Rheumatoid Arthritis: Tishler M

Levy O, Topilski M, Brazowski E, Yaron M, Tishler M. · Department of Medicine B, Assaf Harofeh Medical Center, Zerifin, Israel. · Isr Med Assoc J. · Pubmed #11344808 links to  free full text

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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.

Tishler M, Yaron I, Shirazi I, Yossipov Y, Yaron M. · Department of Rheumatology, Ichilov Hospital, Tel Aviv, Israel. · Rheumatol Int. · Pubmed #10220831 No free full text.

Abstract: This study's purpose was to evaluate salivary interleukin-6 (IL-6) levels in patients with primary Sjögren's syndrome (SS). Salivary and serum IL-6 concentrations were evaluated by ELISA in 36 patients with SS and compared with 19 patients complaining of dry mouth and with normal controls. Salivary IL-6 levels were significantly elevated (P < 0.01) in the 36 patients with SS as compared to the 19 patients with dry mouth (200.5 +/- 43.6 and 12.6 +/- 6.8 pg/ml, respectively). No significant differences were noted in the serum IL-6 levels between these two groups (105.8 +/- 17.1 and 84.8 +/- 17.1 pg/ml, respectively). Both salivary and serum IL-6 levels in the normal controls were below the level of detection of the assay. Positive correlation (r = 0.8613, P < 0.0001) was found between salivary IL-6 levels and the focus score of labial biopsies in SS patients. Elevated salivary IL-6 levels appear to be a consequence of local production and may reflect the component of salivary gland inflammation in SS.

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.

Witte T, Matthias T, Oppermann M, Helmke K, Peter HH, Schmidt RE, Tishler M. · Abteilung Klinische Immunologie, Medizinische Hochschule, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. · J Rheumatol. · Pubmed #14528510 No free full text.

Abstract: OBJECTIVE: To compare the prevalence of antibodies against alpha-fodrin in Sjögren's syndrome (SS) classified according to San Diego and European Community Study Group (ESG) criteria. METHODS: The prevalence and mean concentrations of IgA and IgG autoantibodies against alpha-fodrin were determined and compared in patients with SS classified either according to San Diego criteria or to criteria of the ESG by ELISA. RESULTS: IgA antibodies against alpha-fodrin were detected in 88% and IgG antibodies against alpha-fodrin in 64% and either of these antibodies in 93% of 85 patients classified according to San Diego criteria. Antibodies against Ro were present in 38% of these sera. IgA antibodies against alpha-fodrin were detected in 61%, IgG antibodies against alpha-fodrin in 51%, and any of these antibodies in 73% of 51 patients classified according to the ESG criteria. The mean concentrations of both IgA and IgG antibodies against alpha-fodrin that seem to correlate with disease activity were higher in patients classified according to the San Diego criteria. CONCLUSION: Antibodies against alpha-fodrin are detectable in almost all sera obtained from patients with SS classified according to the San Diego criteria and are significantly more prevalent than antibodies against Ro. The lower prevalence of the autoantibodies in patients classified according to the ESG criteria reflects the lower specificity of these criteria for SS.

Tishler M, Langevetiz P, Nesher G. · No affiliation provided · Harefuah. · Pubmed #12420601 No free full text.

This publication has no abstract.

Tishler M, Yaron I, Shirazi I, Yaron M. · Department of Rheumatology, Tel Aviv Souraski Medical Center and Tel Aviv University Sackler School of Medicine, Israel. · J Rheumatol. · Pubmed #11327252 No free full text.

Abstract: OBJECTIVE: To compare the clinical and laboratory characteristics of patients with primary Sjögren's syndrome (SS) with an elderly onset to those with a younger onset. METHODS: The study group comprised 85 consecutive patients (79 women and 6 men) attending the Sjögren's clinic. Primary SS was diagnosed according to the San Diego criteria. Elderly onset disease (EOD) was determined as the appearance of symptoms suggestive of SS after age 65. Clinical and laboratory variables for EOD were compared to those of a younger onset disease (YOD). Salivary and serum samples of all patients were examined for concentrations of interleukin 6 (IL-6) and hyaluronic acid (HA). RESULTS: Seventeen patients with SS (20%) matched the definition of EOD and their median disease onset was 71 years (range 65-80). No significant differences were noted in the clinical disease manifestations between the 2 groups of patients. Rheumatoid factor and anti-Ro(SSA) antibodies were more common in the YOD group (p = 0.012 and p = 0.023, respectively). Significant elevations of salivary IL-6 and HA levels were detected in the YOD group compared to the EOD group with SS (17.3 +/- 3.6 vs 8.8 +/- 2.1 pg/ml and 230.2 +/- 41.1 vs 128.8 +/- 33.3 ng/ml, respectively) (p < 0.0001). CONCLUSION: EOD SS has somewhat milder clinical symptoms with fewer immunological manifestations than YOD. The elevations of salivary IL-6 and HA in the younger group of SS patients support in part the differences in the inflammatory process between the 2 groups.

Tishler M, Yaron I, Shirazi I, Yaron M. · Department of Rheumatology, Tel Aviv Souraski Medical Center, Tel Aviv University Sackler School of Medicine, Israel. · Ann Rheum Dis. · Pubmed #10364906 links to  free full text

Abstract: OBJECTIVE: To evaluate the effect of hydroxychloroquine treatment on interleukin 6 (IL6), hyaluronic acid (HA), and soluble interleukin 2 receptor (sIL2R) concentrations in the saliva and serum of patients with primary Sjögren's syndrome (SS). METHODS: Fourteen SS patients treated with hydroxychloroquine 200 mg/day for 12 months were investigated in an open prospective study. Clinical parameters of efficacy and routine biochemical and haematological data to assess drug safety and tolerability were determined every three months. Salivary and serum IL6, sIL2R, and HA values were determined at study entry, 6 and 12 months, using ELISA and radiometric assays. RESULTS: After hydroxychloroquine treatment, salivary IL6 concentrations decreased from 13.2 (1.2) to 7.3 (1.1) pg/ml (mean (SEM)) (p < 0.0001). Similarly, salivary HA concentrations were also reduced from 577.8 (120) to 200 (34) ng/ml (mean (SEM) (p < 0.003). Serum IL6 concentrations decreased from 5.4 (0.6) to 2.9 (0.2) pg/ml (mean (SEM) (p < 0.001), while serum HA concentrations remained unchanged. No change has been detected in salivary or serum sIL2R concentrations after 12 months of treatment with hydroxychloroquine. Treatment also resulted in significant reduction in erythrocyte sedimentation rate, serum gamma globulin, and C reactive protein values while only partial clinical improvement was noted in some patients. A more pronounced decrease of salivary IL6 and HA levels was found in the two patients in whom a reduction in the swelling of the parotid gland was noted. CONCLUSION: In this open label study of hydroxychloroquine treatment for SS a significant reduction of some salivary inflammatory markers was seen at the end of 12 months. Although during the treatment period only a partial clinical effect could be noted, the findings suggest that a double blind controlled study of hydroxychloroquine in SS is indicated.

Tishler M, Yaron I, Shirazi I, Levartovsky D, Yaron M. · Department of Rheumatology, Ichilov Hospital, Tel Aviv-Sourasky Medical Center, Israel. · Arch Oral Biol. · Pubmed #10348356 No free full text.

Abstract: Salivary and serum concentrations of soluble interleukin-2 receptor (sIL-2R) were studied in a group of patients with Sjögren's syndrome and a group suffering from dry mouth. Salivary sIL-2R levels was significantly higher (57.9+/-15.1 vs 16.7+/-4.7 pg/ml) (p < 0.05) in the group of 26 patients with Sjögren's syndrome than in the dry-mouth group. Both the salivary and the serum sIL-2R of normal controls were below the level of detection. No significantly statistical differences were noted between the concentrations of serum sIL-2R in either abnormal groups. No correlations were found between salivary or serum sIL-2R and the erythrocyte sedimentation rate, C-reactive protein, the presence of various autoantibodies or the focus score from lip biopsies in the group of patients with Sjögren's syndrome. The results show that, although the salivary sIL-2R does not actually reflect the extent of inflammation, it might have an important role in the diagnosis of Sjögren's syndrome.