Rheumatoid Arthritis: Rubinow A

Rubinow A. · No affiliation provided · Isr Med Assoc J. · Pubmed #11574984 links to  free full text

This publication has no abstract.

Nusair S, Rubinow A. · Division of Medicine, the Hadassah University Hospital and Hebrew University-Hadassah School of Medicine, Jerusalem, Israel. · Semin Arthritis Rheum. · Pubmed #10406404 No free full text.

Abstract: OBJECTIVES: To analyze the role of oral pilocarpine in the treatment of xerostomia of Sjogren's syndrome (SS). METHODS: The medical literature was reviewed for all studies using oral pilocarpine to treat xerostomia caused by SS or radiotherapy registered in the MedLine Silver Platter database from 1966 to 1998. RESULTS: All the studies identified excluded elderly individuals with cardiac or pulmonary disease. Patients with postradiation xerostomia and incomplete resection of the salivary glands were more likely to benefit from oral pilocarpine when there was sufficient residual glandular function than patients with radical surgery for head and neck cancer (HNC). However, patients with SS and other inflammatory disorders seemed to benefit from oral pilocarpine, when compared with patients with postradiation xerostomia. The optimal dose of oral pilocarpine, which was less likely to cause side effects, was 5 mg four times daily. A recent multi-center study in SS patients suggests that oral pilocarpine is effective and safe for long-term administration. Although some studies did not show evidence for increased salivary gland secretion rate as measured by sialometry, symptoms improved, perhaps because of increased secretion from the minor salivary glands or better conditioning of the oral mucosa. CONCLUSIONS: Oral pilocarpine is likely to benefit patients with SS by reducing the symptoms of xerostomia, even if the salivary gland secretion rate does not increase. Further controlled studies are needed in patients with SS and should include elderly patients with cardiovascular disease treated with moderate doses of oral pilocarpine.

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.

Amital H, Barak V, Winkler RE, Rubinow A. · Department of Medicine D, Meir Medical Center, Tshernichovsky 59, Kfar-Saba, 44281, Israel. · Ann N Y Acad Sci. · Pubmed #17911480 No free full text.

Abstract: This article analyzes the serum cytokine profile of a nonrandomized group of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who are destined to be treated with infliximab following failure after failure of different disease-modifiying antirheumatic drugs (DMARDs). Serial serum samples were collected from 11 patients with refractory RA, three with PsA and one with undifferentiated spondyloarthropathy. All were treated with the antitumor necrosis factor (TNF)alpha agent, infliximab, after failing to sustain a clinical remission with conventional DMARDs. Blood samples were obtained at different phases of their therapy. Serum levels of tumor necrosis factor (TNF)alpha, interferon (IFN)gamma, interleukin (IL)-1beta, IL-6, sIL-2R, IL-10, and IL-1 receptor antagonist (IL-1RA) were determined by commercial ELISA kits. Interestingly, only eight of the 11 patients with RA had elevated TNFalpha serum levels (at least once in their serial measurements). Only one was unresponsive to therapy and despite anti-TNFalpha therapy her serum TNFalpha levels remained extremely high. Two RA patients who responded to infliximab had normal TNFalpha serum levels prior to and following infliximab administration. One RA patient improved after infliximab therapy despite unrelenting high serum levels of TNFalpha, IL-6, and sIL-2R. Patients with active PsA who responded to infliximab therapy had sustained high serum TNFalpha levels. In an unselected population of RA and PsA patients, we noticed diverse patterns of serum cytokine profiles. These results imply that the cytokine profiles of RA and PsA are diverse and their pathogenesis is heterogeneous.

Eshkar Sebban L, Ronen D, Levartovsky D, Elkayam O, Caspi D, Aamar S, Amital H, Rubinow A, Golan I, Naor D, Zick Y, Golan I. · Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel. · J Immunol. · Pubmed #17617615 links to  free full text

Abstract: The synovial fluid (SF) cells of rheumatoid arthritis (RA) patients express a specific CD44 variant designated CD44vRA. Using a cellular model of this autoimmune disease, we show in this study that the mammalian lectin, galectin-8 (gal-8), is a novel high-affinity ligand of CD44vRA. By affinity chromatography, flow cytometry, and surface plasmon resonance, we demonstrate that gal-8 interacts with a high affinity (K(d), 6 x 10(-9) M) with CD44vRA. We further demonstrate that SF cells from RA patients express and secrete gal-8, to a concentration of 25-65 nM, well within the concentration of gal-8 required to induce apoptosis of SF cells. We further show that not all gal-8 remains freely soluble in the SF and at least part forms triple complexes with CD44 and fibrinogen that can be detected, after fibrinogen immunoprecipitation, with Abs against fibrinogen, gal-8 and CD44. These triple complexes may therefore increase the inflammatory reaction by sequestering the soluble gal-8, thereby reducing its ability to induce apoptosis in the inflammatory cells. Our findings not only shed light on the receptor-ligand relationships between CD44 and gal-8, but also underline the biological significance of these interactions, which may affect the extent of the autoimmune inflammatory response in the SF of RA patients.

Berkun Y, Abou Atta I, Rubinow A, Orbach H, Levartovsky D, Aamar S, Arbel O, Dresner-Pollak R, Friedman G, Ben-Yehuda A. · Department of Pediatrics, Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. · J Rheumatol. · Pubmed #17611986 No free full text.

Abstract: OBJECTIVE: To investigate the distribution of the A2756G polymorphism of the methionine synthase reductase (MTR) gene in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) compared with a healthy control group; and to examine the relationships among the A2756G polymorphism, plasma total homocysteine (tHcy), serum folate and vitamin B12 levels, disease activity, and MTX toxicity in patients with RA. METHODS: A cross-sectional study was performed on 86 MTX-treated RA patients, consisting of a clinical interview and physical examination to determine disease activity and MTX-related adverse reactions. Genotype analysis of the MTR gene was performed. Fasting plasma tHcy, serum folate, and vitamin B12 levels were measured. Allele and genotype distributions were compared to a healthy control group. RESULTS: The frequency of the 2756GG genotype (16.3%) in the RA study group was higher than that expected in the general population (3.6%; p < 0.000001). This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). No association of disease activity variables or plasma homocysteine with MTR A2756G polymorphisms was observed. The MTR 2756GG genotype, low plasma vitamin B12 levels, and the presence of rheumatoid nodules predicted MIARN. No association of nodulosis with any other indicator of disease activity or medical treatment was found. CONCLUSION: In our population of MTX-treated RA patients the 2756GG genotype of the MTR gene was more common than expected and was associated with MIARN.

Golan I, Nedvetzki S, Golan I, Eshkar-Sebban L, Levartovsky D, Elkayam O, Caspi D, Aamar S, Amital H, Rubinow A, Naor D. · The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. · J Autoimmun. · Pubmed #17383158 No free full text.

Abstract: Selective targeting of cells engaged in pathological activities is a major challenge for medical research. We generated monoclonal antibodies (mAbs) that exclusively bind, at concentrations ranging from 2 to 100 microg/ml, to a modified CD44 variant (designated CD44vRA) expressed on synovial fluid cells from joints of rheumatoid arthritis (RA) patients. These mAbs cross-reacted with keratinocytes expressing wild type CD44vRA (CD44v3-v10) only at a relatively high concentration (200 microg/ml). Sequence analysis of CD44vRA cDNA revealed, in 33 out of 43 RA and psoriatic arthritis patients, an extra intron-derived trinucleotide, CAG, which allows translation of an extra alanine. This insertion imposes a configurational change on the cell surface CD44 of RA synovial fluid cells, creating an immunogenic epitope and potentiating the ability to produce disease-specific antibodies. Indeed, the anti-CD44vRA mAbs (designated F8:33) were able to induce apoptosis in synovial fluid cells from RA patients, but not in peripheral blood leukocytes from the same patients, in keratinocytes from normal donors or in synovial fluid cells from osteoarthritis patients. Furthermore, injection of anti-CD44vRA mAbs reduced joint inflammation in DBA/1 mice with collagen-induced arthritis. These findings show that anti-CD44vRA mAbs are both bioactive and RA-specific.

Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, Abou Atta I, Mevorach D, Friedman G, Ben-Yehuda A. · Department of Paediatrics, Bikur Cholim General Hospital, POB 492, Jerusalem 91004, Israel. · Ann Rheum Dis. · Pubmed #15361376 links to  free full text

Abstract: BACKGROUND: There is an association between C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and methotrexate related toxicity. OBJECTIVE: To examine the relations between the recently described A1298C polymorphism of the MTHFR gene, plasma homocysteine, methotrexate toxicity, and disease activity in patients with rheumatoid arthritis. DESIGN: A cross sectional study on 93 methotrexate treated patients with rheumatoid arthritis, comprising a clinical interview and physical examination to determine disease activity and methotrexate related adverse reactions. Genotype analysis of the MTHFR gene was carried out and fasting plasma homocysteine and serum folate concentrations were measured. The data were analysed using univariate analysis. Allele and genotype distributions were compared with those of a healthy control group. RESULTS: The frequency of the 1298CC genotype (24.7%) in the rheumatoid study group was greater than expected in the general population (12.8%, p<0.001). This genotype was associated with a significantly low rate of methotrexate related side effects. The odds ratio for side effects in patients with wild type 1298AA genotype v 1298CC genotype was 5.24 (95% confidence interval, 1.38 to 20). No correlation of disease activity variables or plasma homocysteine with MTHFR A1298C and C677T polymorphisms was observed. CONCLUSIONS: 1298CC polymorphism was more common in methotrexate treated rheumatoid patients than expected in the population, and was associated with a reduction in methotrexate related adverse effects. The A1298C polymorphism of the MTHFR gene may indicate a need to adjust the dose of methotrexate given to patients with rheumatoid arthritis.

Elinav H, Maly A, Ilan Y, Rubinow A, Naparstek Y, Amital H. · Department of Medicine "A," Institute of Pathology, Hadassah-Hebrew University School of Medicine, Ein-Karem, Jerusalem 91120, Israel. · J Am Acad Dermatol. · Pubmed #15097938 No free full text.

Abstract: Sweet's syndrome has a wide range of clinical manifestations. It may appear as a solitary cutaneous disorder but often it is associated with systemic signs and symptoms. This disorder might be idiopathic but it often is paraneoplastic or associated with medications or autoimmune diseases. In its systemic manifestation Sweet's disease resembles adult-onset Still's disease in many aspects. We present a case of a young man in whom Sweet's syndrome and Still's disease developed. Although the diagnosis of adult-onset Still's disease is made by exclusion, he fulfilled all the criteria of both conditions. Considering the clinical similarities of these diseases, it may be presumed that similar patients may have been overlooked in the past.

Amital H, Aamar S, Rubinow A. · Rheumatology Unit, Division of Internal Medicine, Hadassah-Hebrew University School of Medicine, Jerusalem, Israel. · J Bone Joint Surg Am. · Pubmed #14630854 No free full text.

This publication has no abstract.

Hirshberg B, Muszkat M, Schlesinger O, Rubinow A. · Department of Internal Medicine, Hadassah University Hospital, PO Box 12000, Jerusalem 91120, Israel. · Postgrad Med J. · Pubmed #11085770 links to  free full text

Abstract: Weekly low dose methotrexate is an established treatment for rheumatoid arthritis, but its use in elderly people has not been adequately examined. The aim of this study was to evaluate its safety in elderly patients with rheumatoid arthritis. A retrospective review of the clinical records of rheumatoid arthritis patients over the age of 65 attending a rheumatology unit was conducted. Eligible patients were followed for at least two years and treated with methotrexate in a dose of 7.5 mg/week while being maintained on concurrent treatment. Thirty three patients were studied. Their mean age was 78.8 years; 32 were female and one was male. Treatment was discontinued in four patients, two because of raised serum liver enzymes and two because of gastrointestinal irritation. No serious adverse events were reported. After two years, haemoglobin levels increased from a mean (SD) of 12.4 (1.3) g/dl to 13.0 (1.1) g/dl (r = 0.226, p < 0.005). The white blood count was significantly reduced from 7.9 (1.8) x 10(9)/l to 6.8 (1.7) x 10(9)/l (r = 0.184, p < 0.05). No episodes of neutropenia or agranulocytosis were observed. There was a non-significant decrease in platelet count. The erythrocyte sedimentation rate decreased from 56.8 (30.8) to 35.2 (24.6) mm/h (r = 0.246, p < 0.01). In conclusion, low methotrexate treatment in elderly patients appears to be safe. Routine determination of serum liver enzymes and renal function may reduce individual risk.