Rheumatoid Arthritis: Toubi E

Kessel A, Toubi E. · No affiliation provided · Harefuah. · Pubmed #12017890 No free full text.

Abstract: Leflunomide is an antirheumatic drug. One of its main features is its ability to inhibit de novo pyrimidine ribonucleotide biosynthesis. It has been reported as an effective drug in the treatment of patients with Rheumatoid Arthritis. Recently pilot studies have demonstrated the benefit of leflunomide in systemic lupus erythematosus patients. Herein we describe the successful treatment of two lupus patients with leflunomide and review the current literature.

Toubi E, Shoenfeld Y. · Divison of Allergy and Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel. · Autoimmunity. · Pubmed #15621572 No free full text.

Abstract: Many tissue injuries and immune mediated pathologies such as graft allo-rejections were found to involve CD40-CD40 ligand (CD40L, CD154) signaling pathway. The disruption of this pathway in many animal models led to the improvement of graft survival in these models. CD40-CD154 interactions were also shown to play a significant role in the maintenance of autoimmunity, and the production of auto-antibodies in systemic lupus erythematosus (SLE). High-level expression of CD154 has been detected on T cells from patients with active SLE, rheumatoid arthritis (RA) and other autoimmune diseases, indicating that such cells could account for the high-level expression of immune accessory molecules on B cells of patients with active disease. An increased serum level of soluble CD154 was also reported in SLE, RA, and Sjogren's disease in correlation with the relevant auto-antibodies and with the clinical disease activity. Anti-CD154 antibody therapy prevents auto-antibody production and renal immune complex deposition in lupus nephritis, indicating that disruption of this pathway could be a beneficial treatment in SLE. However, the etiology of the higher than expected number of thromboembolic events in anti-CD154 treated SLE patients should be investigated and preventive measures should be considered.

Rosner I, Rozenbaum M, Toubi E, Kessel A, Naschitz JE, Zuckerman E. · Department of Rheumatology, Bnai Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel. · Semin Arthritis Rheum. · Pubmed #15190523 No free full text.

Abstract: OBJECTIVE: To present the data available supporting the existence of an arthropathy associated with hepatitis C infection. METHODS: The MEDLINE database was searched for "arthritis" intersecting with "hepatitis C" in addition to the authors' investigations and experience on this subject. RESULTS: Arthritis, not otherwise explained, has been noted in 2% to 20% of hepatitis C virus (HCV) patients. This arthritis is rheumatoid-like in two thirds of the cases and a waxing/waning oligoarthritis in the rest. Cryoglobulinemia alone does not explain the arthritis, and there is difficulty in differentiating it from rheumatoid arthritis. The arthropathy is nonerosive/nondeforming. Whereas nonsteroidal anti-inflammatory drugs, low-dose corticosteroids, and hydroxychloroquine may be helpful, conventional treatment of arthritis may be problematic in the context of viral hepatitic arthropathy. Antiviral therapy is most effective, even without viral clearance, but rheumatic complications may ensue. CONCLUSIONS: HCV arthropathy should be considered in the differential diagnosis of new-onset arthritis.

Toubi E, Kessel A, Slobodin G, Boulman N, Pavlotzky E, Zisman D, Rozenbaum M, Rosner I. · Division of Clinical Immunology and Allergy, Bnai Zion Medical Center, P O Box 4940, Haifa 31048, Israel. · Ann Rheum Dis. · Pubmed #17148544 No free full text.

Abstract: OBJECTIVE: To assess changes in macrophage phenotype and function after rituximab-induced B cell depletion in patients with rheumatoid arthritis (RA). METHODS: 10 patients with RA were treated with rituximab, achieving significant B cell depletion 4 months later. Clinical improvement, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, mRNA of B cell activating factor (BAFF), interleukin (IL) 10 and CD86 in human monocyte-derived macrophages (HMDMs) and tumour necrosis factor alpha (TNFalpha) secretion from cultured HMDMs were assessed at baseline and after the depletion. RESULTS: A clinical response of American College of Rheumatology (ACR) 50% improvement was noted in six patients, and another two patients responded with moderate improvement, equivalent to ACR 20-50% improvements. RF and anti-CCP antibodies were positive at baseline in seven of ten patients. RF disappeared or declined in six patients 4 months after treatment, correlating with clinical improvement. By contrast, anti-CCP remained unchanged in six patients. After rituximab treatment, and in association with clinical improvement, BAFF, IL10 and CD86 mRNA expression in HMDM were significantly upregulated compared with values at baseline. A significant decrease in TNFalpha in the supernatant of cultured HMDM was also noted. CONCLUSIONS: In addition to B cell depletion and attenuation in some of the specific autoantibodies, clinical improvement in rituximab-treated patients with RA occurred in association with changes in macrophage function.

Toubi E, Kessel A, Mahmudov Z, Hallas K, Rozenbaum M, Rosner I. · Division of Allergy and Clinical Immunology, Bnai-Zion Medical Center, Golomb Str. 47, P. O. Box 4, Haifa, Israel. · Ann N Y Acad Sci. · Pubmed #16126991 No free full text.

Abstract: Increased secretion of tumor necrosis factor-alpha (TNF-alpha), along with interleukin-1 (IL-1) and interleukin-6 (IL-6), is important in the pathogenesis of rheumatoid arthritis (RA). T regulatory CD4(+)CD25(+) cells play a role in maintaining self-tolerance by downregulating Th1-induced proinflammation. This function has been found to be altered in active RA, whereas anti-TNF-alpha therapy has been found to improve the suppressive abilities of these cells. Our objectives were to investigate whether T regulatory cells in patients with active RA display a higher sensitivity to spontaneous apoptosis than in normals, and to look into the potential of infliximab (anti-TNF-alpha therapy) to reduce the sensitivity of these cells to spontaneous apoptosis. Seventeen patients suffering from active RA, having failed multiple disease-modifying antirheumatic drug (DMARD) therapies, were treated with infliximab. Spontaneous apoptosis (as detected by annexin V binding) was determined in all patients and compared with a group of normal individuals at baseline and after three months on infliximab treatment. Peripheral blood mononuclear cells were incubated in 24-well plates at 1 x 10(6) cells/mL for 48 hours. Annexin V binding on CD4(+)CD25(+) was assessed using three-color assay by flow cytometry. Prior to infliximab initiation, spontaneous apoptosis of T regulatory cells from active RA patients was found to be increased in comparison with controls (26 +/- 4.2% vs. 19.8 +/- 4.8%, respectively; P = 0.01). Three months later (while still on infliximab) spontaneous apoptosis was comparable in the two groups (20.7 +/- 5.2% vs. 20.9 +/- 3.4%; P 5 0.8). The absolute number of CD4(+)CD25(+) cells/mL in the peripheral blood at baseline was reduced in 11 out of 17 active RA patients when compared with that of the control group (24 +/- 7 vs. 32 +/- 11, respectively; P = 0.02). Following anti-TNF-alpha therapy, CD4(+)CD25(+) cell counts of patients were equivalent to those of normals. The alteration and reversal in both spontaneous apoptosis and cell count of T regulatory cells was found to correlate with RA disease activity. CD4(+)CD25(+) T regulatory cells display increased proclivity to undergo spontaneous apoptosis in active RA. Alterations in CD4(+)CD25(+) cell apoptosis and cell count were found to correlate with RA disease activity. Reversal of these deviations from normal was documented in association with the beneficial outcome of infliximab therapy.

Kessel A, Toubi E, Rozenbaum M, Zisman D, Sabo E, Rosner I. · Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, 47 Golomb Street, P.O. Box 4940, Haifa, 31048, Israel. · Rheumatol Int. · Pubmed #15703951 No free full text.

Abstract: BACKGROUND: It is relatively difficult in a community setting to perform salivary gland biopsy or reliable diagnostic tests for salivary gland involvement in a patient suspected to suffer from Sjögren's syndrome (SS). OBJECTIVE: To investigate whether anti-Ro/La antibodies are a good substitute for salivary gland biopsy in community patients suspected to suffer from SS. METHODS: Forty-one patients suspected as having SS due to dry eyes and mouth, articular complaints, and/or serological findings were examined for the presence of anti-Ro/La, and underwent minor salivary gland biopsy. RESULTS: Sixteen patients (39%) were classified as primary SS by the American-European Consensus Group criteria. Twelve subjects had anti-Ro/La antibodies and 11 subjects in this group had positive biopsy findings. Of 29 patients without anti-Ro/La antibodies, only four manifested positive biopsy findings. A significant association was found between the presence of anti-Ro/La antibodies and positive salivary gland findings characteristic for SS (p<0.0001, Fisher's exact test). CONCLUSION: These findings tend to support the suggestion that a patient suspected to suffer from SS in a community setting may be first tested for the presence of anti-Ro/La antibodies to confirm the diagnosis. Only those with a negative result for the presence of anti-Ro/La antibodies need to be referred for salivary gland biopsy.

Toubi E, Zuckerman E, Kessel A, Rozenbaum M, Rosner I. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #12942711 No free full text.

This publication has no abstract.

Toubi E, Kessel A, Grushko G, Sabo E, Rozenbaum M, Rosner I. · Division of Clinical Immunology, Bnai Zion Medical Center, Faculty of Medicine, Technion-Haifa, Israel. · Clin Exp Rheumatol. · Pubmed #12051403 No free full text.

Abstract: OBJECTIVE: Matrix metalloproteinase 3 (MMP-3) is reported to play an important role in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Studies have also investigated the association of different tissue inhibitors of MMPs (TIMPs) with fibrosis in scleroderma (SSc). The aim of this study was to evaluate the correlation of serum MMP-1, 3 and TIMP-1 with severity and disease specific markers of SSc and RA. METHODS: Serum MMP-1,3 and TIMP-1 were measured in 42 SSc patients (age range 28-68 yr mean 47 yr) and compared to 29 RA and 30 healthy age- and sex-matched individuals. Elevated values of MMPs and TIMP-1 were defined as those greater than 2 SD above the normal mean. All SSc and RA patients were scored for disease severity. RESULTS: Serum MMP-1 was significantly elevated in 8/42 (19%) SSc patients (p = 0.01) but only in 2/29 (7%) RA patients (p = 0.2). Whereas MMP-3 levels were elevated in 10/29 (34%) RA patients (p = 0.002), it was elevated in only 5/42 (12%) SSc patients (p = 0.03). TIMP-1 was found elevated in 17/42 (40%) SSc patients (p = 0.001) and in only 4/29 RA patients (with a strong trend towards significance, p = 0.052). We found a significant association between the elevation of both MMPs and TIMP-1 levels, with the severity of SSc. Those who had an increase of more than one MMP and/or TIMP, demonstrated life-threatening major organ involvement such as end stage lung fibrosis, GI aperislasis, and severe cardiacfailure. Contrary to that in SSc, the severity of RA showed some trend of association with MMP-3 only. CONCLUSION: We confirm previous observations that MMPs and TIMPs may play an important role in various rheumatic diseases. Whereas serum increase of MMP-3 correlated with RA severity, SSc severity was more characterized by the increase of both MMP-1 and TIMP-1. This suggests that the MMPs and TIMPs involved in SSc are different than those playing a role in RA, which may indicate that in SSc they are produced in different locations than in RA.

Shoshan Y, Shapira I, Toubi E, Frolkis I, Yaron M, Mevorach D. · Laboratory for Cellular and Molecular Immunology, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel. · J Immunol. · Pubmed #11698475 links to  free full text

Abstract: Impaired handling of apoptotic cells has been suggested as an important factor in the development of systemic lupus erythematosus (SLE), and a role for complement in the removal of apoptotic cells was shown recently. We studied the in vitro function of macrophages from 40 patients with SLE and their matched controls in the removal of heterologous apoptotic cells opsonized by iC3b. Interaction index of apoptotic cells opsonized by iC3b was significantly lower in patients with SLE and averaged 71% +/- 37 of that of healthy individuals (p < 0.002) and 69% +/- 35 of patients with rheumatoid arthritis (p < 0.007). SLE patients had increased apoptosis of both freshly isolated monocytes (p < 0.001) and maturing macrophages (p < 0.04) that led to decreased density of monocyte-derived macrophages. Apoptosis was inhibited by adding soluble Fas receptor indicating Fas-mediated apoptosis. As demonstrated in both healthy controls and patients with SLE, decreased macrophage density by itself caused significant decreased uptake of apoptotic cells by the remaining macrophages. Maintaining normal density in SLE patients either by an increased initial density or by using soluble Fas restored the interaction capacity of the individual macrophages in the majority of patients. We concluded that impaired in vitro interaction of iC3b-opsonized apoptotic cells with macrophages from patients with SLE was mainly associated with Fas-dependent accelerated apoptosis of the monocytes/macrophages. Accelerated apoptosis of phagocytes may represent a novel in vitro mechanism of impairment of interaction with apoptotic cells that, apart from reducing the number of professional phagocytes, alters the function of the remaining macrophages.

Zuckerman E, Keren D, Rozenbaum M, Toubi E, Slobodin G, Tamir A, Naschitz JE, Yeshurun D, Rosner I. · Department of Internal Medicine A, B'nai Zion Medical Center, Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel. · Clin Exp Rheumatol. · Pubmed #11072597 No free full text.

Abstract: OBJECTIVE: To characterize hepatitis C virus (HCV)-related arthropathy and to evaluate the response to treatment with interferon-alpha (INF-alpha). METHODS: We studied 28 HCV-infected patients with arthritis. All patients underwent complete clinical, laboratory and radiological evaluation, including assessment and follow-up by a rheumatologist. Twenty-five patients were treated with INF-alpha for a median period of 12 months. RESULTS: All patients were HCV-RNA positive (genotype 1b in 65%). The mean duration of arthropathy-related symptoms prior to the diagnosis of HCV infection was 12 months. 19 patients (68%) had symmetric polyarthritis and 19 (68%) had morning stiffness > or = 60 min. None of the patients had erosive disease or subcutaneous nodules. 12 (43%) had detectable cryoglobulin (mean cryocrit: 3.6 +/- 3.5%), 17 (61%) had rheumatoid factor (RF) (median titer: 1:80), and only 15 (54%) had elevated ESR. 14 patients (50%) had > or = 4 ACR (American College of Rheumatology) criteria for the diagnosis of rheumatoid arthritis (RA), 9 of whom were mistakenly diagnosed and previously treated as RA patients. Only 3 patients had a satisfactory response to previous treatment with anti-inflammatory or disease modifying drugs. Complete or partial response of arthritis-related symptoms in INF-alpha treated patients was observed in 44% and 32%, respectively. Cryoglobulin became undetectable in 9 of 12 patients. However, a complete biochemical and virological end-of-treatment response was achieved in only 8 (36%) and 5 patients (20%), respectively. CONCLUSION: HCV arthropathy should be considered in the differential diagnosis of any patient with arthritis, even in the absence of liver disease. Treatment with interferon-alpha may lead to substantial clinical improvement of HCV-related arthritis even without a complete biochemical or virological response.

Kessel A, Rosner I, Zuckerman E, Golan TD, Toubi E. · Division of Clinical Immunology and Allergy, Bnai Zion Medical Center and Faculty of Medicine, Technion, Haifa, Israel. · J Rheumatol. · Pubmed #10743797 No free full text.

Abstract: OBJECTIVE: To investigate whether antikeratin antibodies (AKA) could be useful in the differential diagnosis of patients with rheumatoid arthritis (RA) compared to patients with hepatitis C virus (HCV) associated polyarthritis, who are seropositive for rheumatoid factor (RF). METHODS: AKA were assayed in 3 different groups of patients; all were RF seropositive: Group 1: 25 patients with HCV associated polyarthralgia or arthritis. Group 2: 33 patients with RA. Group 3: 13 patients with autoimmune disorders other than RA. Fifteen healthy individuals served as controls. RESULTS: AKA were detected in 20/33 patients with RA (60.6%) compared to only 2/25 patients (8%) with HCV associated arthritis (p < 0.0001). AKA were observed in 2/13 patients of Group 3 (15.3%). These results were also statistically different from those of patients with RA (p = 0.008). AKA were not found in the sera of the healthy controls. CONCLUSION: AKA is a useful marker to differentiate patients with RA from those with hepatitis C arthritis.

Toubi E, Monselise Y. · Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel. · Isr Med Assoc J. · Pubmed #15274545 links to  free full text

This publication has no abstract.