Radiological Joint Destruction Research Articles

Treatment strategies for elderly-onset rheumatoid arthritis in the new era.

Elderly-onset rheumatoid arthritis (EORA) is characterized by acute onset and clinical features of high disease activity. Anti-cyclic citrullinated peptide antibody (ACPA) positivity or the presence of bone erosions predicts a radiological joint destruction of EORA, but ACPA-negative EORA with a polymyalgia rheumatica (PMR) phenotype may also present. Biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors were beneficial both in older and in younger patients in terms of risk-benefit balance. Implementation of a treat-to-target strategy could improve EORA outcomes, but older patients have more age-related comorbidities and interstitial lung disease than younger patients. Baseline comorbidities, more frequent methotrexate dose-dependent adverse events, serious infections, cardiovascular disease events, and malignancy all influence the choice of treatment and the treatment goals for older patients. Based on articles reviewed here, it is suggested that current treatment strategies for younger patients are also useful for ACPA-positive EORA and for ACPA-negative EORA with bone erosion. Differential diagnosis of ACPA-negative EORA without erosive arthritis and PMR with peripheral manifestations is challenging, and the treatment strategy of patients presenting with this overlap phenotype remained unclear. An appropriate treatment strategy for all patients with EORA still needs to be developed.

Прогнозування віддалених наслідків ювенільного ідіопатичного артриту

Актуальність. Ювенільний ідіопатичний артрит (ЮІА) характеризується хронічним запаленням суглобів із прогресуючим перебігом і вираженою тенденцією до ранньої інвалідизації. Тривале спостереження за хворою на ЮІА дитиною дозволяє простежити еволюцію хвороби та оцінити вплив варіанта початку, віку, статі, ступеня активності та інших факторів на перебіг патологічного процесу, що сприятиме прогнозуванню більш чіткого формування несприятливих наслідків хвороби та правильному лікуванню. Метою роботи є удосконалення критеріїв прогнозування суглобової форми ювенільного ідіопатичного артриту (ЮІА) шляхом ретроспективного порівняльного аналізу хворих із тривалістю хвороби 1 рік та 5–7–10 років. Матеріали та методи. Обстежено 47 дітей віком від 2 до 18 років із суглобовою формою ЮІА. Під час уточнення нозологічної форми суглобової патології використовувались клінічні, загальноприйняті лабораторні та інструментальні дослідження. Для розробки прогностичних критеріїв застосовано регресійний аналіз із визначенням інформативності ознак та прогностичних коефіцієнтів для кожної з них. Результати. Установлено, що для прогнозування подальшої 5–7-річної еволюції ЮІА важливе значення мають такі ознаки: стать пацієнтів, наявність ураження дрібних суглобів кистей, наявність ревматоїдного фактора, для 10-річної та довготривалої (понад 10 років) еволюції — наявність уражень очей, кількість як загального числа уражених суглобів, так і числа активних із них. Зростає значущість у прогностичній моделі наявності ревматоїдного фактора, показника тривалості ранкової скутості, рентгенологічної стадії хвороби, лабораторних показників — рівня швидкості осідання еритроцитів, С-реактивного білка. Також для 10-річного прогнозу більше значення має ефективність метотрексату на першому етапі його застосування. Подані моделі визначають варіанти багаторічного перебігу ЮІА: ремісія (до 2 балів), стабілізація патологічного процесу (від 2 до 3 балів) — як сприятливі, а повторні загострення патологічного процесу без прогресування деструктивних змін у суглобах (від 3 до 4 балів), прогресування хвороби із збільшенням рентгенологічних змін у суглобах, що характеризують їх деструкцію (понад 4 бали), — як несприятливі. Висновки. Подані способи прогнозу перебігу ЮІА слід використовувати в перші роки розвитку захворювання, що дозволить вже на цьому етапі еволюції процесу визначити реальну можливість формування несприятливих наслідків та в правильному режимі скоригувати лікування.

Activation of TGR5 alleviates inflammation in rheumatoid arthritis peripheral blood mononuclear cells and in mice with collagen II‑induced arthritis.

Rheumatoid arthritis (RA) is characterized by chronic inflammatory synovitis resulting in progressive joint destruction. Persistent synovial inflammation is induced by activation of various inflammatory cells. G-protein-coupled bile acid receptor 1 (TGR5) is a G-protein-coupled receptor activated by various bile acids, which has been reported to act as a key adaptor in regulating various signaling pathways involved in inflammatory responses and a diverse array of physiological processes, including bile acid synthesis, lipid and carbohydrate metabolism, carcinogenesis, immunity and inflammation. In the present study, TGR5 expression was detected in RA peripheral blood mononuclear cells (PBMCs), and its association with clinical disease activity, histological synovitis severity and radiological joint destruction was analyzed. Subsequently, the role and potential underlying mechanisms of TGR5 in the PBMCs of patients with RA and mice with collagen II-induced arthritis (CIA) were investigated. PBMCs were obtained from 50 patients with RA and 40 healthy controls (HCs). The mRNA and protein expression levels of TGR5 were detected in PBMCs via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence staining, respectively. Additionally, the levels of proinflammatory cytokines were analyzed by RT-qPCR and enzyme-linked immunosorbent assay (ELISA). The activation of nuclear factor-κB (NF-κB) and IκB kinase a was determined via western blot analysis. The anti-arthritic and anti-inflammatory effects of LCA on mice with CIA were then investigated. The arthritis score was assessed, and the protein levels of proinflammatory cytokines in the plasma of mice were detected via ELISA. TGR5 mRNA expression was significantly downregulated in the PBMCs of patients with RA compared with in those of the HCs (0.53±0.58 for patients vs. 1.49±0.83 for HCs; P<0.001); similar findings were observed at the protein level. The mRNA expression levels of TGR5 in the PBMCs of patients with RA with a high 28-Joint Disease Activity Score (DAS28) were significantly decreased compared with in patients with a low DAS28 (0.81±0.65 for low score vs. 0.35±0.46 for high score; P=0.002). Furthermore, TGR5 expression was significantly correlated with the levels of C-reactive protein (r=−0.429; P=0.002) and the DAS28 (r=−0.383; P=0.006). RT-qPCR and ELISA analyses indicated that lithocholic acid (LCA, 10 mg/kg/day) attenuated lipopolysaccharide-induced proinflammatory cytokine production via inhibition of NF-κB activity in the PBMCs of patients with RA. In addition, the arthritis score was significantly decreased in LCA-treated CIA mice compared with in non-treated CIA mice. The increased production of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-8 was significantly reduced in the plasma of LCA-treated CIA mice compared with the control. In conclusion, TGR5 may contribute to the inflammation of PBMCs in patients with RA and mice with CIA.

The association between serious infection and disease outcome in patients with rheumatoid arthritis.

The purpose of this study was to study the association between the past history of serious infection (SI) that required hospitalization and the current disease status of rheumatoid arthritis (RA), including disease activity, physical disability, and radiological joint destruction. The history of hospitalized infection was retrospectively analyzed in a cohort of 370 RA patients. The patients were divided into three groups based on the number of SI events (SI = 0, SI = 1, SI ≥ 2). Disease activity score using 28 joints (DAS28), Health Assessment Questionnaire (HAQ), and modified total sharp score (mTSS) adjusted after disease duration or other confounding factors were compared among the three groups. Among the study patients, 7.3% (27 patients) experienced single SI (SI = 1) and 2.1% (8 patients) experienced multiple SI events (SI ≥ 2). Compared with patients with no SI (SI = 0), patients with SI (SI = 1 or SI ≥ 2) had increased pulmonary and autoimmune comorbidities and were more frequently treated with glucocorticoids. DAS28 was not different among the groups, while HAQ and mTSS increased with the number of SI. After adjustment, only mTSS adjusted after disease duration remained statistically significantly different between patients with SI = 0 and SI ≥ 2 (p = 0.030). Multiple SI events are associated with advanced physical disability and radiological joint destruction in patients with RA.

AB0087 Tissue localisation of acid sensing proteins in synovial biopsies from patients with rheumatoid arthritis

BackgroundIn rheumatoid arthritis (RA), the hypoxic environment of the synovium leads to the generation of lactic acid as synoviocytes switch glucose metabolism from an aerobic pyruvate pathway towards an anaerobic...

Extracellular Acidosis Is a Novel Danger Signal Alerting Innate Immunity via the NLRP3 Inflammasome

Local acidosis has been demonstrated in ischemic tissues and at inflammatory sites. Acidic extracellular pH triggers NLRP3 inflammasome activation and interleukin-1β secretion in human macrophages. Acidic pH represents a novel danger signal alerting the innate immunity. Local acidosis may promote inflammation at ischemic and inflammatory sites. Local extracellular acidification has been demonstrated at sites of ischemia and inflammation. IL-1β is one of the key proinflammatory cytokines, and thus, its synthesis and secretion are tightly regulated. The NLRP3 (nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3) inflammasome complex, assembled in response to microbial components or endogenous danger signals, triggers caspase-1-mediated maturation and secretion of IL-1β. In this study, we explored whether acidic environment is sensed by immune cells as an inflammasome-activating danger signal. Human macrophages were exposed to custom cell culture media at pH 7.5-6.0. Acidic medium triggered pH-dependent secretion of IL-1β and activation of caspase-1 via a mechanism involving potassium efflux from the cells. Acidic extracellular pH caused rapid intracellular acidification, and the IL-1β-inducing effect of acidic medium could be mimicked by acidifying the cytosol with bafilomycin A1, a proton pump inhibitor. Knocking down the mRNA expression of NLRP3 receptor abolished IL-1β secretion at acidic pH. Remarkably, alkaline extracellular pH strongly inhibited the IL-1β response to several known NLRP3 activators, demonstrating bipartite regulatory potential of pH on the activity of this inflammasome. The data suggest that acidic environment represents a novel endogenous danger signal alerting the innate immunity. Low pH may thus contribute to inflammation in acidosis-associated pathologies such as atherosclerosis and post-ischemic inflammatory responses.

Anticitrullinated Protein Antibodies and Radiological Progression in Juvenile Idiopathic Arthritis

The aim of the study was to investigate whether determination of anticitrullinated protein antibodies (ACPA) provides predictive information on severity of disease course and joint destruction in children with juvenile idiopathic arthritis (JIA). Sera from 74 children with JIA were examined for ACPA using the ELISA test. To assess joint destruction, plain radiographs of both hands were scored twice according to the Steinbrocker scale: at the beginning of observation and after 8.9 to 15.2 months (median 11.5 months) of the followup. Correlations between ACPA serum levels and the disease characteristics (type of JIA onset, disease activity, disease duration, radiological status) were investigated. Twenty-six out of 74 examined children with JIA (35.0%) were ACPA-positive [> 5 relative units (RU)/ml]. ACPA were present in all types of JIA onset, including 36.6% of children with early stage JIA (disease duration < 6 months). All of the IgM-rheumatoid factor (RF)-positive children with polyarticular type of JIA onset were simultaneously positive for ACPA. ACPA levels correlated positively with disease activity at the beginning of the study (rho = 0.7196; p < 0.0001) and after followup (rho = 0.2485; p = 0.0486). Disease duration did not significantly affect ACPA serum levels. ACPA levels correlated positively with radiological joint destruction in children with JIA, both at the beginning of the study (rho = 0.4599; p = 0.0004) and after the followup period (rho = 0.5523; p < 0.0001). ACPA were superior to IgM-RF in diagnosing JIA and provided predictive information on severity of disease course and radiological outcome.

Upregulation of tumor necrosis factor receptor-associated factor 6 correlated with synovitis severity in rheumatoid arthritis

IntroductionRheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Focal bone erosion is due to excess bone resorption of osteoclasts. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is one of the critical mediators both in inflammatory signal pathway and differentiation and resorption activity of osteoclasts. Here we aimed to investigate TRAF6 expression in RA synovium and its correlation with histological synovitis severity and radiological joint destruction in RA.MethodsSynovitis score was determined in needle biopsied synovium from 44 patients with active RA. Synovium from nine patients with osteoarthritis (OA) and seven with orthopedic arthropathies (Orth.A) were enrolled as "less inflamed" disease controls. Serial sections were stained immunohistochemically for TRAF6 as well as CD68 (macrophage), CD3 (T cell), CD20 (B cell), CD38 (plasmocyte), CD79a (B lineage cells from pre-B cell to plasmocyte stage), and CD34 (endothelial cell). Double immunofluorescence staining of TRAF6 and CD68 were tested. Densities of positive staining cells were determined and correlated with histological disease activity (synovitis score) and radiographic joint destruction (Sharp score).ResultsTRAF6 expression was found in the intimal and subintimal area of RA synovium, with intense staining found in the endochylema and nucleus of intimal synoviocytes and subintimal inflammatory cells. Double immunofluorescence staining showed TRAF6 was expressed in most of the intimal cells and obviously expressed in CD68+ cells and some other CD68- cells in subintimal area. Synovial TRAF6 was significantly over-expressed in the RA group compared with the OA and Orth.A group (2.53 ± 0.94 vs. 0.72 ± 0.44 and 0.71 ± 0.49, P < 0.0001). Synovial TRAF6 expression in RA correlated significantly with synovitis score (r = 0.412, P = 0.006), as well as the inflammatory cell infiltration (r = 0.367, P = 0.014). Significant correlation was detected between synovial TRAF6 expression and intimal CD68+ cells, as well as the cell density of subintimal CD68+ cells, CD3+ cells, CD20+ cells, CD38+ cells, and CD79a+ cells (all P < 0.05).ConclusionsElevated synovial TRAF6 expression correlated with synovitis severity and CD68+ cell density in RA. It is, therefore, hypothesized that synovial TRAF6 is involved in the pathogenesis of synovial inflammation and osteoclast differentiation in RA.

Predicting arthritis outcomes--what can be learned from the Leiden Early Arthritis Clinic?

In order to allow personalized medicine, adequate prediction of disease outcome is required. In early undifferentiated arthritis (UA), prediction of the development of RA is crucial, and in case of RA predicting the severity of the disease course may guide individualized treatment decisions. A total of 570 UA patients and 676 RA patients included in the Leiden Early Arthritis Clinic cohort were studied for baseline characteristics. The disease outcomes studied were fulfillment of the 1987 ACR-RA criteria and arthritis persistence in UA patients and the rate of radiological joint destruction and achieving sustained DMARD-free remission in RA patients. Predictive factors for fulfillment of the 1987 ACR-RA criteria and for persistent arthritis in UA were largely similar. Risk factors for a severe rate of joint destruction were: older age (P<0.001); male gender (P<0.001); longer symptom duration at first visit (P=0.048), involvement of lower extremities (P<0.001); BMI (P<0.001); high acute phase reactants, presence of IgM-RF (P<0.001); anti-CCP2 antibodies (P<0.001); anti-modified citrullinated vimentin antibodies (P<0.001) and HLA-DRB1 shared epitope alleles (P=0.001). A high BMI was associated with a lower rate of joint destruction but with a higher risk of disease persistence. The proportion of variance in joint destruction explained was 32% Predictors for RA development, previously used to develop a prediction rule in UA patients, are largely similar to predictors for arthritis persistency. Only part of the joint destruction level in RA is explained by the currently known risk factors. New factors need to be identified in order to guide pharmaceutical intervention at the level of individual RA patients.

How to avoid phenotypic misclassification in using joint destruction as an outcome measure for rheumatoid arthritis?

Joint destruction is a measure for RA severity that is accurate, sensitive and reflective of the cumulative disease burden. Risk factors for this outcome measure may be used to arrive at individualized treatment strategies. Currently, relatively few risk factors for joint destruction are known. New risk factors, genetic risk factors in particular, may have relatively small effects on the rate of joint destruction. A sensitive determination of joint damage is then crucial in order to identify these risk factors and will reduce the risk on type 2 errors. The present article addresses the question how the rate of joint destruction is ideally measured. Different methods are discussed and suggestions for corrections of factors that affect the natural course of joint destruction, such as applied treatment strategies, are made. It is concluded that a precise estimation of the rate of radiological joint destruction is obtained by using quantitative and validated scoring methods as well as repetitive measurements over time in order to reduce within patient variation.

A high body mass index has a protective effect on the amount of joint destruction in small joints in early rheumatoid arthritis

Background:Obesity is a state of chronic low-grade inflammation that predisposes people to several diseases and that is increasingly prevalent. Rheumatoid arthritis (RA) is marked by the presence of proinflammatory cytokines...

Rheumatoid nodulosis. Two cases with destructive polyarthritis after 20 years

The term “rheumatoid nodulosis” was coined by Ginsberg in 1975 to designate a rare and distinctive form of rheumatoid disease. Anecdotal case reports suggest a benign nondestructive course, although prolonged follow-up data are usually unavailable. We describe two cases of typical rheumatoid nodulosis with follow-ups exceeding 25 years. Onset occurred at 14 and 22 years of age, respectively. Both patients presented with palindromic rheumatism, positive tests for rheumatoid factors, negative tests for other biological markers, and normal radiographs. Multiple subcutaneous nodules developed after 4 and 6 years with palindromic flares, respectively. Functional impairments and disfigurement required several surgical procedures to remove nodules. Histology was typical for rheumatoid nodules. Neither patient responded to disease-modifying anti-rheumatic drugs (gold, antimalarials, and d-penicillamine). Treatment consisted of nonsteroidal anti-inflammatory drugs combined with prednisone as needed. After 20 and 22 years of follow-up, respectively, both patients had typical rheumatoid arthritis with deformities and radiological joint destruction. In conclusion, these two cases establish that rheumatoid nodulosis can occur as a presentation of rheumatoid arthritis with a potential for severe joint damage after many years.

Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis.

Delay of disease-modifying anti-rheumatic drug (DMARD) therapy is a major contributing factor for poor outcome in rheumatoid arthritis (RA). Although early therapy has been shown to be particularly effective, there is still uncertainty about the optimal time point of DMARD introduction. We wanted to test if a therapeutic window of opportunity may exist within the first few months of the disease. In this case-control parallel-group study, 20 very early RA (VERA) patients with median disease duration of 3 months were age and gender matched to a group of 20 late early RA (LERA) patients with median disease duration of 12 months until first DMARD initiation. Follow-up time was 36 months. Primary outcome measures were the disease activity score (DAS28) and radiological joint destruction using the Larsen method. Already after 3 months of DMARD therapy we found a significant difference of improvement in favour of the VERA patients in the DAS28. This trend continued over the study period. At study end the DAS28 showed an improvement of 2.8+/-1.5 in the VERA vs 1.7+/-1.2 in the LERA group (P(c)<0.05). The Larsen scores showed a statistically significant retardation of progression in the VERA compared with the LERA. Our results indicate that there is a window of opportunity for highly successful treatment of RA in the first year, and especially within the first 3 months of therapy. Thus, early diagnosis and therapy may be the crucial step in achieving optimal control of disease progression and prognosis in RA.

Retain or sacrifice the posterior cruciate ligament in total knee arthroplasty? A histopathological study of the cruciate ligament in osteoarthritic and rheumatoid disease

Background—The decision whether to retain or resect the posterior cruciate ligament in total knee arthroplasty is at present determined clinically by preoperative radiological variables focusing upon the amount of joint...

Single- versus dual-energy quantitative computed tomography for spinal densitometry in patients with rheumatoid arthritis

Lumbar bone mineral density was measured by both single- and dual-energy quantitative computed tomography in 109 patients with rheumatoid arthritis. The results were corrected for the age-related increase in vertebral fat content by converting them to percentages of expected densities, using sex and energy-level specific regression equations obtained in a normal reference population. The percentages of expected density are approximately 10% lower in the single- than in the dual-energy mode, both in the patients with and without prednisone therapy. This difference is statistically highly significant, and is positively correlated with the duration of the disease and with the degree of radiological joint destruction. The data suggest that the vertebral fat content may be increased in patients with rheumatoid arthritis, as a consequence of disease-dependent mechanisms.