Effects Of Antirheumatic Drugs Research Articles

Effect of Anti-Rheumatic Drugs on Cardiovascular Disease Events in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, which can involve multiple systems. Patients with RA may have a variety of comorbidities, including cardiovascular disease (CVD), lung cancer, lymphoma, infection, osteoporosis, fatigue, depression, colon cancer, breast cancer, prostate cancer, and Alzheimer's disease. Among these comorbidities, the incidence of CVD, lung cancer, lymphoma, infection, and osteoporosis is higher. CVD is a serious complication of RA. The risk of CVD and associated mortality rate in patients with RA is high, and the treatment rate is low. In addition to traditional risk factors, such as age, sex, blood pressure, and diabetes, RA is also associated with inflammation. Furthermore, therapeutic drugs for RA, including non-steroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying anti-rheumatic drugs, have beneficial or harmful effects on cardiovascular events in patients with RA. This article discusses the effects of therapeutic drugs for RA on cardiovascular events.

Hyperuricemia in Psoriatic Arthritis: Epidemiology, Pathophysiology, and Clinical Implications.

Psoriatic arthritis (PsA) represents the articular component of the systemic psoriatic disease and the extra-cutaneous disorder most frequently found in patients with psoriasis. Besides the articular involvement, PsA is associated with several metabolic abnormalities such as insulin resistance, hypertension, diabetes and hyperuricemia. Uric acid is the final product of purine metabolism and the etiological substrate of gout. Accumulating evidence highlights the emerging role of hyperuricemia as a major cardiovascular risk factor. Moreover, different studies evaluated the interplay between hyperuricemia and psoriatic disease, suggesting that individuals affected by psoriasis or PsA might present higher serum levels of uric acid and that hyperuricemia might affect severity of clinical manifestations and degree of inflammation in PsA patients. In this review, we focus on the bidirectional relationship between uric acid and PsA, analyzing how uric acid may be involved in the pathogenesis of psoriasis/PsA and how clinical manifestations of PsA and inflammatory mediators are affected by uric acid concentrations. Finally, the effects of anti-rheumatic drugs on uric acid levels and the potential benefit of urate-lowering therapies on psoriasis and PsA were summarized.

Periodontal Condition in Patients with Rheumatoid Arthritis: Effect of Anti-rheumatic Drugs.

Statement of the Problem: Rheumatoid arthritis and periodontitis are chronic inflammatory diseases with a possible bidirectional relationship. This link may be affected by many factors like drug consumption. Purpose: This study was designed to evaluate the periodontal condition in patients with rheumatoid arthritis, considering the effect of disease modifying anti-rheumatic drugs. Materials and Method: This case-control study included 25 newly diagnosed rheumatoid arthritis patients with negative history of taking anti-rheumatic drugs, 25 patients who received anti-rheumatic drugs for more than three years and 50 healthy individuals as a control group. Periodontal indices, including plaque index, gingival index, probing depth, clinical attachment loss, and rheumatologic indices were recorded and compared between these groups. Results:Rheumatoid arthritis patients were significantly more affected by periodontitis compared with healthy subjects (p= 0.006). There was no significant difference in rheumatologic indices between patients with and without periodontitis. Clinical attachment loss in old rheumatoid arthritis patients and gingival index in newly diagnosed ones were significantly more compared to the control group (p= 0.003 and p< 0.001 respectively). We could not find a linear relationship between the severity of rheumatoid arthritis and chronic periodontitis (p= 0.1, r= -0.224). Conclusion:Periodontitis and clinical attachment loss were more in patients with rheumatoid arthritis than the healthy group, especially in drug consumers. Gingival index in patients without the history of consuming anti-rheumatic drugs was significantly higher than those who were drug consumers, indicating the effect of the medications on the signs of inflammation.

I082 To stop or not to stop? The effect of anti-rheumatic drugs in pregnancy

I082 To stop or not to stop? The effect of anti-rheumatic drugs in pregnancy

Vascular brain-derived neurotrophic factor pathway in rats with adjuvant-induced arthritis: Effect of anti-rheumatic drugs

Background and aimsIn rheumatoid arthritis, the control of both disease activity and standard cardiovascular (CV) risk factors is expected to attenuate the increased CV risk. Evidence that brain-derived neurotrophic factor (BDNF) plays a role in vascular biology led us to investigate the vascular BDNF pathway in arthritis rats as well as the interaction between endothelial nitric oxide (NO) and BDNF production. MethodsThe aortic BDNF pathway was studied in rats with adjuvant-induced arthritis, (AIA) using Western blot and immunohistochemical analysis. Control of arthritis score was achieved by administration (for 3 weeks) of an equipotent dosage of etanercept, prednisolone, methotrexate, celecoxib or diclofenac. Aortas were exposed to an NO donor or an NO synthase inhibitor and vasoreactivity experiments were performed using LM22A-4 as a TrkB agonist. ResultsVascular BDNF and full length tropomyosin-related kinase B receptor (TrkB-FL) were higher in AIA than in control rats. These changes coincided with decreased endothelial immunoreactivity in BDNF and pTrkBtyr816 and were disconnected from arthritis score. Among anti-rheumatic drugs, only prednisolone and methotrexate prevented AIA-induced vascular BDNF loss. The effect of AIA on aortic BDNF levels was reversed by an NO donor and reproduced by an NOS inhibitor. Finally, LM22A-4 induced both NO-dependent vasodilation and phosphorylation of endothelial NO synthase at serine 1177. ConclusionsOur study identified changes in the BDNF/TrkB pathway as a disease activity-independent component of AIA-associated changes in endothelial phenotype. It provides new perspectives in the understanding and management of the high CV risk reported in rheumatoid arthritis.

Platelets in Rheumatic Diseases: Friend or Foe?

Platelets are intimately involved in hemostasis, inflammation, innate and adaptive immunity, tissue regeneration and other physiological and pathological processes. Their granular structure is programmed to release a wide range of bioactive substances in response to agonists. Upon activation, platelet membranes display thrombotic and inflammatory agents, which may take an active part in the pathophysiology of autoimmune and autoinflammatory disorders. The aim of this review is to analyze current evidence of platelet (dys)function in inflammatory rheumatic diseases and overview platelettargeting mechanisms of antirheumatic drug therapies. A comprehensive search through Medline/PubMed, SciVerse/Scopus and Web of Science was performed for English-language original research papers, using the keywords related to platelets in autoimmune and autoinflammatory rheumatic disorders. Additionally, the Cochrane Collaboration database was searched for the literature on the effects of antirheumatic drugs on platelet function. A variety of platelet markers have been tested in systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, spondyloarthropathies, vasculitides, and some autoinflammatory disorders. It has been shown that platelets circulate in an activated state in most of these disorders and tend to form complexes with other inflammatory and immune cells. Thrombotic and inflammatory agents, released from platelets, may trigger disease-specific complications (e.g., extraarticular features, fibrosis in systemic sclerosis) and propagate endothelial dysfunction. Whether platelet activation is a primary or secondary feature in rheumatic disorders remains to be elucidated. Some widely used antirheumatic drugs may suppress thrombopoiesis and platelet activity, however the clinical implications of this effect have yet to be examined in specifically designed prospective studies. Large retrospective cohort studies supported the use of low-dose aspirin for suppressing platelet function and preventing cerebrovascular events in giant-cell arteritis. However, emerging data suggest that the release rate of activated platelets applied topically to the inflamed cartilage in arthritis or skin ulcers in scleroderma may suppress the inflammation and facilitate tissue repair. Taken together, current evidence necessitates a balanced approach to platelet-activating and suppressing drug therapies in inflammatory rheumatic diseases.

Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: Risk reduction in a chronic inflammatory disease

To perform a systematic literature review of the potential association among molecular markers of inflammation, alterations in body composition, and insulin resistance (IR), a precursor to type 2 diabetes mellitus (DM), in rheumatoid arthritis (RA) patients. To determine the impact of tumor necrosis factor α (TNFα) as a pivotal proinflammatory cytokine in the pathophysiology of type 2 DM and RA, and the effect of antirheumatic drugs on glycemic control. We performed a search of PubMed to identify articles on IR and body habitus in patients with RA. Patients with RA had characteristics placing them at high risk for IR and type 2 DM. The incidence and prevalence of type 2 DM in RA was not clearly increased compared with the general population; however, studies suggested that patients with RA are likely to have IR and have increased risk of cardiovascular disease (CVD). The prevalence of type 2 DM and IR could be estimated from reports of risk factors for CVD in RA patients. The TNFα antagonists provided rapid and effective control of RA-related inflammation. Evidence indicated that extended use of TNFα antagonists in RA may provide the additional benefit of improving insulin sensitivity. These treatment-related changes may contribute to an overall reduction in the risk of type 2 DM and CVD in RA patients. Controlling inflammation may improve insulin sensitivity and subsequently reduce the risk of developing type 2 DM in RA patients. This may also reduce the risk of CVD in this high-risk group. Future studies are required to elucidate the relationships between inflammation, body composition, IR, TNFα antagonist use, and the risk of developing type 2 DM in RA patients.

Treatment of experimental amyloidosis with antirheumatic drugs

Background. Because at present there is no known specific effective therapy for secondary amyloidosis, the aim of this study was to determine whether antirheumatic drugs inhibit the development of experimental AA amyloidosis induced in C57BL/6 mice by casein and fibrin injections. Materials and methods. Monotherapy with sulfasalazine (SSL) and diclofenac (D) and a combined treatment with diclofenac and prednisolone (D/P) according to prophylactic and therapeutic treatment protocols were investigated. The drugs were administered through intragastric gavage 5 times a week for 5 or 4 weeks in the following doses: D – 1 mg/kg, P – 10 mg/kg, and SSL – 100 mg/kg. A histopathological examination of splenic, kidney and hepatic tissues of mice was performed. The amount of amyloid was assessed semi-quantitatively by polarizing microscopy after Congo red staining. Results. Our study indicated that no positive effect of the prophylactic treatment with D could be seen on amyloid deposition in the target organs. Prophylactic combined treatment with D/P resulted in a significant improvement of disease symptoms and markedly reduced amyloid deposits in the spleen, kidneys and liver (p &lt; 0.02–0.001). SSL therapy alone was more successful in the prophylactic treatment of experimental amyloidosis: the decrease of amyloid deposits was statistically significant in all examined organs (p &lt; 0.04–0.001), and the suppression of amyloid formation was most significant in the kidneys and liver (p &lt; 0.004–0.001). In the therapeutic treatment of experimental amyloidosis, combined treatment with D/P showed the most pronounced inhibition of amyloid formation in the internal organs (p &lt; 0.006–0.001). The suppression (by 86.7%; p &lt; 0.001) of amyloid deposits was most notable in the liver. Treatment of mice with D alone produced a significant reduction in amyloid deposition only in the liver (p &lt; 0.03) and with SSL only in the spleen (p &lt; 0.03). Conclusions. These findings suggest that D/P and SSL at relevant doses suppress amyloidogenesis, and this suppression is possibly related to the anti-inflammatory effect of antirheumatic drugs. Although these drugs cannot completely inhibit the disease in this model, a possibility remains that they may be clinically useful in rheumatic diseases associated with the formation of amyloidogenic derivatives. Keywords: mice, experimental AA amyloidosis, antirheumatic drugs

Rheumatoid arthritis in patient with homozygous haemoglobin C disease

To date, few cases of hemoglobinopathies in patients with rheumatoid arthritis (RA) have been reported (Marino and Mcdonald in J Rheumatol 17:970-972, 1990; Gladman and Bombardier in Arthritis Rheum 30:1065-1068, 1987; Michel et al. in Semin Arthritis Rheum 38:228-240, 2008). These haemoglobin diseases are associated with characteristics abnormalities of the skeleton. Haemoglobin C disease is a benign hemoglobinopathy rarely associated with skeletal disorders [Piéron et al. in la semaine des hôpitaux 57(1-2):22-25, 1981]. We report a case of RA in a 60-year-old woman with homozygous haemoglobin C disease. This coexistence may be a pure coincidence, although we discuss the difficulties with RA treatment in this case due to the unknown effect of anti-rheumatic drugs on the progression of haemoglobin C disease.

Effect of disease modifying anti-rheumatic drugs on radiographic progression in rheumatoid arthritis

Because of a paradigm shift in the therapeutic strategy of RA by biologics, the goal of RA therapy became not only the clinical remission, but also the imaging remission. From the results of randomized controlled clinical trials of disease modifying anti-rheumatic drugs (DMARDs), decreased radiographic progression has been documented. In particular, methotrexate (MTX) is described as "anchor drug" of RA therapy because inhibitory effects of MTX on radiographic progression are proved by many clinical trials. Although DMARDs can slow down the radiographic progression with the achievement of clinical remission in RA, some patients still have subclinical synovitis detected by imaging technique. Such subclinical inflammation may explain the observed discrepancy between disease activity and radiographic progression in RA during DMARD therapy.

Systemic-onset juvenile rheumatoid arthritis and ANCA-associated glomerulonephritis

Systemic-onset juvenile rheumatoid arthritis (SoJRA) associated renal lesions are unusual, except for amyloidosis or side effects of antirheumatic drugs. We report on 3 children with SoJRA diagnosed in the first years of life, who presented a perinuclear antineutrophil cytoplasmic antibodies (pANCA) associated glomerulonephritis during the disease course. ANCA glomerulonephritis was diagnosed after 5, 6 and 1 year follow-up for SoJRA in Patients 1, 2 and 3 respectively. Treatment and outcome of the kidney lesions were as follows: Pt1 was treated with steroids bolus associated to rituximab then switched for mycophenolate mofetyl (MMF). At the age of 7, he benefited from anakinra for the still ongoing systemic symptoms of the SoJRA with excellent results on both inflammation baseline and proteinuria. Despite steroids bolus and azathioprine in Pt2, renal lesions led gradually to end stage renal disease (ESRD) when she was 17. She benefited from kidney transplantation and interestingly both systemic symptoms and renal function are well under triple immunosuppressant (MMF, tacrolimus and steroids) with a follow up of 3 years after transplantation. Pt3 evolved to ESRD despite the use of steroids bolus, cyclophosphamide, cyclosporine and immunoglobulin. She died when she was 16 years, after 4 years of dialysis, from a severe sepsis with digestive occlusion. ANCA vasculitis is exceptional in the JRA. Outcome is poor and can lead to ESRD and death. ANCA-associated glomerulonephritis were related to SoJRA with uncontrolled inflammation baseline. These data suggest a common pathogenesis between SoJRA and ANCA glomerulonephritis and underline overlapping syndrome in the pediatric practice.

Scientific basis for the efficacy of combined use of antirheumatic drugs against bone destruction in rheumatoid arthritis

Finding a means to ameliorate and prevent bone destruction is one of the urgent issues in the treatment of rheumatoid arthritis. Recent studies revealed bone-resorbing osteoclasts to be essential for arthritic bone destruction, but to date there has been scarce experimental evidence for the underlying mechanism of the bone-protective effect of antirheumatic drugs. Here we examined the effects of one or a combination of disease-modifying antirheumatic drugs (DMARDs) on osteoclast differentiation to provide a cellular and molecular basis for their efficacy against bone destruction. The effects on osteoclast precursor cells and osteoclastogenesis-supporting cells were distinguished by two in vitro osteoclast culture systems. Methotrexate (MTX), bucillamine (Buc) and salazosulphapyridine (SASP) inhibited osteoclastogenesis by acting on osteoclast precursor cells and interfering with receptor activator of NF-κB ligand (RANKL)-mediated induction of the nuclear factor of activated T cells (NFAT) c1. MTX and SASP also suppressed RANKL expression on osteoclastogenesis-supporting mesenchymal cells. Interestingly, the combination of three antirheumatic drugs exerted a marked inhibitory effect on osteoclastogenesis even at a low dose at which there was much less of an effect when administered individually. These results are consistent with the reported efficacy of combined DMARDs therapy in humans and suggest that osteoclast culture systems are useful tools to provide an experimental basis for the bone-protective effects of antirheumatic drugs.

Effects of antirheumatic drugs on adhesiveness of endothelial cells and neutrophils

Because disease-modifying antirheumatic drugs might exert part of their effects on adhesion of polymorphonuclear neutrophils (PMN) to endothelial cells, this being the first step for PMN migration to inflammatory lesions, we evaluated such drug effects in vitro. Gold sodium thiomalate (GSTM) impaired the ability of interleukin 1β (IL-1β)-stimulated human umbilical vein endothelial cells (HUVEC) to express E-selectin and to bind PMN but had no effect on the expression of intercellular adhesion molecule 1 (ICAM-1) or on hyperadhesivity of N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN. Auranofin (AF) interacted with HUVEC and PMN adhesiveness but in opposite directions: this drug hampered IL-1β-induced HUVEC hyperadhesiveness and expression of E-selectin and intercellular adhesion molecule 1, but augmented PMN adherence and CD18 expression. The net effect of auranofin was a reduction of cytokine-driven adhesiveness and enhancement of formylpeptide-induced adhesion. Salazopyrin did not affect HUVEC or PMN adhesiveness or E-selectin and intercellular adhesion molecule 1 expression. Thus, the gold-containing drugs modulated HUVEC and PMN adhesiveness by different mechanisms but ones involving surface adhesion molecules.

Effect of Tenidap on Metalloproteinase Gene Expression in Rheumatoid Arthritis

This study evaluated measures of metalloproteinase gene expression in synovial biopsies as a means of differentiating the activities of two antirheumatic therapies: piroxicam and tenidap. Synovial biopsies and quantitative in situ hybridization for stromelysin (STR), collagenase (COL), tissue inhibitor of metalloproteinase-1 (TIMP), and actin mRNA were performed in a subset of patients with rheumatoid arthritis in a larger doubleblind randomized crossover trial comparing 120 mg/day of tenidap for 6 weeks with 20 mg/day of piroxicam for 6 weeks. There were no consistent differences between tenidap and piroxicam on COL or TIMP mRNA expression, but STR mRNA was significantly lower after tenidap compared with piroxicam (p = 0.037). There were no significant associations between measures of local or systemic clinical activity and STR, COL, or TIMP gene expression. However, changes in STR gene expression were significantly correlated with changes in serum C-reactive protein (p = 0.016). Because tenidap and piroxicam are both potent inhibitors of prostaglandin production, the effect of tenidap on STR gene expression may be due to its additional cytokine modulating activity. Clinical trials with data from synovial biopsies may be useful in evaluating the potential for disease-modifying effects of antirheumatic drugs.

The effects of antirheumatic drugs on reproductive function

The effects of antirheumatic drugs on reproductive function

ＩＬ‐１βによるラット線維芽細胞様滑膜細胞ＮＯ産生に対する抗リウマチ薬の作用

Effects of anti-rheumatic drugs, gold sodium thiomalate (GST), methotrexate (MTX), D-penicillamine (D-P) and bucillamine (BU), on rhIL-1β-induced nitric oxide (NO) production in rat synovial fibroblast-like cells (SFC) cultured in vitro were investigated. The SFC (passage 4) were cultured for 48hrs in Dulbecco's modified Eagle's medium containing an NO inducer, LPS or rhIL-1β. NO production by SFC was assessed by using Griess reagent. RhIL-1β but not LPS, induced a significant increase in NO production in SFC. The rhIL-1β-induced NO production was inhibited by the presence of GST in a dose dependent manner, whereas MTX (100 ng/ml) had no effect. In contrast, both D-P (10 μg/ml) and BU (3 μg/ml) significantly stimulated rhIL-1β-induced NO production in SFC. This effect of SH-containing antirheumatic drugs was completely abolished by the presence of NO inhibitors, aminoguanidine (AG : 1 mM) and cycloheximide (CH : 2 μM) . AG but not CH, added at a later stage of culture (24-48hrs) abolished rhiL 1β induced NO production, indicating that these SH-compounds stimulate NO synthase activity in SFC.The present study suggests that SH-anti-rheumatic drugs stimulate rhIL-1β-induced NO production in SFC, and that the increase in NO may partly inhibit the bone destruction in rheumatoid arthritis.

O-197 - Effects of anti-rheumatic drugs on rhlL-1β-induced nitric oxide production in rat synovial fibroblast-like cells

O-197 - Effects of anti-rheumatic drugs on rhlL-1β-induced nitric oxide production in rat synovial fibroblast-like cells

Action of anti-inflammatory drugs on interleukin-1β-mediated glucose uptake by synoviocytes

Synovial cell cultures prepared from samples taken from osteoarthritic and rheumatoid patients were treated with different anti-inflammatory agents (cortisol, indomethacin, ibuprofen and piroxicam) to determine their ‘anti-interleukin-1β’ action, using inhibition of interleukin-1β-mediated glucose uptake stimulation as a biological test. Confluent cells were treated for 24 h with different concentrations of these drugs (10 −5, 10 −6 and 10 −7 mol/l) to study their effect on the inflammation process. 6 h before glucose uptake studies, interleukin-1β (1 ng/ml) was added. Whereas non-steroid anti-inflammatory agents were inefficient, cortisol inhibited the action of interleukin-1β on glucose uptake. In osteoarthritic cells, cortisol, 10 −5 mol/l, reduced interleukin-1β-mediated glucose uptake by 27% after a 24-h incubation. In rheumatoid cells, stimulated 2-deoxy- d-glucose uptake was reduced by 40.6%. Results were similar when interleukin-1β and cortisol were added simultaneously, 6 h before glucose uptake was measured. This rapid effect of cortisol was protein synthesis-dependent (inhibited by cycloheximide). Cortisol decreased glucose uptake by synoviocytes by acting on basal and interleukin-1β-mediated glucose uptake. This effect was more pronounced in rheumatoid synovial cells. The inhibition of interleukin-1β-mediated glucose uptake could be proposed as a new model for studying the anti-interleukin-1β effects of anti-rheumatic drugs.

P-634 - Effects of anti-rheumatic drugs on nitric oxide production from peritoneal macrophages in adjuvant arthritis rats.

P-634 - Effects of anti-rheumatic drugs on nitric oxide production from peritoneal macrophages in adjuvant arthritis rats.

Pharmacokinetic interactions and adverse drug experiences in rheumatoid arthritis

While numerous kinetic interactions between anti-rheumatic drugs have been documented, this review deals only with those of clinical significance. Pharmacokinetic interactions clearly do not explain all the toxic effects of anti-rheumatic drugs, but, through effects on drug absorption, distribution, metabolism, and excretion, kinetic interactions can help to explain some of the toxicity seen when anti-rheumatic drugs are used.