Immunological Aspect of Ozone in Rheumatic Diseases Prof. Dr. med. Z. Fahmy Chief Consulting Rheumatologist Augusta Clinic for Rheumatic Diseases And Rehabilitation Bad Kreuznach Germany
Rheumatoid arthritis is an autoimmune disease Rheumatoid arthritis is associated with immunological and inflammatory mechanisms. The initial, not yet well defined immunological mechanisms lead to inflammatory reactions which alter between acute and chronic stages. Immunological event Cytokines Acute reaction New cytokines Chronic reaction Inflammation New cytokines
Exogenous mechanisms Immuno-inflammatory response Endogenous mechanisms Natural predisposition to disease The question of balance Natural host defense Pro-inflammatory cytokines Anti-inflammatory cytokines Symptoms, tissue lesions
RA: IMPACT, PATHOGENESIS, AND TREATMENT Cytokine disequilibrium Adapted from Feldmann M et al. Cell 85:307-310, 1996 and Moreland LW et al. Arthritis Rheum 40:397-409, 1997.
RA: IMPACT, PATHOGENESIS, AND TREATMENT Physical manifestations Joints usually involved symmetrically, with wrists, MCP joints, and PIP joints most commonly affected 1 Articular manifestations include tenosynovitis, which diminishes strength and flexibility 1,2 Extra-articular manifestations most prevalent when RF is positive; up to 50% of patients demonstrate nodules 1,2 References: 1. Harris ED Jr, in Kelley WN, Harris ED Jr, Ruddy S et al, Textbook of Rheumatology. Vol 1. 4th ed. Philadelphia, Pa: WB Saunders Company, 1993, pp 874-911. 2. Anderson RJ, in Klippel JH (ed), Primer on the Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation, 1997, pp 161-167.
RA: IMPACT, PATHOGENESIS, AND TREATMENT The inflammatory cascade Activation of T cells triggers a series of intercellular reactions 1 T Cell B Cell Macrophage Lymphocytes and macrophages release proinflammatory cytokines 1,2 Pannus Cytokines induce synovial proliferation and release of destructive enzymes 1,2 Cartilage TNF IL-1 References: 1. Rosenberg AE, in Cotran RS, Kumar V, Robbins SL, Robbins Pathologic Basis of Disease. 5th ed. Philadelphia, Pa: WB Saunders Company, 1994, pp 1213-1271. 2. Goronzy JJ, Weyand CM, in Klippel JH (ed), Primer on the Rheumatic Diseases. 11th ed. Atlanta, Ga: Arthritis Foundation, 1997, pp 155-161.
RA: IMPACT, PATHOGENESIS, AND TREATMENT The role of cytokines Serve as natural mediators of cell function 1 Induce production of other cytokines 2 Reduce inflammation by binding to cell-surface receptors or preventing cell activation 3 Soluble TNF receptor TNF IL-1 Cell-surface TNF receptor References: 1. Arend WP, Dayer J, in Kelley WN, Harris ED Jr, Ruddy S et al, Textbook of Rheumatology. Vol 1. 4th ed. Philadelphia, Pa: WB Saunders Company, 1993, pp 227-247. 2. Baumgartner SW. South Med J 93:753-759, 2000. 3. Moreland LW. Cleve Clin J Med 66:367-374, 1999.
RA: IMPACT, PATHOGENESIS, AND TREATMENT Importance of targeting TNF The binding of TNF to cell-surface receptors triggers multiple destructive events 1 Soluble TNF receptor TNF Cell-surface receptor TNF induces production of other proinflammatory cytokines, including IL-1 1 Thus, targeting TNF may inhibit the destructive activity of both TNF and other destructive cytokines 2,3 Cell activation References: 1. Moreland LW. J Rheumatol 26(Suppl 57):7-15, 1999. 2. Choy EHS, Panayi GS. N Engl J Med 344:907-916, 2001. 3. Feldmann M, Brennan FM, Maini RN. Cell 85:307-310, 1996.
RA: IMPACT, PATHOGENESIS, AND TREATMENT The central role of TNF Drives events in the inflammatory cascade 1,2 Triggers production of other cytokines, including IL-1 1,2 TNF PROINFLAMMATORY IL-6, IL-8, IFN, LT IL-1 ANTI-INFLAMMATORY IL-4, IL-10, TGF stnfr, sil-1r, IL-1Ra Adapted from Feldmann et al, 1996. 1 References: 1. Feldmann M, Brennan FM, Maini RN. Cell 85:307-310, 1996. 2. Baumgartner SW. South Med J 93:753-759, 2000.
RA: IMPACT, PATHOGENESIS, AND TREATMENT Destructive effects of TNF
IL-1 Plays a Pivotal Role in Many Mechanisms of the RA Disease Process Synovial inflammation Bone destruction Impairment of tissue repair process IL-1 Pannus formation Production of prostaglandins and inflammatory mediators Cartilage degradation Dinarello C. N Engl J Med. 2000;343:732-734; van den Berg W. Ann Rheum Dis. 2000;59(suppl 1)i81-i84; Joosten L et al. J Immunol. 1999;163:5049-5055; Gravallese E, Goldring S. Arthritis Rheum. 2000;43:2143-2151; Bresnihan B, Dayer J-M. IL-1Ra Therapy in the Treatment of Rheumatoid Arthritis. 2001, Martin Dunitz Ltd, London, UK.
RA is Characterised by Synovitis and Joint Destruction Synovial membrane NORMAL RA Inflamed synovial membrane Cartilage Pannus Major cell types: T lymphocytes macrophages Minor cell types: fibroblasts plasma cells endothelium dendritic cells Capsule Synovial fluid Major cell type: neutrophils Cartilage thinning Adapted from Feldmann M, et al. Ann Rev Immunol. 1996;14:397-440; Pincus T. Drugs. 1995;50(suppl 1):1-14; Tak P, Bresnihan B. Arthritis Rheum. 2000;43:2619-2633.
IL-1 Plays a Pivotal Role in the Inflammatory and Destructive Processes of RA IL-1 Activates monocytes/ macrophages Induces fibroblast proliferation Activates chondrocytes Activates osteoclasts Inflammation Synovial pannus formation Cartilage breakdown Bone resorption Dinarello C. N Engl J Med. 2000;343:732-734; Arend W, Dayer J-M. Arthritis Rheum. 1990;33:305-315; van den Berg W. Ann Rheum Dis. 2000;59(suppl 1):i81-i84.
Role of IL-1 in Joint Destruction IL-1 has a higher potency for inducing joint destruction than TNF 1 In TNF-transgenic mice, arthritis can be completely inhibited by blocking IL-1 signalling 2 TNF-independent IL-1 production has been shown in models 3 No erosive arthritis is observed in IL-1 -deficient mice 4 Spontaneous, destructive arthritis is observed in IL-1Ra-deficient mice 5 1. van de Loo F, et al. Arthritis Rheum. 1995;38:164-172; 2. Probert L, et al. Eur J Immunol. 1995;25:1794-1797; 3. van den Berg W. Ann Rheum Dis. 2000;59(suppl 1):i81-i84; 4. van den Berg W. Semin Arthritis Rheum. 2001;30 (suppl 2):7-16; 5. Horai R, et al. J Exp Med. 2000;191:313-320.
IL-1 Plays a Central Role in Cartilage Destruction Proteoglycan synthesis (aggrecanase) IL-1 Chondrocyte death (NO, inos) Collagen damage ( prommp-13, type II collagen) Immune complex deposits Cartilage surface erosion (pannus, PMN) inos = inducible nitric oxide synthase; MMP = matrix metalloprotease; NO = nitric oxide; PMN = polymorphonuclear cell Adapted from van den Berg W. Semin Arthritis Rheum. 2001;30(suppl 2):7-16; van den Berg W. Ann Rheum Dis. 2000;59(suppl 1):i81-i84; Dinarello C. Blood. 1996;87:2095-2147.
IL-1 Regulates Osteoclast Differentiation and Activity Osteoclast progenitor + IL-1 OPGL + IL-1 induces osteoblast apoptosis IL-1 Osteoblast Osteoclast OPGL = osteoprotegerin ligand BONE Adapted from Tsuboi M, et al. J Lab Clin Med. 1999;134:222-231; Gravallese E, Goldring S. Arthritis Rheum. 2000;43:2143-2151; Gravallese E, et al.arthritis Rheum. 2000;43:250-258.
The effect of ozone of the immune system 1. The effect of the immune competent cells of the lymphocytes 2. The induction of the cytokin through the effect of the lymphocytes 3. Regulation of the immune system
Cytokin-Induction (in %) In dependence on ozone concentration 250 200 oxygen 42 µg 78 µg 150 100 50 0 IL-1 IL-2 GM-CSF
RA: IMPACT, PATHOGENESIS, AND TREATMENT The evolving RA treatment paradigm CURRENT APPROACH EARLY TREATMENT EVOLVING PARADIGM EARLY TREATMENT Traditional DMARDs Aggressive DMARD therapy Biologic agent Monotherapy or Combination IF POOR RESPONSE IF POOR RESPONSE IF DISEASE CONTROLLED Add additional DMARDs Add biologic agent Combination therapy Discontinuation/ reduction of DMARDs
Study identification and inclusion criteria Groups of patients with Rheumatoid Arthritis each group n = 25 patients 1. Group: NSADs Diclofenac 100 150 mg 2. Group: Ozone 3 x weekly 3. Group: Ozone + Methotrexat 7,5 15 mg 4. Group: Ozone + Enbrel 50 mg weekly + MTX 7,5 15 mg
Mean score (+/-se) Serum CRP concentration (mg/l) over time 50 45 Ozone MTX MTX+Ozone 40 35 30 25 20 15 10 5 0 0 30 60 90 120 150 180 Study Day
Patient assessment of disease activity over time (group 1 and 2) 5 4,5 4 Pain At Rest Tenderness Pain active Mot. Joint Swelling Joint Effusion 3,5 3 2,5 2 1,5 1 0,5 0 30 60 90 120 150 180 Study Day
5 4,5 4 3,5 Patient assessment of disease activity over time (group 3 and 4) Pain At Rest Tenderness Pain active Mot. Joint Swelling Joint Effusion 3 2,5 2 1,5 1 0,5 0 30 60 90 120 150 180 Study Day
The effect of different groups of the cytokines % I n h i b i t i o n 120 100 80 60 40 20 Diclofenac Ozone MTX+Ozone MTX+Ozone+Enbrel 0 IL-1 IL-6 TNF
Improvement baseline, 180 days : MTX-Enbrel-Ozone S e v e r i t y 3,5 3 2,5 2 1,5 1 Pain at rest Tenderness Pain active mot. Joint swelling Joint effusion 0,5 0 30 60 90 120 150 180 Days
Improvement baseline, 180 days: (without Ozone) S e v e r i t y 3 2,5 2 1,5 1 Pain at rest Tenderness Pain active mot. Joint swelling Joint effusion 0,5 0 30 60 90 120 150 180 Days
Summary 1. Ozone is more effective in combined form than single form in the treatment of RA 2. Ozone provided efficacy comparable to combination of MTX 3. Rapid significant decrease in CRP and ESR in combined form (MTX and Ozone) than in single form 4. The incidence of clinically significant treatment in relation laboratory abnormalities was similar among treatment groups with NSADs 5. The ability of ozone to reduce level of acute phase Proteins, and Enbrel in the blood was significant greater in combined form than in single form 6. The ozone effect of the cytokines could be due to either inhibition of the production of cytokines or inhibition of response to cytokines 7. Ozone in clinically and biochemical superior in combined form than single form in treatment of RA
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