Rheumatoid Arthritis: Furuzawa-Carballeda J

Furuzawa-Carballeda J, Cabral AR, Zapata-Zuñiga M, Alcocer-Varela J. · Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. · J Rheumatol. · Pubmed #12563677 No free full text.

Abstract: OBJECTIVE: To determine the efficacy, tolerance and safety of subcutaneous injections of porcine type I collagen-polyvinylpyrrolidone (PVP) in patients with rheumatoid arthritis (RA). METHODS: Eleven patients with active RA on stable therapy with methotrexate (MTX) were enrolled in a 3 month prospective and longitudinal study. Patients were treated weekly with subcutaneous injections of 0.2 ml of collagen-PVP (1.7 mg of collagen) in the 8 most painful joints. The primary endpoints included the Ritchie index (RI), swollen joint count, disease activity score (DAS), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The secondary endpoints included morning stiffness, pain intensity on a visual analog scale (VAS), and the Spanish-Health Assessment Questionnaire Disability Index (HAQ-DI). Improvement was determined using American College of Rheumatology (ACR) response criteria. RESULTS: Collagen-PVP was safe and well-tolerated and there were no adverse events. Patients had a statistically significant improvement (p < 0.05) in basal versus 3 month's treatment in morning stiffness (Delta -32.3, -68.6%), RI (Delta -10.2, -46.4%), swollen joint count (Delta -10.7, -71.8%), VAS (Delta -39.9, -63.8%), HAQ-DI (Delta -0.5, -48.5%), DAS (Delta -1.35, -70.5%) and ACR20, 50, and 70 (80.0%; 60.0% and 20.0% respectively). We found no differences in serologic or hematologic variables. CONCLUSION: Collagen-PVP was a safe and well-tolerated drug for the short term treatment of RA. The combination of collagen-PVP plus MTX was more efficacious than MTX alone. However, double-blind placebo-controlled phase II and III clinical trials are necessary to determine whether this drug could be useful in the longterm treatment of RA.

Furuzawa-Carballeda J, Macip-Rodríguez PM, Cabral AR. · Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City, Mexico. · Clin Exp Rheumatol. · Pubmed #18799084 No free full text.

Abstract: OBJECTIVE: Pannus in osteoarthritis (OA) has only recently been characterized. Little is known, however, regarding the behavior of OA pannus in vitro compared to rheumatoid arthritis (RA) pannus. The purpose of our study was to compare OA with RA pannus. METHODS: Pannus and synovial tissue co-cultures from 5 patients with OA and 5 patients with RA obtained during arthroplasty were studied. Pannus was defined as the microscopic invasive granulation tissue covering the articular surface. Tissues were cultured for 7 days and stained with Alcian Blue technique. Interleukin-1beta (IL-1beta), IL-8, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were also determined in supernatants by ELISA. Cartilage oligomeric matrix protein (COMP), type II collagen, TNF-alpha, IL-10 and Ki-67 expression were also detected by immunohistochemistry. RESULTS: All patients had vascular or fibrous pannus. Synovial proliferation, inflammatory infiltrates and a decrease of extracellular matrix proteins were observed in all tissue samples. Chondrocyte proliferation was lower in OA than RA cartilage. OA synovial tissue expressed lower levels of proteoglycans than RA synoyium. Type II collagen levels were lower in OA than in RA cartilage. Significantly higher levels of IL-1beta were found in the supernatants of RA pannus compared to OA pannus (p<0.05). High but similar levels of TNF-alpha, IL-8 and TIMP-1 were detected in OA and RA pannus supernatants. IL-10, IL-12 and IFN-gamma were undetectable. CONCLUSION: RA and OA pannus had similar pro-inflammatory and anti-inflammatory cytokine profile expression. OA cartilage, synovial tissue and pannus had lower production of proteoglycans, type II collagen and IL-1beta. It remains to be elucidated why OA pannus invades the cartilage surface but does not cause the marginal erosions typically seen in RA.

Furuzawa-Carballeda J, Vargas-Rojas MI, Cabral AR. · Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15 Tlalpan, Mexico City 14000, Mexico. · Autoimmun Rev. · Pubmed #17289553 No free full text.

Abstract: Recent studies demonstrated an IL-17-producer CD4+ T cell subpopulation, termed Th17, distinct from Th1 and Th2. It represents a different pro-inflammatory Th-cell lineage. This notion is supported by gene-targeted mice studies. Mice lacking IL-23 (p19-/-) do not develop experimental autoimmune encephalomyelitis (EAE) or collagen-induced arthritis (CIA), while knockout mice for the Th1 cytokine IL-12 (p35-/-) strongly develop both autoimmune diseases. Disease resistance by IL-23 knockout mice correlates well with the absence of IL-17-producing CD4(+) T lymphocytes in target organs despite normal presence of antigen-specific-IFN-gamma-producing Th1 cells. This finding may thus explain previous contradictory reports showing that anti-IFN-gamma-treated mice, IFN-gamma- or IFNR-deficient mice develop CIA or EAE. TGF-beta, IL-6 and IL-1 are the differentiation factors of Th17 cells. IL-23 is dispensable for this function, but necessary for Th17 expansion and survival. The master regulator that directs the differentiation program of Th17 cells is the orphan nuclear receptor RORgammat. IL-27, a member of the IL-12/IL-23 family, potently inhibits Th17 development. Evidence suggesting rheumatoid arthritis and multiple sclerosis as primarily IL-17 autoimmune inflammatory-mediated diseases is rapidly accumulating. The IL-17/23 axis of inflammation and related molecules may rise as therapeutic targets for treating these and perhaps other autoimmune diseases.

Furuzawa-Carballeda J, Fenutria-Ausmequet R, Gil-Espinosa V, Lozano-Soto F, Teliz-Meneses MA, Romero-Trejo C, Alcocer-Varela J. · Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. · Clin Exp Rheumatol. · Pubmed #17181919 No free full text.

Abstract: OBJECTIVE: To determine the efficacy, tolerance and safety of intramuscular injections of porcine type I collagen-PVP in patients with RA in a long term-therapy. METHODS: The study was a double blind placebo-controlled and included 30 patients with active RA (ACR). Patients were treated with intramuscular injections of 2 ml of collagen-PVP (3.4 mg of collagen) or 2 ml of placebo during 6 months. The follow up was done during the next 6 months. The primary endpoints included the Ritchie index (RI), swollen joint count, disease activity score (DAS), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The secondary endpoints included morning stiffness, pain intensity on a visual analogue scale (VAS), and Spanish-health assessment questionnaire (HAQ-DI). Improvement was determined using American College of Rheumatology response criteria (ACR20, 50 and 70). RESULTS: Collagen-PVP was safe and well tolerated. There were no adverse events. Patients had a statistically significant improvement (p < 0.05) in collagen-PVP-treated vs. placebo at 6 months of treatment in: swollen joint count (7.1 +/- 0.8 vs. 16.0 +/- 1.6), RI (8.1 +/- 0.8 vs. 15.2 +/- 1.5), morning stiffness (9.2 +/- 3.1 vs. 29.1 +/- 5.9 min), HAQ-DI (50.0 +/- 10.8 vs. 22.9 +/- 10.3), DAS (3.0 +/- 0.2 vs. 4.9 +/- 0.3), ACR20 (78.6 vs. 71.4%), ACR50 (57.1 vs. 0%) and ACR70 (7.1 vs. 0%) and CRP (1.1 +/- 0.4 vs. 2.5 +/- 0.7). Patients treated with collagen-PVP required lower doses of methotrexate vs. placebo (12.6 +/- 0.6 vs. 14.2 +/- 0.7 at 6 months and 12.3 +/- 0.8 vs. 15.4 +/- 0.6 at 12 months; p < 0.05). Serological or haematological parameters remained unchanged. CONCLUSION: Collagen-PVP has been shown to be a safe and well-tolerated drug for the long-term treatment of RA. Combination of collagen-PVP plus methotrexate was more efficacious than methotrexate alone. This biodrug can be useful in the treatment of RA.

Furuzawa-Carballeda J, Rodríquez-Calderón R, Díaz de León L, Alcocer-Varela J. · Department of Cellular Biology, Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico. · Clin Exp Immunol. · Pubmed #12296865 links to  free full text

Abstract: The aim of the study was to determine whether collagen-polyvinylpyrrolidone (collagen-PVP) modifies some proinflammatory responses in synovium cultures from rheumatoid arthritis (RA) patients. Synovium from 10 RA patients were cultured with or without 1% collagen-PVP. Tissues on the 3rd, 5th and 7th culture day were sectioned and stained by the Herovici technique. Total collagen and type I/III collagen ratios were evaluated by the Woessner micromethod and by interrupted gel electrophoresis, respectively. Collagenolytic activity was assessed by degradation of [3H]-collagen in supernatants. TIMP-1, IL-1beta and TNF-alpha were determined in supernatants by ELISA, and the results were normalized by DNA concentration. IL-1beta, TNF-alpha, IL-6, IL-8, MMP-1, TIMP-1, Cox-1, VCAM-1, ICAM-1 and Fas/APO95 expression was evaluated by immunohistochemistry. Apoptosis was detected by TUNEL technique. The histological analysis and electrophoresis revealed a 1.7-fold increase of type III collagen in a time-dependent fashion in collagen-PVP-treated cultures. Proinflammatory cytokines (IL-1beta: 58 +/- 9 versus 22 +/- 10; TNF-alpha: 41 +/- 6 versus 11 +/- 3; IL-8: 59 +/- 12 versus 29 +/- 9; treated versus untreated), adhesion molecule (ICAM-1: 57 +/- 11 versus 29 +/- 15; VCAM-1: 49 +/- 7 versus 21 +/- 13; treated versus untreated) as well as Cox-1 (59 +/- 10 versus 20 +/- 3) expression was down-regulated in RA synovium treated. Meanwhile, TIMP-1 (36 +/- 7 versus 57 +/- 11) and Fas expression (20 +/- 10 versus 55 +/- 13) and apoptosis (14 +/- 3 versus 55 +/- 5) were up-regulated in treated cultures compared with controls. In supernatants, the collagenolytic activity, as well as IL-1beta and TNF-alpha, levels were all down-regulated in treated cultures (two, three, fourfold, respectively). The addition of collagen-PVP to synovium-induced down-modulation of some inflammatory parameters and an increase in apoptosis of synovial cells. Perhaps this mechanism could contribute to inhibit outgrowth of pannus formation and to down-regulate inflammation of joints in patients with RA.

Furuzawa-Carballeda J, Alcocer-Varela J. · Department of Immunology and Rheumatology, Instituto Nacional de la Nutrición Salvador Zubirán, Mexico City, Mexico. · Scand J Immunol. · Pubmed #10447928 No free full text.

Abstract: The aim of this work was to determine differences in pro- and anti-inflammatory cytokine and adhesion molecule expression in synovial tissue from patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Synovial tissue samples were obtained from patients with RA and OA, and from healthy individuals. The expression of mRNA of interleukin (IL)-1beta, IL-4, IL-6, IL-8, IL-10, IL-13, tumour necrosis factor-alpha (TNF-alpha) and transforming growth-factor-beta1 (TGF-beta1) was evaluated by the polymerase chain reaction (PCR). In addition, IL-8 and IL-10 transcripts were measured by quantitative PCR. The expression of IL-8 and IL-10 proteins was determined by immunoperoxidase staining. To evaluate the inflammatory stage of synovial tissue, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) protein expression was also determined. RA patients were found to display higher levels of adhesion molecules than patients with OA. PCR analysis showed a similar profile of cytokine transcripts between the OA and RA groups. Gene expression of IL-4 and IL-13 in synovium was undetectable. In contrast, IL-1beta, IL-6, IL-8, IL-10, TNF-alpha and TGF-beta1 transcripts were expressed by both groups. Increased levels of IL-8 and IL-10 transcripts and their proteins were observed in synovium from RA patients when compared to patients with OA and healthy controls. Thus, our data show that IL-8, IL-10, ICAM-1 and VCAM-1 expression levels are higher in synovial tissue from patients with RA than in similar tissue from patients with OA.

Furuzawa-Carballeda J, Alcocer-Varela J, Diaz de León L. · Department of Cellular Biology, U.N.A.M. Ciudad Universitaria, Mexico City, Mexico. · Ann N Y Acad Sci. · Pubmed #10415784 No free full text.

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