scholarly journals Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs

2016 ◽  
Vol 76 (3) ◽  
pp. 504-510 ◽  
Author(s):  
A Strangfeld ◽  
A Richter ◽  
B Siegmund ◽  
P Herzer ◽  
K Rockwitz ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Daily Practice ◽  
Incidence Rates ◽  
Biologic Dmards ◽  
Reactive Protein ◽  
Intestinal Perforations ◽  
History Of ◽  
Synthetic Dmards ◽  
Randomised Controlled ◽  
Factor Α

ObjectiveTo investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ).MethodsIn 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure.Results37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2−0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment.ConclusionsThe incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

Genetic Variation in TNF-α, its Relation with Inflammatory Biomarkers and Susceptibility to Rheumatoid Arthritis

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Khadiga Ahmed Ismail
Keyword(s):  
Rheumatoid Arthritis ◽  
Serum Level ◽  
Functional Disability ◽  
Serum Levels ◽  
Amplification Refractory Mutation System ◽  
Reactive Protein ◽  
Tnf Α ◽  
Mutation System ◽  
Potential Factor ◽  
Factor Α

Background: Tumor necrosis Factor-α (TNF-α) is encoded and controlled by TNF-α gene, which is involved in rheumatoid arthritis (RA) susceptibility. This research aimed to identify genetic variations of TNF-α (G308A) and to establish its association with inflammatory markers in Rheumatoid Arthritis predisposition. Methods: In the present study, fifty RA patients and fifty volunteers were involved and evaluated for the C-reactive protein, rheumatoid factor, and TNF-α were estimated by ELISA, Erythrocyte Sedimentation Rate (ESR) by Wintergreen method and for TNF-α-308 G>A polymorphism by polymerase chain reaction with amplification refractory mutation system (PCR-ARMS). Results: The CRP, RF, ESR and TNF-α were significantly elevated in RA patients relative to controls. The serum level TNF-α was also significantly elevated in female patients and in patients ≥50 years. Analysis of TNF-308 gene polymorphism revealed that GG genotypes were more prevalent in RA patients than in the healthy individuals and that GG genotype may be a potential factor to RA. The G allele was more common in RA than in the control. Elevated TNF-α serum levels were significantly associated the GG genotype and functional disability in RA patients. Conclusion: TNF-α promoter 308polymorphism GG genotype may be considered as a risk factor for RA and the TNF-α serum level was significantly related to the functional disability in the disease.

scholarly journals Tofacitinib Citrate for Ulcerative Keratitis in a Patient with Rheumatoid Arthritis

2014 ◽  
Vol 2014 ◽  
pp. 1-3 ◽  
Author(s):  
Philip B. Meadow ◽  
Jacqueline Nguyen ◽  
Keerthana Kesavarapu
Keyword(s):  
Rheumatoid Arthritis ◽  
Reactive Protein ◽  
Laboratory Values ◽  
Body Sensation ◽  
History Of ◽  
Blurry Vision ◽  
Citrullinated Peptide ◽  
Preservative Free ◽  
Ulcerative Keratitis ◽  
Normal Laboratory

Purpose.To report a case of a patient with rheumatoid arthritis (RA) treated with tofacitinib citrate.Methods.Observational case report.Results.A 59-year-old patient, with a history of rheumatoid arthritis, on methotrexate 10 mg PO qwk and IV abatacept 750 mg/month, presented with photosensitivity, foreign body sensation, pain, redness, and blurry vision of her right eye (RE). Visual acuity of the RE was 20/200 and 20/20 of the left eye (LE). The slit lamp examination of the RE revealed dryness, 2+ injection of the conjunctiva, and pericentral ulceration of the cornea with 20–30% stromal thinning, pannus, and diffuse punctate epithelial erosions. The anterior chamber appeared normal. Laboratory values revealed elevated levels of rheumatoid factor, anticyclic citrullinated peptide antibodies, and C-reactive protein. The patient was switched to tofacitinib citrate 5 mg PO b.i.d, underwent corneal gluing, and was given prednisone acetate 1% gt TID, polytrim gt TID, neomycin-polymyxin-dexameth gt QD, FreshKote lubricant 1.8% gt QID, moxifloxacin 0.5% gt QID, and preservative free artificial tears Q1H. Within one week, laboratory values normalized, symptoms diminished, and the cornea reepithelialized.Conclusion.RA can present with ulcerative keratitis. Tofacitinib citrate, steroids, and corneal gluing were found to halt the progression of keratolysis and promote reepithelialization.

scholarly journals Vitamin D as a Key Player in Modulating Rheumatoid Arthritis-derived Immune Response

2020 ◽  
Vol 14 (4) ◽  
pp. 2453-2465
Author(s):  
Ramadan Yahia ◽  
Shereen M. Mohammed ◽  
Manal M. Hassanien ◽  
Shabaan H. Ahmed ◽  
Helal F. Hetta
Keyword(s):  
Rheumatoid Arthritis ◽  
Vitamin D ◽  
Serum Level ◽  
Growth Function ◽  
Enzyme Linked Immunosorbent Assay ◽  
Reactive Protein ◽  
Vitamin D Levels ◽  
Systemic Inflammatory Disease ◽  
Anti Inflammatory ◽  
Factor Α

Rheumatoid arthritis (RA) is a systemic inflammatory disease with chronic nature of joints related to autoimmunity. Vitamin D was found to modulate cell growth, function of immune cells and anti-inflammatory action. The aims of that study were to investigate serum level of vitamin D and some cytokines and to identify the correlation between vitamin D and these cytokines in RA. Totally 40 RA patients without vitamin D supplement were involved in this study. Serum level of vitamin D, interleukin-6 (IL-6), IL-10, IL-35, C-reactive protein (CRP) and tumor necrosis factor α (TNF-α), all of them were measure in all patients by enzyme-linked immunosorbent assay (ELISA). Patients were classified according to Vitamin D levels into two groups; RA patients with Vit. D deficiency (n=25) and RA patients with Vit. D sufficiency (n=15). IL-6 was lower significantly (P = 0.03) in RA patients with Vit. D sufficiency than RA patients with Vit. D deficiency. IL-10 and IL-35 were higher significantly (P = 0.0234, P = 0.0356 respectively) in RA patients with Vit. D sufficiency than RA patients with Vit. D deficiency. Vit. D was significantly positively correlated with both IL-10 (r = 0.4516, P = 0.0034) and IL-35 (r = 0.3424, P = 0.0329) and negatively correlated with IL-6 (r = -0.3188, P = 0.0479). Sufficient serum level of Vit. D is correlated with higher level of anti-inflammatory cytokines (IL-10 and IL-35) and lower level of IL-6. This support the immunomodulatory effect of Vit. D in RA.

scholarly journals Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 880 ◽  
Author(s):  
Yen-Ju Lin ◽  
Martina Anzaghe ◽  
Stefan Schülke
Keyword(s):  
Rheumatoid Arthritis ◽  
Side Effects ◽  
Bone Erosion ◽  
Treatment Options ◽  
Joint Damage ◽  
Cartilage Destruction ◽  
Biologic Dmards ◽  
Clinical Benefits ◽  
Synthetic Dmards ◽  
Inability To Work

Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally. It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion. While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease. Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage. The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules). While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs. This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs.

scholarly journals Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

2004 ◽  
Vol 200 (3) ◽  
pp. 277-285 ◽  
Author(s):  
Michael R. Ehrenstein ◽  
Jamie G. Evans ◽  
Animesh Singh ◽  
Samantha Moore ◽  
Gary Warnes ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Significant Rise ◽  
Activated T Cells ◽  
Reactive Protein ◽  
Suppressive Phenotype ◽  
Factor Α

Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.

scholarly journals Obesity reduces the real-world effectiveness of cytokine-targeted but not cell-targeted disease-modifying agents in rheumatoid arthritis

Rheumatology ◽  
2019 ◽  
Vol 59 (8) ◽  
pp. 1916-1926 ◽  
Author(s):  
Martin Schäfer ◽  
Yvette Meißner ◽  
Jörn Kekow ◽  
Sylvia Berger ◽  
Sven Remstedt ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Effectiveness ◽  
Negative Impact ◽  
Daily Practice ◽  
Observation Time ◽  
Tnf Inhibitors ◽  
Biologic Dmards ◽  
Drug Effectiveness ◽  
Disease Modifying Agents ◽  
The Impact

Abstract Objectives The effectiveness of TNF inhibitors in RA has been shown to be affected by obesity. No such effect has been found for abatacept and rituximab, while for tocilizumab results are ambiguous. Additionally, it remains unresolved whether sex is an effect modifier for obesity. We investigated the impact of obesity on the drug effectiveness of conventional synthetic or biologic DMARDs, taking into account potential sex-specific differences. Methods Data from 10 593 RA patients included in the German observational cohort study Rheumatoid Arthritis: oBservation of BIologic Therapy (RABBIT) since 2009 were analysed. Patients had to have a BMI ≥18.5 kg/m2, at least one follow-up and 6 months of observation time. The influence of obesity on drug effectiveness was investigated by regression analysis, adjusting for potential confounders. Results Obesity had a negative impact on improvement in the DAS with 28 joints using ESR as an inflammation marker of –0.15 (95% CI: –0.26; –0.04) units for women receiving conventional synthetic DMARDs, –0.22 (95% CI: –0.31; –0.12) units for women receiving TNF inhibitors, –0.22 (95% CI: –0.42; –0.03) units for women receiving tocilizumab and –0.41 (95% CI: –0.74; –0.07) units for men receiving tocilizumab. Overall, no negative obesity effects on the effectiveness of rituximab and abatacept were found. Conclusion Obesity has a negative impact on the effectiveness of cytokine-targeted but not cell-targeted therapies in daily practice, affecting more outcomes and therapies in women than in men. Overall, no effects of obesity on treatment effectiveness were found for rituximab and abatacept.

scholarly journals SAT0057 PREDICTING INADEQUATE RESPONSE TO JAK INHIBITORS BY CLUSTER ANALYSIS IN PATIENTS WITH RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 960.1-961
Author(s):  
M. Sugawara ◽  
Y. Fujieda ◽  
A. Noguchi ◽  
S. Tanimura ◽  
Y. Shimizu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cluster Analysis ◽  
Bone Erosion ◽  
Japanese Patients ◽  
User Group ◽  
Biologic Dmards ◽  
Chugai Pharmaceutical ◽  
Significant Difference ◽  
History Of ◽  
Group B

Background:Oral Janus kinase inhibitors (JAKi) have dramatically altered outcomes in patients with rheumatoid arthritis (RA). However, there remains some proportion of patients who respond to inadequately JAKi treatment (JAKi-IR) [1,2]. The characteristics in RA patients associated with JAKi-IR have not been fully demonstrated.Objectives:To clarify the characteristics of JAKi-IR in patients with RA by cluster analysis.Methods:This retrospective study comprised 120 RA patients who were treated with JAKi (Tofacitinib or Baricitinib) between July 2013 and September 2019 in five facilities. The disease status at the baseline, at 12 weeks after JAKi treatment and at the time point of withdrawing JAKi was assessed using the Disease Activity Score (DAS28) and the American College of Rheumatology (ACR) response criteria. JAKi-IR was defined as follows, primary non-response at 12 weeks after JAKi treatment: withdrawal of JAKi with ACR20 non-response or non-improvement in DAS28-CRP (ΔDAS28-CRP<1.2 from baseline), secondary non-response: withdrawal of JAKi without clinical remission after 12 weeks. Hierarchical cluster analysis was performed with the following variables: gender, age, disease duration, bone erosion, ACR functional classification (Class ≥3), comcomitant rheumatoid arthritis related interstitial lung disease (RA-ILD) or other autoimmune disease (AID), anti-citrullinated protein antibody (ACPA) positivity, rheumatoid factor (RF) at baseline, use/dose of methotrexate (MTX) and prednisolone (PSL), serum ESR/CRP, tender/swollen joint counts (TJC/SJC), visual analog scale by patients (VAS-Pt), and prior of biologic DMARDs.Results:The 120 enrolled patients were classified into 4 groups by cluster analysis(Figure1), The characteristics of each group are as follows, Group A(n=21): female + bone erosion + RF/ACPA positive + AID + MTX non-user, Group B(n=36): male + older age + RA-ILD + RF/ACPA positive + MTX non-user, Group C(n=35): RF/ACPA positive + absence of RA-ILD + MTX user, Group D (n=28): seronegative + MTX user + absence of RA-ILD + history of biologic DMARDs failure. The rate of JAKi-IR was A:9%, B:8%, C:20%, D:32%, and the significant difference between Group B and D was identified (p=0.02). In multiple comparison of 4 groups, no significant difference was identified (p=0.06) (Figure2).Conclusion:JAKi-IR would be more likely to be seronegative, MTX use, absence of RA-ILD and history of biologic DMARDs failure. Cluster analysis is an exploratory tool that aids in the analysis of huge amount of data.References:[1] Takeuchi T, Yamanaka H, Yamaoka K, Arai S, Toyoizumi S, DeMasi R, et al. Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data. Mod Rheumatol. 2019;29(5):756-66.[2] Tanaka Y, Atsumi T, Amano K, Harigai M, Ishii T, Kawaguchi O, et al. Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgroup analyses of four multinational phase 3 randomized trials. Mod Rheumatol. 2018;28(4):583-91.Disclosure of Interests:Masanari Sugawara: None declared, Yuichiro Fujieda: None declared, Atsushi Noguchi: None declared, Shun Tanimura: None declared, Yuka Shimizu: None declared, Ikuma Nakagawa: None declared, Michihito Kono: None declared, Masaru Kato: None declared, Kenji Oku: None declared, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc.

Circulating Dickkopf-1 Is Correlated with Bone Erosion and Inflammation in Rheumatoid Arthritis

2011 ◽  
Vol 38 (5) ◽  
pp. 821-827 ◽  
Author(s):  
SHI-YAO WANG ◽  
YAN-YING LIU ◽  
HUA YE ◽  
JIAN-PING GUO ◽  
RU LI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatic Diseases ◽  
Bone Erosion ◽  
Interleukin 1 ◽  
Healthy Controls ◽  
Serum Samples ◽  
Reactive Protein ◽  
Tnf Α ◽  
Factor Α ◽  
Dickkopf 1

Objective.To explore the potential role of Dickkopf-1 (DKK-1) in rheumatoid arthritis (RA) and to evaluate the effect of a tumor necrosis factor-α (TNF-α) inhibitor (infliximab) and an interleukin 1 receptor antagonist (IL-1Ra; anakinra) on DKK-1 secretion in patients with RA.Methods.Serum samples were collected from 100 patients with RA, 100 patients with other rheumatic diseases (e.g., osteoarthritis and ankylosing spondylitis), and 40 healthy controls. DKK-1 and osteoprotegerin (OPG) levels in serum were detected by ELISA. Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), rheumatoid factor (RF) titers, and anti-cyclic citrullinated peptide antibody were also measured in patients with RA.Results.The serum level of DKK-1 was significantly higher in patients with RA than in healthy controls and those with other rheumatic diseases (p < 0.01); the serum DKK-1 level was correlated with levels of CRP (r = 0.488, p = 0.003) and ESR (r = 0.458, p = 2.4 x 10−4) and the Sharp score of radiologic change (r = 0.449, p = 0.001) in RA. In contrast to the increasing level of OPG, DKK-1 was significantly decreased in RA patients treated with TNF-α inhibitor (p < 0.01). DKK-1 was significantly decreased in RA patients treated with IL-1Ra (p < 0.01).Conclusion.DKK-1, as an important mediator, was correlated with bone erosion and inflammation in RA. The change of DKK-1 level may serve as a biomarker of disease activity and bone erosion.

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