Rheumatoid Arthritis: Mader R

Mader R, Keystone E. · Rebecca McDonald Centre for Arthritis and Autoimmune Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · J Rheumatol Suppl. · Pubmed #17985419 No free full text.

Abstract: Disability and joint damage in rheumatoid arthritis (RA) occur rapidly and early in the course of the disease. Disease activity is predominantly responsible for the disability in the early stages of RA. Nonreversible joint damage increases disability later in the course of RA. In recent years, several strategies that employed combination therapies with conventional disease modifying antirheumatic drugs (DMARD) were studied with the aim of rapidly bringing the disease under control. The ultimate goal was to alleviate symptoms and slow or halt the progression of joint damage. The introduction of highly efficient biologic agents allows introduction of a number of new strategies, including early administration of a biologic agent alone or in combination with high-dose methotrexate. Other options for the use of biologic therapies include the use of biologic agents for moderate disease, and early use of a biologic agent for induction of remission and subsequent treatment with a conventional DMARD. A strategy for tight control of disease with targeted outcomes for decision-making may offer further improvement in disease control irrespective of the treatment approach. The remarkably improved outcomes that can be achieved by initiating aggressive therapy early, with close monitoring of disease progression and modification of ineffective therapeutic strategies, support the use of biologics in the optimal management of RA.

Silverman MH, Strand V, Markovits D, Nahir M, Reitblat T, Molad Y, Rosner I, Rozenbaum M, Mader R, Adawi M, Caspi D, Tishler M, Langevitz P, Rubinow A, Friedman J, Green L, Tanay A, Ochaion A, Cohen S, Kerns WD, Cohn I, Fishman-Furman S, Farbstein M, Yehuda SB, Fishman P. · Can-Fite BioPharma Ltd, Petach Tikva, Israel. · J Rheumatol. · Pubmed #18050382 No free full text.

Abstract: OBJECTIVE: Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor (A3AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A3AR agonist. METHODS: This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A3AR expression levels were analyzed in PBMC from 18 patients. RESULTS:. Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed. CONCLUSION: CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A3AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way.

Kacsur C, Mader R, Ben-Amotz A, Levy Y. · Department of Medicine A, Rheumatic Disease Unit, HaEmek Medical Center, Rappaport Family Faculty of Medicine, Technion, National Institute of Oceanography, Haifa, Israel. · Harefuah. · Pubmed #11905085 No free full text.

Abstract: We present a clinical study aimed to compare plasma antioxidant vitamins, vitamin E, beta-carotene and vitamin A. The study consisted of a group (15 patients) with rheumatoid arthritis (RA) compared to a healthy control group. There was a significant decrease in plasma vitamin E, beta-carotene and vitamin A (vitamin E 30.4 +/- 4.9 VS 43.6 +/- 8.2 micrograms/ml, beta-carotene 0.73 +/- 0.26 VS 1.02 +/- 0.22 micrograms/ml and vitamin A 0.22 +/- 0.07 VS 0.46 +/- 0.15 microgram/ml, P < 0.01 patients VS control, respectively). Supplementation of Dunaliella (natural)--beta-carotene to the RA patients for 3 weeks, resulted in a significant increase in plasma vitamin E (47.9 +/- 5.5 micrograms/ml) beta-carotene (0.87 +/- 0.21 microgram/ml) and vitamin A (0.55 +/- 0.15 microgram/ml). There were no changes in the activity indexes of RA. Low plasma antioxidant vitamins in patients with RA are consistent with the observation that oxidative processes occur in the inflammed joints. The validity of antioxidant vitamins as supplementary therapy for RA is not clear.

Ochaion A, Bar-Yehuda S, Cohn S, Del Valle L, Perez-Liz G, Madi L, Barer F, Farbstein M, Fishman-Furman S, Reitblat T, Reitblat A, Amital H, Levi Y, Molad Y, Mader R, Tishler M, Langevitz P, Zabutti A, Fishman P. · Can-Fite Biopharma Ltd, 10 Bareket Street, Kiryat-Matalon, Petah-Tikva, 49170, Israel. · Arthritis Res Ther. · Pubmed #17101059 links to  free full text

Abstract: Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A3 adenosine receptor (A3AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A3AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A3AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A3AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A3AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A3AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A2AAR and A3AR over-expression in paw cells from treated animals. Moreover, increased A3AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A3AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A3AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA.

Habib GS, Saliba WR, Mader R. · Department of Internal Medicine B, Carmel Medical Center, Haifa, Israel. · Isr Med Assoc J. · Pubmed #10897233 links to  free full text

Abstract: BACKGROUND: Acute rheumatic fever is considered a relatively uncommon disease in developed countries. Although cases are encountered in the Nazareth area in Israel, no systematic study of this disease has been done in the last 20 years. OBJECTIVE: To study the incidence and characteristics of acute rheumatic fever cases in the Nazareth area during the last decade. METHODS: Cases of acute rheumatic fever diagnosed according to the modified Jones criteria were identified in two hospitals in the Nazareth area during the 10 years. These two hospitals receive about 75% of non-obstetric referrals to the emergency room. Clinical, laboratory and treatment data of these patients were documented and the incidence of disease calculated. The population census in the Nazareth area was obtained from the Central Bureau of Statistics. RESULTS: Forty-four patients, with a mean age of 18 years, were identified. The mean annual incidence was 5 cases/100,000 population. Arthritis was found in 98% of the patients (migratory in 52%) and carditis in 34%, but only one patient had a subcutaneous nodule, and none had either erythema marginatum or chorea. Only one patient with carditis developed heart failure a few months later due to severe mitral stenosis. CONCLUSION: Rheumatic fever in the Nazareth area is still manifest. The mean age of the patients was higher than found previously. In only half of the patients was the arthritis migratory, with other major manifestations of rheumatic fever found only rarely.