, and in vivo immunomodulatory properties.ResultsThe presence of MSC populations in the SF from RA patients was identified. We found that L-SF-MSCs exhibited impaired proliferation, intensified cellular senescence, reduced immunomodulatory properties, and attenuated anti-arthritic capacity in an RA animal model. In particular, E-SF-MSCs demonstrated cellular senescence progression and attenuated immunomodulatory properties similar to those of L-SF-MSC in an RA joint-mimetic milieu due to hypoxia and pro-inflammatory cytokine exposure. Due to a long-term exposure to the chronic inflammatory milieu, cellular senescence, attenuated immunomodulatory properties, and the loss of anti-arthritic potentials were more often identified in SF-MSCs in a long-term RA than early RA.ConclusionWe conclude that a chronic RA inflammatory milieu affects the MSC potential. Therefore, this work addresses the importance of understanding MSC characteristics during disease states prior to their application in patients.Graphical abstract

The Assessment of Muscle Mass and Function in Patients with Long-Standing Rheumatoid Arthritis.

Muscular dysfunction in rheumatoid arthritis (RA) can affect the quality of life and comorbidities. We enrolled 320 patients with RA, and evaluated their muscle mass, grip strength, and physical performance. Seven (2.2%) and 21 RA patients (6.6%) had sarcopenia, as defined by the European and Asian Working Group for Sarcopenia (EWGS and AWGS), respectively; 54 patients (16.9%) were determined to have low muscle mass with normal muscle function, as defined by the EWGS; 38 patients (11.9%) reported sarcopenia by SARC-F questionnaire. Male sex (odds ratio (OR) 140.65), low body mass index (BMI) (OR 0.41), and use of tumor necrosis factor (TNF) inhibitors (OR 4.84) were associated with a low muscle mass as defined by the EWGS, while male sex, old age, and low BMI were associated with sarcopenia as defined by the AWGS. Old age (OR 1.11), high BMI (OR 1.13), and a high Disease Activity Score 28 (OR 1.95) were associated with sarcopenia as reported on the SARC-F. Male, low BMI, and use of TNF inhibitors were associated with a low muscle mass, while male sex, old age, and low BMI were associated with sarcopenia in patients with long-standing RA.

How do central sensitisation features affect symptoms among patients with rheumatoid arthritis? Analysis of pain descriptors and the effect of central sensitivity syndrome on patient and evaluator global assessments.

Central sensitivity syndrome (CSS) comprises various symptoms caused by central sensitisation (CS). Using the central sensitisation inventory (CSI), a screening questionnaire developed for detecting CSS, this syndrome was recently identified in patients with long-standing rheumatoid arthritis (RA). However, the descriptors of CS-related pain and the effects of CSS on symptoms in patients with rheumatoid arthritis (RA) remain unknown. We examined the characteristics of pain and influence of CSS on patient and evaluator global assessment among multiple clinical variables. We used the central sensitisation inventory (CSI) and short-form McGill pain questionnaire to evaluate CSS and characteristics of pain in 240 outpatients with RA. Disease activity, fibromyalgia, neuropathic pain, anxiety, depression, pain catastrophising, and health-related quality of life were evaluated. We used multivariate analysis to analyse the characteristics of CS-related pain according to CSI and the effect of CSS on patient global assessment (PGA), evaluator global assessment (EGA), and PGA minus EGA among relevant clinical variables. In patients with RA, the main descriptors of pain according to severity of CSI scores were "sharp" and "stabbing", whereas those of pain according to disease activity were "tender" and "throbbing". CSS was associated with EGA (p=0.000, β=- 0.199) and PGA minus EGA (p=0.021, β=0.147), but not with PGA. In patients with RA, descriptors for CS-related pain differ from those for disease activity-related pain. CSS may have an important impact on EGA and PGA minus EGA. Additionally, CSI may be helpful in identifying why there is discordance between PGA and EGA.

Giant Intraosseous Cyst-Like Lesions of the Metacarpal Bones in Rheumatoid Arthritis

The purpose of this study was to illustrate the clinical and imaging properties of giant intraosseous cyst-like lesions (GICLs) of the metacarpal bones extending beyond the central diaphysis in rheumatoid arthritis (RA) patients on magnetic resonance (MR) images. A keyword search was conducted to extract GICLs of the metacarpal bones out of MR reports in RA patients. There were nine GICLs extending from the subchondral bone region beyond the central diaphysis of the metacarpal bones on MR images in eight subjects with RA (seven females, one male). The age range was from 60 to 87 years with a median age of 65.5 years. The average disease duration was 13.1 years. As for the disease activity, one was low, six were moderate and one was high. None of the nine lesions were visible on radiography. The Steinbrocker stage distribution was as follows: I (n = 3), II (n = 2), and III (n = 3). Intraosseous cyst-like lesion of the metacarpal bones on MR images is a relatively rare manifestation in patients with long-standing RA. Although the lesion seems to be derived from subcortical bone break, it is not necessarily erosive in nature.

Potential for Major Therapeutic Changes to Produce Significant Clinical Response Across a Broad Range of Disease Activity: An Observational Study of US Veterans With Rheumatoid Arthritis.

To examine the impact of major therapeutic change (MTC) on clinical response across a broad range of disease activity in US veterans with rheumatoid arthritis (RA). This historical cohort analysis evaluated patient visits from the Veterans Affairs RA registry between January 1, 2006 and September 30, 2017. Eligible patient visits were a rheumatology visit with 3 disease activity measures, including the Disease Activity Score in 28 joints, the Clinical Disease Activity Index, and the Routine Assessment of Patient Index Data 3; the follow-up visit for all 3 disease activity measures was 2-6 months later. The full population and a subset of patients with active disease (≥6 tender joints, ≥6 swollen joints) were evaluated. Clinical outcome was based on the American College of Rheumatology criteria for 20% improvement in disease activity (ACR20). The effect of MTC on ACR20 response was presented as crude descriptive statistics and evaluated using standardized regression for population- and disease activity-level conditional effects. The full population comprised 1,208 patients (6,138 visits) and the active disease subpopulation included 383 patients (1,109 visits). Overall, visits with MTC were associated with increased likelihood of ACR20 response across all disease activity measures for the full population. Risk ratios for overall risk of ACR20 response for visits with MTC versus those without MTC ranged from 1.67 to 2.22 across disease activity measures among the full population and from 1.51 to 1.60 for the subpopulation with active disease. MTC was associated with clinical improvement, even among patients with longstanding RA who had received multiple prior therapies, which emphasizes the utility of therapy modifications for patients with established and active RA.

Tumour necrosis factor inhibitors reduce aortic stiffness progression in patients with long-standing rheumatoid arthritis

BackgroundAortic stiffness index (AoSI) has to be considered a proxy outcome measure in patients with rheumatoid arthritis (RA). The aim of this study was to comparatively describe AoSI progression in two groups of RA patients on long-term treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with or without tumour necrosis factor inhibitors (TNFi).MethodsAoSI was evaluated by Doppler echocardiography at the level of the aortic root, using a two-dimensional guided M-mode evaluation. Eligible participants were assessed at baseline and after 12 months. Changes in serum lipids, glucose and arterial blood pressure were assessed. All patients who did not change DMARD treatment during follow-up were consecutively selected for this study.ResultsWe included 107 (64 TNFi and 43 csDMARDs) RA patients. Most patients (74%) were in remission or low disease activity and had some CVD risk factors (45.8% hypertension, 59.8% dyslipidaemia, 45.3% smoking). The two groups did not differ significantly for baseline AoSI (5.95±3.73% vs 6.08±4.20%, p=0.867). Follow-up AoSI was significantly increased from baseline in the csDMARDs group (+1.00%; p<0.0001) but not in the TNFi group (+0.15%, p=0.477). Patients on TNFi had significantly lower follow-up AoSI from baseline than the csDMARDs group (−1.02%, p<0.001; ANCOVA corrected for baseline AoSI, age and systolic blood pressure). Furthermore, follow-up AoSI was significantly lower in TNFi than in csDMARDs users with an increasing number of CVD risk factors.ConclusionLong-term treatment with TNFi was associated with reduced aortic stiffness progression in patients with established RA and several CVD risk factors.

Felty syndrome: a case report

BackgroundFelty syndrome is a rare manifestation of chronic rheumatoid arthritis in which patients develop extraarticular features of hepatosplenomegaly and neutropenia. The typical presentation of Felty syndrome is in Caucasians, females, and patients with long-standing rheumatoid arthritis of 10 or more years. This case report presents a patient with an early-onset and atypical demographic for Felty syndrome.Case presentationOur patient is a 28-year-old African American woman with past medical history of rheumatoid arthritis diagnosed in 2017, asthma, pneumonia, anemia, and mild intellectual disability who was admitted to inpatient care with fever, chills, and right ear pain for 7 days. The patient’s mother, also her caregiver, brought the patient to the hospital after symptoms of fever and ear pain failed to improve. Our patient was diagnosed with sepsis secondary to pneumonia and urinary tract infection. She had been admitted twice in the past year, both times with a diagnosis of pneumonia. During this visit in September 2019, it was discovered that the patient had leukopenia and neutropenia. Bone marrow biopsy revealed increased immature mononuclear cells with left shift and rare mature neutrophils. During the hospital course, the patient was provisionally diagnosed with Felty syndrome and treated with adalimumab and hydroxychloroquine for her rheumatoid arthritis. Her sepsis secondary to pneumonia and urinary tract infection was treated with ceftriaxone and doxycycline, which was later switched to cefepime because of positive blood and urine cultures for Pseudomonas aeruginosa. She was discharged with stable vital signs and is continuing to control her rheumatoid arthritis with adalimumab.ConclusionThis case report details the clinical course of sepsis secondary to pneumonia and urinary tract infection in the setting of Felty syndrome. Our patient does not fit the conventional profile for presentation given her race, age, and the length of time following diagnosis of rheumatoid arthritis.

Oral Health in Rheumatoid Arthritis: Listening to Patients.

Rates of periodontal disease and tooth loss are increased in individuals with rheumatoid arthritis (RA). Understanding factors that contribute to the increased burden of periodontal disease in RA is critical to improving oral health and arthritis outcomes. To determine the perceptions held by people with RA relating to their oral health, to identify patient-centered priorities for oral health research, and to inform optimal strategies for delivering oral health knowledge. Semistructured interviews were conducted with patients with RA. Recorded interview transcripts were iteratively reviewed to reveal surface and latent meaning and to code for themes. Constructs were considered saturated when no new themes were identified in subsequent interviews. We report themes with representative quotes. Interviews were conducted with 11 individuals with RA (10 women [91%]; mean age, 68 y), all of whom were taking RA medication. Interviews averaged 19 min (range, 8 to 31 min) and were mostly conducted face-to-face. Three overall themes were identified: 1) knowledge about arthritis and oral health links; 2) oral health care in RA is complicated, both in personal hygiene practices and in professional oral care; and 3) poor oral health is a source of shame. Participants preferred to receive oral health education from their rheumatologists or dentists. People with RA have unique oral health perceptions and experience significant challenges with oral health care due to their arthritis. Adapting oral hygiene recommendations and professional oral care delivery to the needs of those with arthritis are patient priorities and are required to improve satisfaction regarding their oral health. Patients living with long-standing rheumatoid arthritis described poor oral health-related quality of life and multiple challenges with maintaining optimal oral health. Study findings indicate a need for educational materials addressing oral health maintenance for patients with rheumatic diseases and their providers.

Rheumatoid Vasculitis as an Initial Presentation of Rheumatoid Arthritis.

Extra-articular manifestations like rheumatoid vasculitis and pericarditis rarely present as initial manifestations of rheumatoid arthritis.A high index of suspicion is required to make the diagnosis, especially in an adult who presents with multiorgan manifestations, rash, and a high titre of rheumatoid factor and anti-CCP antibody levels.

Pulmonary abnormalities on high-resolution computed tomography in patients with long standing rheumatoid arthritis

Background. Rheumatoid arthritis (RA) is a systemic inflammatory disease, associated with a number of extra-articular organ manifestations. Pulmonary involvement is a frequent and severe extraarticular manifestations of rheumatoid arthritis. RA can affect lung parenchyma, airways and pleura. Objectives. To identify RA-related lung disease on chest computed tomography (CT). Material and methods. We performed high-resolution computed tomography (HRCT) on a total of 92 patients with longstanding RA. Results. The subjects were predominantely female (79.3%), the age at entry was 63.77 ±11.56 years, and 42.9% had a history of smoking. Disease duration was 15.00±11.55 years. Pulmonary CT abnormalities were found in 71 of the 92 patients (77.2%). The most common HRCT anomalies were: linear attenuation (reticulation) (52.11%), bronchiectasis andbronchial wall thickening (45%), nodular attenuation (39.43%) and pleural involvement (pleural effusion or thickening) (39.43%). Conclusions. We conclude that RA-related lung disease was commonly detected on chest CT imaging in longstanding RA patients.

Rheumatoid Vasculitis Following Change to Naturopathic Remedies

A 66-year old femal with longstanding seropositive rheumatoid arthritis was admitted to the internal medicine service with bilateral foot pain and new painless raised fluid filled black lesions on her feet. Two weeks prior she underwent a right great toe amputation for "gangrene" by podiatric surgery. Five months prior, the patient discontinued all disease modifying therapies to pursue naturopathic remedies. The patient was diagnosed with rheumatoid arthritis vasculitis and despite immunosupressive therapies, the patient ultimately underwent bilateral transmetatarsal amputations for progression disease progression. This case reinforces the imporance for physicians to strongly discourage only using naturopathic remedies in rheumatoid arthritis and to consider vasculitis in any patient with rheumatoid arthritis presenting with new skin lesions as late detection can have severe implications.

Aseptic meningitis in rheumatoid arthritis after anti-TNF administration: a case-based literature review

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular and extra-articular manifestations. Among extra-articular involvement, rheumatoid meningitis (RM) is a rare condition, which may exhibit variable symptoms including headache, focal and/or generalized neurologic deficits. It may develop as the preceding manifestation of RA or occur at any time of the disease course. Some drugs used for the treatment of RA may give rise to aseptic meningitis or create a tendency to infectious meningitis due to their immunosuppressive effect. All these possibilities may lead to difficulties in the differential diagnosis. Achieving a diagnosis in a short time is crucial in terms of prognosis. Here, we would like to report a case with longstanding RA manifested by left-sided weakness and seizure shortly after initiating etanercept (ETA) therapy. ETA-induced meningitis was confirmed with appropriate diagnostic tools. Our aim with this case-based review is to attract the attention of this rare condition and discuss diagnostic challenges.

Fibrocytes in early and long-standing rheumatoid arthritis: a 6-month trial with repeated synovial biopsy, imaging and lung function test

ObjectivesTo correlate the level of fibrocytes in peripheral blood, synovial tissue and in vitro culture in rheumatoid arthritis (RA) with changes in disease activity, imaging and pulmonary function.MethodsTwenty patients with...

Central sensitisation features are associated with neuropathic pain-like symptoms in patients with longstanding rheumatoid arthritis: a cross-sectional study using the central sensitisation inventory.

Several studies have indicated that arthralgia may be driven by central sensitisation. Central sensitivity syndrome (CSS) is a concept that unifies various symptoms due to central sensitisation. Recently, the central sensitisation inventory (CSI) was developed as a screening questionnaire to detect CSS. Using the CSI, we examined the prevalence, the clinical characteristics of CSS, and the association between CSS and neuropathic pain (NP)-like symptoms among rheumatoid arthritis (RA) patients. The CSI was administered to 240 RA outpatients. We evaluated their disease activity and several potentially relevant patient-reported outcomes. We compared the clinical parameters depending on the severity of CSS and examined the effect of the CSI score on NP-like symptoms among the relevant clinical parameters using multivariate analyses. The mean disease duration was 9.58 ± 7.76 years. Eighteen (7.5 %) patients had CSS, which was associated with evaluator global assessment (EGA) (odds ratio (OR) 0.860); fibromyalgia symptom scale (OR 1.46); painDETECT questionnaire score (OR 1.24); hospital anxiety and depression scale-anxiety (OR 1.35); and physical (OR 0.898), mental (OR 0.828), and role-social (OR 0.946) component summary scores on the Short-Form 36-Item Health Survey. CSI score was the factor that contributed most to NP-like symptoms (p=0.000, β=0.266). NP-like symptoms might be one of the symptoms of CSS in longstanding RA patients. In longstanding RA patients who have disproportionately greater NP-like symptoms and/or widespread pain compared with degree of inflammation, detecting CSS using CSI might help to understand the pathogenesis of patients.

Mitral valvulitis as a severe extra-articular manifestation of rheumatoid arthritis: a case report.

BackgroundExtra-articular manifestations (EAMs) are common in patients with rheumatoid arthritis (RA). Cardiac EAMs are rare but may cause complete heart block and damage to the heart valves.Case summaryWe present the case of a middle-aged woman with long-standing RA and EAMs as the most prominent symptoms. The patient experienced complete atrioventricular heart block and developed nodular vegetations affecting the mitral valve, ultimately leading to severe mitral regurgitation and valve replacement.DiscussionThe diagnosis of cardiac EAMs in RA may be challenging for the clinicians. Symptoms and findings may mimic more common conditions such as malignancy and infectious endocarditis. A multidisciplinary approach is of paramount importance in order to make an early diagnosis and to provide optimal treatment to patients with RA and cardiac complications.

Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity.

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.

Efficacy and safety of rituximab in peripheral ulcerative keratitis associated with rheumatoid arthritis

ObjectivePeripheral ulcerative keratitis (PUK) is a rare but severe ocular complication of rheumatoid arthritis (RA). It can be considered as an ocular manifestation of rheumatoid vasculitis (RV). Our case series...

The role of novel genes in rheumatoid arthritis pathogenesis

Rheumatoid arthritis (RA) is a debilitating disease characterized by chronic symmetric polyarthritis involving peripheral small joints. Heterogeneity in RA pathophysiology extends to a molecular level. Understanding the complicated interaction between genetics, environment, and autoimmunity, and their function in pathogenesis, is necessary for getting further insight into the mechanisms and outcomes that manage disease development and progression. Pharmacogenomics emphasizes the relations of numerous genetic signatures with responses to traditional disease-modifying drugs and biologics. More than 100 genetic susceptibility loci have been recognized for RA through studies directed on patients with longstanding RA compared with healthy controls. So the interaction between genes and the environment may determine who is more susceptible to develop RA. This review pays attention to some recently discovered genetic risk loci in RA; ZNF804a, CDK1, YWHAH 14-3-3 η, and IL-17A. Also, their involvement in the etiology, pathogenesis, and outcome of the disease is explained, aiming to provide new insights into the pathogenesis of RA and the possibility to develop novel therapeutic approaches through targeting these genes.

A Posteriori Dietary Patterns and Rheumatoid Arthritis Disease Activity: A Beneficial Role of Vegetable and Animal Unsaturated Fatty Acids.

To our knowledge, no studies have investigated the relationship between a posteriori dietary patterns (DPs)—representing current dietary behavior—and disease activity in patients with rheumatoid arthritis (RA). We analyzed data from a recent Italian cross-sectional study including 365 RA patients (median age: 58.46 years, 78.63% females). Prevalent DPs were identified through principal component factor analysis on 33 nutrients. RA activity was measured according to the Disease Activity Score on 28 joints (DAS28) and the Simplified Disease Activity Index (SDAI). Single DPs were related to disease activity through linear and logistic regression models, adjusted for the remaining DPs and confounders. We identified five DPs (~80% variance explained). Among them, Vegetable unsaturated fatty acids (VUFA) and Animal unsaturated fatty acids (AUFA) DPs were inversely related to DAS28 in the overall analysis, and in the more severe or long-standing RA subgroups; the highest score reductions (VUFA: 0.81, AUFA: 0.71) were reached for the long-standing RA. The SDAI was inversely related with these DPs in subgroups only. This Italian study shows that scoring high on DPs based on unsaturated fats from either source provides independent beneficial effects of clinical relevance on RA disease activity, thus strengthening evidence on the topic.

Crescent-shaped anterior lamellar keratoplasty as treatment of corneal perforation in peripheral ulcerative keratitis

Purpose: to raise awareness of potential severe ocular complications associated with autoimmune diseases and to describe the surgical technique of crescent-shaped anterior lamellar keratoplasty to treat a corneal perforation in peripheral ulcerative keratitis. Methods and Materials: Case report. Results: A female patient with 59 years old, with history of longstanding rheumatoid arthritis, presented with redness and photophobia in the right eye. As past ocular history, the patient had a severe keratoconjunctivitis sicca and a corneal ulcer in the right eye. Clinical examination revealed an epithelial defect with a significant inferior corneal thickness decrease. Topical steroids, antibiotics and a therapeutic contact lens were prescribed. One month later, a corneal perforation was observed and a crescent-shaped deep anterior lamellar keratoplasty was then performed. Conclusion: The clinical course of peripheral ulcerative keratitis depends on the associated systemic pathology, being essential a multidisciplinary approach by ophthalmologists and rheumatologists to allow systemic control of the autoimmune disease, avoiding possible complications such as eye perforation.