Radiological Progression In Rheumatoid Arthritis Research Articles

The Role of Etanercept in Controlling Clinical and Radiological Progression in Rheumatoid Arthritis: A Systematic Review.

Etanercept (ETN) is a disease-modifyinganti-rheumatic drug (DMARD) used in the treatment of rheumatoid arthritis (RA) that works as a tumor necrosis factor inhibitor (TNF inhibitor) by blocking the effects of naturally occurring TNF. This review will evaluate the effect of ETN as a monotherapy or combination therapy with methotrexate (MTX) in the treatment of RA. This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. A systematic search was done on PubMed and Google Scholar from 1999 to 2023. Predefined eligibility criteria were set for selected studies, which include: free full-text articles published; randomized control trials (RCTs); systematic reviews and meta-analyses; and observational studies in a patient with RA treated with ETN as initial therapy or as an add-on to conventional disease-modified therapy. Hence, the data had been extracted, and a quality assessment of each study was done by two individual authors. When comparing patients who received 15-25 mg of MTX with those who also received 25 mg of ETN in combination, 71% achieved American College of Rheumatology 20 (ACR20) by 24 weeks, compared to 27% in the MTX and placebo groups (p<0.001), and 39% achieved American College of Rheumatology 50 (ACR50), compared to 3% in the placebo + MTX group (p<0.001). Low disease activity (DAS 28)was more common in patients who had both MTX and ETN (64.5% with DAS <2.4 and 56.3% with DAS 28 <3.2) compared to patients who received only one medication (44.4% with DAS <2.4 and 33.2% with DAS 28 <3.2 for ETN and 38.6% with DAS <2.4 and 28.5% with DAS 28 <3.2 for MTX, with P<0.01). ETN demonstrated smaller changes from baseline in the modified Sharp score (TSS) and erosion scores (ES) at 12 months and two years, as well as a decreased change in the ES score at one year (with a trend of P value = 0.06 for the TSS score), in comparison to those receiving DMARD. Reactions at the injection site (42% vs. 7%, P<0.001) were the only events that occurred significantly more frequently in the ETN plus-MTX group. Combining ETN and MTX appears to help control RA symptoms by decreasing the American College of Rheumatology (ACR) response and DAS score, as well as halting the disease's progression on X-rays. The most common adverse effects were reactions to ETN administered alone at the injection site, likely because of patient awareness of the treatment received. There was also concern about tuberculosis and malignancy, but no recent data is available. Therefore, a larger clinical trial with longer follow-up is required to ascertain long-term safety and benefits.

Bone resorption during therapy with denosumab in patients with rheumatoid arthritis, positive for the main immunological markers

Objective. Inflammation in rheumatoid arthritis (RA) leads to the development of local and generalized bone loss. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACCP) are believed to play a negative role in the radiological progression of RA. The use of such antiresorptive therapy as denosumab – monoclonal antibodies to RANKL (receptor activator of nuclear factor kappa-B ligand), reduces the activity of osteoclasts, increases bone mineral density (BMD), and also potentially affects the erosive process at RA. The aim of the study is to evaluate the effect of denosumab therapy on BMD and erosion count in patients with RA and osteoporosis (OP) in consideration of the positivity in the RF and ACCP in serum and the baseline RA activity. Materials and methods. The 12-month prospective study of the efficacy of denosumab therapy (60 mg subcutaneously every 6 months) in patients with RA and OP included 66 postmenopausal women; age – 59.4±7.5 years, duration of RA – 17.8±10.6 years, RF-positive – 47 (72%) patients, ACCP-positive – 48 (74%) patients. At baseline and after 12 months, dual-energy X-ray absorptiometry was performed with an assessment of BMD in the lumbar spine (L1– L4), proximal femur (hip neck and total hip), distal forearm; X-ray of the hands and distal parts of the feet in direct projection, followed by assessment of erosive-destructive changes according to the Sharp/van der Heijde method. Results. A significant increase in BMD was established in all studied sites of the skeleton despite the positivity of the RF and ACCP (for the hip neck p=0.05), while a significant increase in BMD in the RF- and ACCP-negative group was detected only in L1–L4 site. The progression of the increase in erosion count was noted in the RF- and ACCP-positive group while in the RF- and ACCP-negative group this indicator did not change. Regardless of the baseline activity of RA (by DAS28 (Disease Activity Score 28)) the BMD of most parts of the skeleton were stabilized. In patients with moderate RA activity, BMD increased significantly in L1–L4 in both groups: RF- and ACCP-positive and -negative , as well as in the total hip – in RF- and ACCP-positive group. The dynamics of the erosion count in RA patients did not depend on the baseline degree of DAS28 activity, no significant changes were detected in the analyzed groups. Conclusions. RF and ACCP positivity in serum in patients with RA and OP treated with denosumab did not have a negative effect on the dynamics of BMD, while the number of erosions increased. The baseline RA activity level did not affect the dynamics of the erosion count and the dynamics of BMD in most subgroups – BMD levels have been increased or stabilized.

Predicting the effectiveness of methotrexate therapy based on basal expression of the AMP-activated protein kinase gene in the blood of patients with rheumatoid arthritis

Objective: to search for an association between basal expression of the AMP-activated protein kinase (adenosine monophosphate-activated protein kinase, AMPK) gene in the blood of patients with rheumatoid arthritis (RA) and disease activity, as well as joint destruction before and after 24 months of methotrexate (MT) therapy.Patients and methods. The study included 40 patients with RA who met the 1987 ACR classification criteria, with a disease duration of not more than 2 years, with a mean age of 47.5±15.5 years. All patients received 15 mg/week of MT. The number of swollen joints (SJC) out of 44, the number of tender joints (TSC) out of 53, the duration of morning stiffness (in minutes) and RA activity were assessed using the DAS28 index. The concentration of CRP and IgM rheumatoid factor (RF), antibodies to cyclic citrullinated peptide (ACCP) were assessed. To evaluate the radiological progression of RA, the Sharp method modified by van der Heijde was used. Gene expression in peripheral blood cells was determined by reverse transcriptase reaction and real-time polymerase chain reaction.Results and discussion. During MT therapy, there was a decrease in disease activity by DAS28 index, CRP level, duration of morning stiffness, SJC and TJC. After 2 years, there were no statistically significant changes in the number of erosions, while the number of joints with narrowing of the joint space increased by the end of the study (p=0.004). Treatment with MT resulted in a decrease in AMPK expression. At the same time, patients who achieved remission had the highest level of AMPK before therapy, as did seronegative patients compared to seropositive ones. Based on the ROC analysis, the threshold value of AMPK gene expression was determined, which makes it possible to predict a high probability of a positive effect of MT therapy.Conclusion. AMPK gene expression is associated with disease activity. Its high initial blood level in RA patients is associated with greater efficiency of MT and, possibly, plays a protective role. With an AMPK gene expression index greater than 3.83, the probability of a positive response to MT is high.

Early radiological progression remains associated with long-term joint damage in real-world rheumatoid arthritis patients treated to the target of remission

Objective To evaluate radiological damage and to explore characteristics associated with radiological progression in rheumatoid arthritis (RA) treated to the target of remission in a real-world setting. Methods Baseline to 6 year follow-up data were used from an observational early RA cohort. Radiographs of hands and feet at baseline, 6 months, and 1, 3, and 6 years were scored using the modified Sharp/van der Heijde score (SHS). The threshold for rapid radiological progression (RRP) after 6 months was based on the calculated smallest detectable change of 3.95. Negative binomial generalized linear mixed model and logistic regression analyses were performed to examine which variables were associated with RRP and 6 year radiological progression. Results Most radiological damage occurred in the first year of treatment [median 2.0 interquartile range (IQR) 1.0–4.0 SHS points] compared to the subsequent 5 years of follow-up (median 3.0 IQR 1.0–5.0 SHS points). While low disease activity was achieved within 6 months on average, 18.8% of the patients developed RRP. Anti-cyclic citrullinated peptide (anti-CCP) positivity [incidence rate ratio (IRR) 1.42, p = 0.03], baseline erosive disease (IRR 1.60, p = 0.02), and RRP (IRR 3.28, p < 0.001) were associated with 6 year radiological progression. Erosive disease was the strongest predictor of RRP (odds ratio 8.8, p < 0.001). Conclusion Long-term radiological outcome is limited in most real-world RA patients treated to the target of remission, but RRP still occurs. Anti-CCP positivity, baseline erosive disease, and RRP remain associated with long-term radiological outcome.

Matrix metalloproteinase-3 levels in relation to disease activity and radiological progression in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory and systemic disease of unknown etiology that primarily affects synovial joints and involves progressive destruction around the joints. Inflammation starting in the joint synovium causes the destruction of cartilage, bone and other adjacent tissues with pannus formation. The aim of this study was to evaluate serum matrix metalloproteinase-3 (MMP-3) levels and their clinical and radiological significance in patients with rheumatoid arthritis. The study included 59 patients with RA and 30 healthy controls. Serum MMP-3 levels were measured using the enzyme-linked immunosorbent assay (ELISA) method. Patients with a Disease Activity Score 28 (DAS28) ≤3.2 were categorized as having lower disease activity, while a DAS28 score >3.2 indicated patients with moderate/high disease activity. Additionally, the patients were divided into 2 groups in terms of disease duration: early RA (disease duration ≤2 years) and established RA (disease duration ≥2 years). Functional disability was evaluated using the Health Assessment Questionnaire (HAQ) and Nottingham Health Profile (NHP). Radiographs were scored using modified Larsen scoring. Serum MMP-3 levels in patients with RA were significantly higher than in controls (p = 0.001). Serum MMP-3 levels were correlated with laboratory and clinical parameters of disease activity, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), DAS28, and HAQ score; the exceptions were rheumatoid factor (RF) and cyclic citrullinated peptides (CCP). The serum MMP-3 levels of RA patients with moderate/high disease activity were found to be significantly higher than those of the patients with low disease activity (p < 0.001). However, MMP-3 levels were found to be similar in both established and early RA patients (p = 0.927). Additionally, the modified Larsen scores, which indicate structural damage, correlated significantly with serum MMP-3 levels (p = 0.001). These results indicate that serum MMP-3 levels may be used as an indicator for structural damage such as erosions in the early stages of the disease, and to monitor disease activity.

Systemic calprotectin and chronic inflammatory rheumatic diseases.

Calprotectin is a calcium binding protein produced by neutrophils and monocytes locally at the site of inflammation in order to trigger the innate immunity receptors. This unique characteristic makes it a good proxy for evaluation of local inflammation in chronic inflammatory rheumatic diseases. Complete data suggest, in inflammatory rheumatic diseases, a relevant role of calprotectin in the inflammatory process. The interest of serum or plasma calprotectin dosage has been studied intensively, in the current years, especially in rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis and ANCA associated vasculitis. Calprotectin seems to be a great candidate as biomarker to assess and monitor disease activity, to predict structural progression or response to the treatment. Calprotectin showed its ability to predict radiological progression in rheumatoid arthritis and ankylosing spondylitis. Serum calprotectin can predict the risk of relapse in ANCA associated vasculitis and the risk of inflammatory bowel disease in spondyloarthritis. Nevertheless, studies report controversial result requiring replication in other large cohort. The lack of assay standardization between studies is a problem to replicate and compare studies. In this review, we discuss on the interest of systemic calprotectin in chronic inflammatory rheumatic disease as a diagnostic, activity or prognostic biomarker.

Spotlight on sirukumab for the treatment of rheumatoid arthritis: the evidence to date.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease primarily affecting synovial joints and is characterized by persistent high-grade systemic inflammation. Proinflammatory cytokines, particularly interleukin-6 (IL-6), are of crucial importance in the pathogenesis of the disease, driving both joint inflammation and extra-articular comorbidities. Tocilizumab, a humanized IL-6 receptor-inhibiting monoclonal antibody, has been the first, and, to date, the only, IL-6 inhibitor approved for the treatment of RA. Many studies have demonstrated the potency and effectiveness of tocilizumab in controlling disease activity and radiological progression of RA. These successful results have encouraged the development of novel IL-6 inhibitors, among which a promising agent is sirukumab (SRK), a human anti-IL-6 monoclonal antibody currently under evaluation in Phase II/III studies in patients with RA, systemic lupus erythematosus, giant-cell arteritis, and major depressive disorder. The evidence to date indicates SRK as an effective and well-tolerated new therapeutic tool for patients with active RA, with some preliminary data suggesting a specific beneficial impact on relevant systemic complications associated with the disease, such as depression and cardiovascular disease. Conversely, although pathophysiological considerations make plausible the hypothesis that IL-6 blockade with SRK may also be beneficial in the treatment of many diseases other than RA (either autoimmune or not), available clinical data in patients with systemic lupus erythematosus do not seem to support this view, also giving rise to potentially relevant concerns about drug safety. If large Phase III clinical trials currently in progress in patients with RA confirm the efficacy and tolerability of SRK, then in the long term, this drug could, in the near future, occupy a place in the treatment of the disease, potentially also opening the doors to a more extended use of SRK in a wide range of disorders in which IL-6 plays a key pathogenic role.

PTGER4 gene variant rs76523431 is a candidate risk factor for radiological joint damage in rheumatoid arthritis patients: a genetic study of six cohorts.

IntroductionProstaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism. The aim of this study was to analyze its role in radiological joint damage in rheumatoid arthritis (RA).MethodsSix independent cohorts of patients with RA of European or North American descent were included, comprising 1789 patients with 5083 sets of X-rays. The Hospital Clínico San Carlos Rheumatoid Arthritis, Princesa Early Arthritis Register Longitudinal study, and Hospital Universitario de La Paz early arthritis (Spain) cohorts were used as discovery cohorts, and the Leiden Early Arthritis Clinic (The Netherlands), Wichita (United States), and National Databank for Rheumatic Diseases (United States and Canada) cohorts as replication cohorts. First, the PTGER4 rs6896969 single-nucleotide polymorphism (SNP) was genotyped using TaqMan assays and available Illumina Immunochip data and studied in the discovery and replication cohorts. Second, the PTGER4 gene and adjacent regions were analyzed using Immunochip genotyping data in the discovery cohorts. On the basis of pooled p values, linkage disequilibrium structure of the region, and location in regions with transcriptional properties, SNPs were selected for replication. The results from discovery, replication, and overall cohorts were pooled using inverse-variance–weighted meta-analysis. Influence of the polymorphisms on the overall radiological damage (constant effect) and on damage progression over time (time-varying effect) was analyzed.ResultsThe rs6896969 polymorphism showed a significant association with radiological damage in the constant effect pooled analysis of the discovery cohorts, although no significant association was observed in the replication cohorts or the overall pooled analysis. Regarding the analysis of the PTGER4 region, 976 variants were analyzed in the discovery cohorts. From the constant and time-varying effect analyses, 12 and 20 SNPs, respectively, were selected for replication. Only the rs76523431 variant showed a significant association with radiographic progression in the time-varying effect pooled analysis of the discovery, replication, and overall cohorts. The overall pooled effect size was 1.10 (95 % confidence interval 1.05–1.14, p = 2.10 × 10−5), meaning that radiographic yearly progression was 10 % greater for each copy of the minor allele.ConclusionsThe PTGER4 gene is a candidate risk factor for radiological progression in RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0830-z) contains supplementary material, which is available to authorized users.

Do Genetic Susceptibility Variants Associate with Disease Severity in Early Active Rheumatoid Arthritis?

Genetic variants affect both the development and severity of rheumatoid arthritis (RA). Recent studies have expanded the number of RA susceptibility variants. We tested the hypothesis that these associated with disease severity in a clinical trial cohort of patients with early, active RA. We evaluated 524 patients with RA enrolled in the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trials. We tested validated susceptibility variants - 69 single-nucleotide polymorphisms (SNP), 15 HLA-DRB1 alleles, and amino acid polymorphisms in 6 HLA molecule positions - for their associations with progression in Larsen scoring, 28-joint Disease Activity Scores, and Health Assessment Questionnaire (HAQ) scores over 2 years using linear mixed-effects and latent growth curve models. HLA variants were associated with joint destruction. The *04:01 SNP (rs660895, p = 0.0003), *04:01 allele (p = 0.0002), and HLA-DRβ1 amino acids histidine at position 13 (p = 0.0005) and valine at position 11 (p = 0.0012) significantly associated with radiological progression. This association was only significant in anticitrullinated protein antibody (ACPA)-positive patients, suggesting that while their effects were not mediated by ACPA, they only predicted joint damage in ACPA-positive RA. Non-HLA variants did not associate with radiograph damage (assessed individually and cumulatively as a weighted genetic risk score). Two SNP - rs11889341 (STAT4, p = 0.0001) and rs653178 (SH2B3-PTPN11, p = 0.0004) - associated with HAQ scores over 6-24 months. HLA susceptibility variants play an important role in determining radiological progression in early, active ACPA-positive RA. Genome-wide and HLA-wide analyses across large populations are required to better characterize the genetic architecture of radiological progression in RA.

AB0407 Dermatologic Adverse Events in A Cohort of Patients with Rheumatoid Arthritis Using Anti-TNFs in A Real-Life Setting

BackgroundBiological therapy is a major therapeutic tool to prevent clinical and radiological progression of rheumatoid arthritis (RA). On the other hand, adverse effects of these medications are a problem in...

AB1138-HPR Systemic Adverse Events in A Cohort of Patients with Rheumatoid Arthritis Using BIOLOGICS in A Real-Life Setting

BackgroundBiological therapy is a major therapeutic tool to prevent clinical and radiological progression of rheumatoid arthritis (RA). On the other hand, adverse effects of these medications are a problem in...

THU0472 Amino Acid Position 10 in the HLA-DRB1 Protein Associates with Radiological Erosions in Early Active RA

BackgroundAdvances in imputation methods have enabled association studies of HLA protein amino acid polymorphisms and rheumatoid arthritis (RA) susceptibility. A recent meta-analysis of this region has attributed most of its...

Smoking as a risk factor for the radiological severity of rheumatoid arthritis: a study on six cohorts

BackgroundSmoking is a risk factor for the development of anti -citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). Whether smoking predisposes to severe joint damage progression is not known, since...

SAT0418 Prediction of rate of adjudication of radiological progression in rheumatoid arthritis (RA) randomized controlled trials (RCTS) in early and established disease

BackgroundFor the evaluation of radiographic progression in RCTs, at least 2 readers should read all films in order to constrain measurement error. If differences in change scores between readers exceed...

AB0283 Dermatologic adverse events in a cohort of patients with rheumatoid arthritis using anti-tnf therapy in a real-life setting

BackgroundBiological therapy is a major therapeutic tool to prevent clinical and radiological progression of rheumatoid arthritis (RA). On the other hand, adverse effects of these medications are a problem in...

SAT0120 Anti TNF therapy with adalimumab restores the bone metabolism balance through a dual mechanism in rheumatoid arthritis

BackgroundLarge clinical studies have demonstrated that TNF blockade delays radiological progression in rheumatoid arthritis (RA) independent of the clinical response.ObjectivesWe aimed to investigate the mechanisms by which adalimumab, a human...

AB0152 Low avidity anti-citrullinated protein antibodies (ACPA) are associated with enhanced radiological progression in rheumatoid arthritis

ObjectivesAnti-citrullinated protein antibodies (ACPA) are specific for Rheumatoid Arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared...

Measurement error in the assessment of radiographic progression in rheumatoid arthritis (RA) clinical trials: the smallest detectable change (SDC) revisited

ObjectivesTo evaluate if the mean smallest detectable change (SDC) of multiple time intervals using the Bland & Altman (B&A) levels of agreement (LoA) method is an appropriate surrogate for the...

Rate of adjudication of radiological progression in rheumatoid arthritis randomized controlled trials depending on preset limits of agreement: a pooled analysis from 15 randomized trials

The aim of this study is to provide data on the adjudication rate for a predetermined threshold of difference in change score between two readers in randomized controlled trials (RCTs). Fifteen datasets from RCTs in RA were scored by 13 experienced readers as pairs according to the modified Sharp-van der Heijde method. The theoretical adjudication rates for thresholds of between 3 and 20 units were calculated. We investigated the influence of the number of time points within the same session, the length of the interval and disease duration on the adjudication rates. A total of 21,295 time points from 7643 patients from 15 databases were included in the analysis. The adjudication rate was inversely related to the threshold. Higher adjudication rates were observed with a higher number of time points, longer time intervals and in early versus established RA. The adjudication rates ranged from 0% to 22% depending on the scenario. With trained and experienced readers, the adjudication rate in RA RCTs is low even with very conservative adjudication thresholds.

Effect of biologic therapy on radiological progression in rheumatoid arthritis: what does it add to methotrexate?

There have been substantial advances in the treatment of rheumatoid arthritis in recent years. Traditional disease-modifying antirheumatic drugs (DMARDs) have been shown to have small effects on the progression of radiographic damage. This quantitative overview summarizes the evidence for biologic DMARDs and radiographic damage either alone or in combination with methotrexate. Two outcomes were used (standardized mean difference and odds of progression). A total of 21 trials were identified of which 18 had useable data. For biologic monotherapy, tocilizumab, adalimumab, and etanercept were significantly better than methotrexate, with tocilizumab ranking first in both outcomes while golimumab was ineffective in both outcomes. For a biologic in combination with methotrexate compared with methotrexate alone, most therapies studied (etanercept, adalimumab, infliximab, certolizumab, tocilizumab, and rituximab) were effective at slowing X-ray progression using either outcome, with infliximab ranking first in both outcomes. The exceptions to this were golimumab (no effect on standardized mean difference) and abatacept (no effect on odds of progression). This effect was additional to methotrexate; thus, the overall benefit is moderate to large in magnitude, which is clearly of major clinical significance for sufferers of rheumatoid arthritis and supports the use of biologic DMARDs in those with a poor disease prognosis.