Drugs Used in Rheumatoid Arthritis and Gout Treatment PDF

DRUGS USED IN RHEUMATOID ARTHRITES AND GOUT THREATMENT Prof. Dr.Aşkın TAŞ RHOMATOID ARTHIRITIS • It is a chronic autoimmune disease of unknown etiology, systemic inflammation that can involve many joints at the same time. • Joint involvement can cause deformity and lead to significant disability...

DRUGS USED IN RHEUMATOID ARTHRITES AND GOUT THREATMENT Prof. Dr.Aşkın TAŞ RHOMATOID ARTHIRITIS • It is a chronic autoimmune disease of unknown etiology, systemic inflammation that can involve many joints at the same time. • Joint involvement can cause deformity and lead to significant disability over time. • Since it can affect other organs in the body, it is not correct to see this disease as a pure joint disorder. • In 85% of patients with rheumatoid arthritis, there is an autoantibody called rheumatoid factor (RF), which is mostly IgM in the structure of IgG, formed against the Fc part of IgG. GOUT • It is a chronic disease that manifests itself with hyperuricemia and acute arthritis seizures caused by impaired uric acid metabolism. • Over time, sodium urate deposits in the joints and kidneys can cause the formation of urate stones. • Painful distal monoarthritis leads to joint destruction, subcutaneous deposits (tofus) and kidney stones and injury. GOUT • Primary Gout • Secondary Gout • Causes: • Leukemia, myeloid metaplasia and polycythemia with increased nucleus destruction • Drugs that reduce uric acid excretion (thiazide group, fold group diuretics, pyrazinamide and ethambutol). • Hyperlactacidemia due to diabetic acidosis, starvation or alcoholism • Excessive hyperuricemia due to increased core destruction during antineoplastic therapy DRUGS USED IN RHEUMATOID ARTHRITES 1. 2. Symptom-modifying drugs Anti-arthritic (or antirheumatic) drugs or Disease modifying antirhumatic (DMARDs) that modify the disease DRUGS USED IN RHEUMATOID ARTHRITES Symptom-modifying drugs, • • Aspirin and similar NSAIDs with rapid anti-inflammatory activity are used in the treatment of rheumatoid arthritis, and glucocorticoids are used in special cases. DRUGS USED IN RHEUMATOID ARTHRITES • Symptom-modifying drugs • Glucocorticoids • Mechanism of action: • They prevent T lymphocytes from secreting cytokines (IL-1, IL-2, and TNF-α) and the initiation of a cellular immunological reaction, • They also inhibit the formation of antibodies by B lymphocytes (at high dose), • They inhibit the migration and phagocytosis ability of macrophages, monocytes, PMNLs, stabilize their lysosomes. • They increase lymphocyte destruction (Lymphocytopenia) (T>>B), • They inhibit the activation of the complement system DRUGS USED IN RHEUMATOID ARTHRITES • Symptom-modifying drugs • Glucocorticoids • Use in treatment • They are used in severe cases that cannot be controlled by NSAIDs. • The effects are immediate. • It slows down the formation of new bone erosions. • They also improve the extra-articular symptoms of RA, such as pericarditis and eye involvement. • In long-term treatment, the risks outweigh the benefits • It should be used for the shortest possible duration • Natural glucocorticoids are not used due to their mineralocorticoid effects • Prednisone and prednisolone, dexamethasone DRUGS USED IN RHEUMATOID ARTHRITES • Symptom-modifying drugs • Glucocorticoids • Side effects: • When high doses are used for a long time • Cushing like symptoms • Adrenal cortex atrophy • Intolerance to infection and stress • GI ulcers and bleeding • Glucose intolerance • Muscle weakness DRUGS USED IN RHEUMATOID ARTHRITES • Disease-modifying anti-arthritic (or antirheumatic) drugs (DMARDS) • They do not immediately affect the symptoms and physical signs of the disease. • They show late therapeutic efficacy by inhibiting the cellular immune response. • They usually do not have a direct analgesic effect. They have a late analgesic effect due to their inflammation-reducing effects. • Response begins 3-4 months after starting treatment. If there is no response to treatment within 6 months, they are discontinued and used as a second-line drug in RA. DRUGS USED IN RHEUMATOID ARTHRITES • Disease-modifying anti-arthritic (or antirheumatic) drugs (DMARDS) • Methotrexate, sulfasalazine are the best tolerated. • Chloroquine and hydroxychloroquine • Gold compounds (Orotioglucose, orothiomalate, oranofin) • Penicillamine • Azathioprine, cyclophosphamide and cyclosporine • Lymphflunomide • Cytokine modulators DRUGS MECHANISM OF ACTION Methotrexate Suppresses inflammation formation of neutrophils, macrophages, dendritic cells and lymphocytes by inhibition of amino-imidazolocarbamide ribonucleotide (AICAR) transformylase and thymidylate synthase Sulfasalazine RF synthesis is reduced, the response of T cells to concovalin is suppressed, inhibition of B cell proliferation Chloroquine and hydroxychloroquine Suppression of the T lymphocyte response, reduction of leukocyte chemotaxis, lysosomal enzyme stabilization, ROS formation ↓ Gold compounds Disrupt macrophage and Polymorphonuclar neutrophyl (PMN) functions Penicillamine ↓ The number of T lymphocytes Azathioprine Nucleotide antimetabolite (Purine synthesis inh) Cyclophosphamide DNA-alkylating agent suppresses T and B cell function Cyclosporine Kalsineurin inhibitor inhibit IL-1 and IL-2 formation and macrophage-T cell interaction and response. Leflunomide Dihydropholate Dihydrogenase inhbitor, inhibit (pyrimidine synthesis inhibitor ) T-cell profileration and B-cell autoantibody production Mycophenolate Mofetil İnozin monofosfat dehidrogenaz inhibitor (Pürin sentez inh) T ve B suppression of cell proliferation and leukocyte adhesion due to E and P select, ICAM-1 inhibition Anakinra IL1 receptor antagonist MONOCLONAL ANTIBODIES • They are produced by DNA recombination technology (biopharmaceutical or biotechnology product) • Monoclonal Antibodies: These are uniform antibodies produced by plasma cells formed by the proliferation of uniform cells stimulated against a single antigenic determinant. 9.11.2023 13 MONOCLONAL ANTIBODIES 9.11.2023 Joanna K. Soczynska et al. Neurotoxicology 2009;30:497-521 14 CYTOKINE MODULATOR MECHANISM OF ACTION TNF-alpha Blockers They bind to TNF-α and cause its inactivation Adalimubab It is a purely human IgG1. Sertozilumab pegol The humanized recombinant attached to TNF-α is the Fab fragment Etanersept It is a fusion protein obtained by combining the TNF-α receptor that binds TNF-α and the Fc part of IgG. Golimubab It is a human IgG monoclonal antibody that binds to TNF-α. İnfliksimab It is chimeric IgG1 with human fixed (Fc) regions and mouse variable regions. Abatasept It is a recombinant fusion protein obtained by fusion of the extracellular strand of cytotoxic T-lymphocyte-companion antigen 4 with the human IgG1 region. The antigen-presenting cell modulates the immune response by binding to CD80/CD86. Inhibits CD28 binding and T-cell activation on T cells Rituksimab Human-mouse chimeric monoclonal IgG1 that binds to the CD-20 molecule on the surface of B lymphocytes. Depletion of B lymphocytes, suppression of antigen presentation↓ to T cells and release of proinflammatory cytokines Tosilizumab It is recombinant humanized IgG1 that binds to the IL-6 receptor. DRUGS USED IN RHEUMATOID ARTHRITES METHOTREKSAT • DMARD is the first choice in the treatment of RA. • It is used in 50-70% of patients because it is easy to tolerate. • It is used at a lower dose (15-25mg per week) than the doses required for cancer chemotherapy. • It is used to treat RA, juvenile chronic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, Wegener's granulomatosis, giant cell arteritis, systemic lupus erythematosus (SLE). • Nausea and mucous membranes are the most common side effects. • Can cause leukopenia, anemia, stomatitis, GI ulcer and alopecia. • Also can increase liver enzymes and lead to hepatotoxicity (independent of dose). • Folic acid and leukoverin reduce side effects, but also reduce effectiveness. • Contraindicated in pregnancy. DRUGS USED IN RHEUMATOID ARTHRITES Chloroquine phosphate and hydroxychloroquine sulfate, • They are 4-aminoquinoline-derived antimalarial drugs, are not used extensively in the treatment of rheumatoid arthritis and lupus erythematosus. • They are not used as the first drug in these diseases, but as a backup drug in patients who do not respond adequately to aspirin and other classical anti-inflammatory analgesic drugs. • Treatment usually becomes evident only after 3-6 months. • Dose-dependent, ocular disorders and neuropsychiatric disorders are the most important side effects and drawbacks. • The most important ocular toxic effect is the formation of microdeposits in the cornea. • Retinopathy is a more serious side effect because it can cause vision loss; However, it is dependent on total dose and is rare. • Ophthalmoscopic monitoring should be performed at the beginning of treatment and every 3-6 months thereafter. DRUGS USED IN RHEUMATOID ARTHRITES Gold compounds: • Orothioglucose (i.m), sodium orothiomalate (i.m) and oranofin (oral) • Organic gold compounds are used in adult, juvenile and psoriasis type active rheumatoid arthritis in patients who do not respond adequately to classical anti-inflammatory drug therapy. • Toxic effects can occur at any time, including the start of treatment; The incidence of side effects is around 50% and can sometimes be serious enough to interrupt treatment. • When using gold compounds, NSAIDs are not discontinued. • The most common side effects during gold treatment are dermatitis and inflammation of the mucous membranes • Nephrotoxic, hepatotoxic • Anaphylactoid reaction DRUGS USED IN RHEUMATOID ARTHRITES Penisilamin: • It is a sulfidrille chelator for use against Wilson's disease and heavy metal poisoning. • It has been found to be effective only against some types of RA. • Penicillamine is similar to gold compounds in that its toxicity is excessive, sensitivity to the therapeutic effect of the drug varies greatly between individuals, and improvement in appropriately responding cases occurs after a few months of administration. • The most common side effects are itching, skin rashes and taste disturbances. • The most serious but rare are bone marrow depression, nephrotic syndrome and other kidney disorders and autoimmune syndromes (myasthenia gravis, polymyositis, lupus-like syndrome) DRUGS USED IN RHEUMATOID ARTHRITES • Anakinra: • (Kineret® from abroad) is an interleukin-1 receptor antagonist (IL-1Ra). • It is used in diseases such as RA, adults Still's disease (high fever, skin rash, arthritis), gout, pseudo-gout (calcium pyrophosphate in the joint), juvenile arthritis, ankylosing spondylitis (AS) and familial mediterranean fever (FMF) when there is no response to other treatments. • Anakinra binds to this protein called IL-1 and prevents it from exerting its negative effects. • The therapeutic effects occurs in 4-6 weeks in RA and immediately in Adult Still's Disease, gout, FMF and other autoinflammatory diseases. DRUGS USED IN RHEUMATOID ARTHRITES • Leflunomid: • It has been found to be at least as effective as methotrexate and sulfasalazine in improving disability and the progression of radiological symptoms of RA. • It is used in patients with active RA and psoriatic arthritis who cannot tolerate these medications. • The therapeutic effect generally begins after 4 to 6 weeks and may increase further up to a period of 4-6 months. DRUGS USED IN RHEUMATOID ARTHRITES • Leflunomid: • Prior to initiation of treatment, complete blood counts, including ALT (SGPT), leukocytes and platelets should be performed with every 2 weeks and every 8 weeks thereafter during the first 6 months of treatment. • During the use of leflunomide it is necessary to use an effective method of contraception. • After leflunomide is discontinued, it is necessary not to have children for two years. • Live vaccines should not be used. DRUGS USED IN RHEUMATOID ARTHRITES • Sulfasalazin: • It is metabolized by bacteria in the intestinal flora to sulfapyridine and 5-aminosalicylic acid. • Sulfapyridine is thought to be effective in the treatment of RA. • RA is used in juvenile chronic arthritis, ankylosing spondylitis and associated uveitis. • Nausea, vomiting, headache and skin rash are the most common side effects. • Neutropenia in 1-5% • Pulmonary toxicity • Men have reversible infertility (not observed in women). • It is not teratogenic. DRUGS USED IN RHEUMATOID ARTHRITES • Rituksimab: • Human-mouse chimeric monoclonal IgG1 that binds to the CD-20 molecule on the surface of B lymphocytes. • Suppression of B lymphocyte depletion, decreases antigen presentation to T cells and inhibits the release of pro-inflammatory cytokines • They are used in the treatment of chronic lypmhocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma. • One or more TNF-alpha antagonists are given in combination with methotrexate in patients who do not respond adequately to the drug. DRUGS USED IN RHEUMATOID ARTHRITES • Abatacept: • It inhibits CD28 binding and T-cell activation on T cells • It is used in the treatment of moderate to severe RA that does not respond to TNF antagonist and other DMARDS. • It is also used in the treatment of juvenile arthritis. DRUGS USED IN RHEUMATOID ARTHRITES • Tocilizumab: • It is recombinant humanized IgG1 that binds to the IL-6 receptor. • It is used to treat moderate-to-severe active RA in adult patients who do not respond adequately to one or more TNF-alpha antagonist treatment. • It can be used alone or in combination with nonbiological DMARDs. • Can cause tuberculosis, fungal, viral and other opportunistic infections. • A decrease in neutrophil and platelet count may occur. • Liver enzymes and lipid profile should also be monitored. DRUGS USED IN RHEUMATOID ARTHRITES • Anti-TNF-AFA Monoclonal Antibodies: • They bind to TNF-α, causing its inactivation • They are used to threat rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, psoriatic arthritis. • M. Tuberculosis, hepatitis B virus and invasive systemic fungal infections or the risk of their reactivation are frequently observed during treatment. • Increase in malignancies such as lymphoma are observed. DRUGS USED IN GOUT THREATMENT • OBJECTIVES • To reduce the symptoms of an acute attack • To reduce the frequency of recurrence of attacks • To reduce serum urate levels • DRUGS USED • Drugs that relieve inflammation and pain (NSAIDs, colchicine, glucocorticoids) • Drugs that prevent the inflammatory response to crystals (colchicine, NSAIDs) • Those that inhibit urate formation (allopurinol, febuxostat) or increase urate excretion (probeneside, benzbromaron) DRUGS USED IN GOUT THREATMENT • • • • • • Colcichin Allopurinol Febuxostat ksantin oxidase inhibitor Probenecid Benzbromaron Antiinflammatory analgesics: İndomethacin, naproxen, piroxicam, sulindakc fenoprofen, ibuprofen • Colcichin and antiinflammatory drugs are used during episodes. • Others are used for prophylaxis. DRUGS USED IN GOUT THREATMENT • Colcichin • Gout, FMF and Behçet's Disease • It is an alkaloid obtained from the onion and seed of the Crocus (Colchicum autumnale) plant and has been used in the treatment of gout since ancient times. • It does not affect uric acid metabolism and has no uricosuric effect. • It has an anti-inflammatory effect only in gouty arthritis, it has no such effect in other types of arthritis. • It has benefficial effects also in FMF (recurrent episodes of fever, abdominal pain, chest pain and joint pain) and Behçet's syndrome DRUGS USED IN GOUT THREATMENT • Colcichin • It stops cell division by inhibiting microtubulus and spindle formation (antimitotic effect, neutrophil and GI epithelium). • Acute gouty arthritis is initiated by phagocytosy of urate crystals which precipitates in the periarticular tissue, by granulocytes. • Colchicine inhibits the phagocytosis of urate crystals, thereby preventing recrystallization and leukocyte migration, reducing the secretion of chemotactic factors and superoxide anions from leukocytes. DRUGS USED IN GOUT THREATMENT • Colcichin • Colcichin is found in high proportions in the kidney, liver and spleen when applied. • In case of renal and liver insufficiency and dialysis, it is necessary to reduce the dose. • • Side effects: • Nausea, vomiting, diarrhea, abdominal pain, hemorrhagic gastropathy • Bone marrow suppression (leukopenia, granulocytopenia, thrombocytopenia), rhabdomyolysis DRUGS USED IN GOUT THREATMENT • Allopurinol • Reduces the formation of uric acid; It has no uricosuric or anti-inflammatory effect. • It is an inhibitor of the xanthine oxidase enzyme , which provides the conversion of hypoxanthine to uric acid • The most common side effects of allopurinol are skin rashes of varying severity, ranging from urticaria to exfoliative dermatitis. These usually appear after several months of treatment. • The drug also has a hepatotoxic effect. • The drug can cause fever, vasculitis and leukopenia. DRUGS USED IN GOUT THREATMENT • Allopurinol • It is indicated in the long-term treatment of hyperuricemia related to primary or secondary gout. • It prevents the progression of the disease in primary or secondary uric acid nephropathy with or without signs of gout. • It is indicated in the treatment and prophylaxis of secondary hyperuricemia in patients with leukemia, lymphoma and other neoplastic diseases undergoing cancer chemotherapy. • Allopurinol prevents complications of hyperuricemia such as acute uric acid nephropathy, kidney stones or urate accumulation in tissues in these patients. DRUGS USED IN GOUT THREATMENT • Probeneside • In the kidneys, it affects the proximal tubules, reducing the reabsorption of urates in the ultrafiltrate. • Thus, it exerts a uricosuric effect and lowers uricemia. • It has no effect on uric acid metabolism; It does not have an anti-inflammatory effect. • It is used continuously for the prophylaxis of gout attacks in people with gout or secondary hyperuricemia. • Probenecid is an acidic drug that is secreted by proximal tubule cells. • When it arrives at the side of the cell from the peritubular face of the lumen, it does not completely detach from the carrier, but remains partially bound, unlike many other drugs carried by the same carrier. • It cannot take up and bind uric acid from the lumen therefore uric acid reabsorption is reduced. DRUGS USED IN GOUT THREATMENT • Rasbukiraz • Recombinant urate oxidase enzyme Lowers urate level better than allopurinol It is used in the treatment of acute hyperuricemia after antineoplastic therapy in pediatric patients with leukemia, lymphoma and solid tumors No indication for gout