Rheumatoid Arthritis

Pharmacotherapy of rheumatoid arthritis Contributed Dr. Preethi Department KMC,

By: G Pai MD of Pharmacology Mangalore

Rheumatoid arthritis • Chronic, systemic, inflammatory disease predominantly affecting joints & periarticular tissues

etiology

• Autoimmune disease: autoantibodies to Fc portion of IgG antibody are produced by B lymphocytes • High titres of serum RA factor

Pathophysiology

• Inflammation • Synovial proliferation • Joint tissue destruction

Principles of management Rest to acutely inflamed joints Relief of pain & stiffness Reduction of inflammation Prevention of articular damage Preservation of joint function & muscle strength • Improve general well being of patient • • • • •

PHARMACOTHERAPY OF RHEUMATOID ARTHRITIS

classification • Symptomatic drugs: NSAIDs • Disease modifying agents: Gold, dPenicillamine, Chloroquine or Hydroxychloroquine, Sulfasalazine, Leflunomide, ImmunosuppressantsMethotrexate, Azathioprine, Cyclosporine • Biologic response modifiers:Infliximab, Adalimumab, Etanercept, Anakinra • Adjuvant drugs: Corticosteroids

methotrexate • DMARD of first choice & standard drug • Immunosuppressant & antiinflammatory agent • Dihydrofolate reductase inhibitor • Inhibits cytokine production, chemotaxis & cell mediated immune reaction

methotrexate • Oral low dose (7.5-15 mg) weekly regimen • Rapid onset of action⇨ preferred for initial treatment • Sustained & predictable response • Variable oral bioavailability; affected by presence of food

methotrexate • Side effects: nodulosis, oral ulceration & GI upset – Prolonged courses: liver cirrhosis,⇪ chest infections

• C/I: Pregnancy, lactation, liver disease, kidney disease, active infection, leucopenia & peptic ulcer

azathioprine • Purine antimetabolite • Azathioprine ⇨ 6-mercaptopurine Thiopurine methyl transferase • Suppressant of cell mediated immunity & inflammation • Azathioprine + corticosteroids: Steroid sparing effect • Not combined with methotrexate

Mycophenolate mofetil Semisynthetic fungal antibiotic Active metabolite: Mycophenolic acid Inhibits B & T cell proliferation Inhibits inosine monophosphate dehydrogenase ⇨ reduces production of cytotoxic T cells • Also interferes with leucocyte adhesion • • • •

sulfasalazine • Sulfapyridine + 5-amino salicylic acid • Active moiety: sulfapyridine • Suppresses generation of superoxide radicals & cytokine elaboration • Used as second line drug in milder cases • A/E: neutropenia/thrombocytopenia, hepatitis

Chloroquine hydroxychloroquine • Milder non erosive disease refractory to methotrexate/sulfasalazine; especially when only a few joints are involved • Reduce monocyte IL-1⇛inhibit Blymphocytes; also interfere with antigen processing

Hydroxychloroquine… • HYDROXYCHlOROQUINE IS PREFERRED OVER CHLOROQUINE – As they are given for long periods in RA: predominent toxicty⇛ retinal damage & corneal opacity

• A/e: rashes, graying of hair, irritable bowel syndrome, myopathy & neuropathy

leflunomide • Similar in efficacy to Methotrexate • Faster onset of action • Symptomatic cure + retards radiological progression of disease • Used as alternative to methotrexate • Leflunomide + Methotrexate ⇛⇪Hepatotoxicity • Can be combined with Sulfasalazine

Leflunomide… • Leflunomide ⇛active metabolite ⇨ inhibits dihydro-orotate dehydrogenase & pyrimidine synthesis in actively divided cells • Inhibits proliferation of activated lymphocytes in active RA • Long t1/2= 2 weeks

Adverse effects of Leflunomide

• Diarrhoea, headache, nausea, rashes, loss of hair, thrombocytopenia, leucopenia, chest infections, hepatic transaminases • C/I: Pregnant, Lactating & children

gold • Most effective agent to arrest rheumatoid process – Reduces • chemotaxis • Phagocytosis • macrophage & lysosomal activity • monocyte differentiation – inhibits cell mediated immunity – Prevents joint destruction; induces bone healing

Gold… • Highly cumulative drug; high toxicity • A/E: postural hypotension, dermatitis, pruritic rashes, stomatitis, membranous glomerulonephropathy (albuminuria), hepatitis, peripheral neuritis, encephalopathy, pulmonary fibrosis & eosinophilia • Salts used: Sodium aurothiomalate, aurothiosulfate, aurothioglucose

Auranofin Orally active Bioavailability: 25% Lower efficacy Lower toxicity to skin, mucous membranes, kidney & bone marrow • Main A/E: diarrhoea, abdominal cramps • • • •

– Rarely pruritis, taste disturbances, mild anaemia & alopecia

BIOLOGIC RESPONSE MODIFIERS

TNF-alpha blockers • INFLIXIMAB • ADALIMUMAB • ETANERCEPT

infliximab • Chimeric monoclonal anti TNF antibody • Binds to soluble + membrane bound TNF-alpha ⇨ dose dependent neutralisation ⇛down regulation of macrophage & T cell functions⇛ prevents release of cytokines

infliximab • Distributed mostly in vascular compartment • Terminal t1/2= 8-12 days • Not metabolised by hepatic cytochrome P450 enzymes • A/E: headache, nausea, rash & cough – Can ppt URTI; activation of latent TB – Antibodies may develop to infliximab

Infliximab • Given IV once in 2 months • More beneficial when combined with methotrexate • Sustained & consistent benefit even in DMARD & methotrexate resistant cases • Also approved for Crohn’s disease, juvenile chronic arthritis, psoriatric arthritis, wegener’s granulomatosis & sarcoidosis

adalimumab • Recombinant human-anti-TNF monoclonal antibody • Given SC • T1/2 = 9-14 days • Similar actions as infliximab • Lesser immunogenicity

etanercept • Genetically engineered fusion protein • Dimer: TNF receptor+ Fc domain of human IgG • Binds to TNF alpha & also TNF beta (cytokine lymphotoxin alpha) • Given SC twice a week • Useful in RA including juvenile RA where infliximab is less effective

Interleukin-1 blockerAnakinra • Used in combination with methotrexate in methotrexate resistant cases

Potential side effects • • • •

Injection site reactions Infections & neutropenia Malignancy Immunogenicity

•Given Subcutaneously OD •C/I: in case of infection Never to be combined with TNF alpha inhibitors

Toclizumab • Humanized anti-interleukin 6 receptor agent that blocks the action of the inflammatory cytokine. • Phase III trials worldwide • Licensed in Japan as an orphan drug for treatment of Castleman's disease.

STATUS OF NEWER BIOLOGICS

• Rituximab: FDA-approved for lymphoma in

UPDATE

1997 - FDA-approved February, 2006 for - patients with moderately severe RA - inadequate response to >1 DMARDs - use in combination with MTX

•Abatacept: - FDA-approved December, 2005 for - patients with moderately severe RA - inadequate response to >1 DMARDs - use as monotherapy or with DMARDs other than TNF antagonists or anakinra

Rituximab: Mechanism of Action

Abatacept: Mechanism of Action

Abatacept modulates the immune response by binding to CD80/CD86 on an antigen-presenting cell (APC), such as a dendritic cell, thus preventing costimulatory binding of CD28 on naive T cells and attenuating T-cell activation.

Tenidap sodium • IL-1 synthesis inhibitor

corticosteroids • Potent immunosuppressant & antiinflammatory action • Adjuvant drugs: symptomatic improvement + arrest rheumatoid process + delay bony erosions • Low doses-Disadv: steroid dependency • High doses over short periods for severe systemic manifestations

Indications for local intraarticular therapy • One or two joints : resistant in patients otherwise well controlled on medical therapy • Patients with one active joint in whom oral NSAID are contraindicated Caution: Avoid injection more often than once in 3 months

Choice of drug therapy • Early treatment with DMARD ⇨ improves quality of life & long term outcome • Aspirin/NSAID given initially for quick symptomatic relief • Start concurrently DMARDmethotrexate, hydroxychloroquine, sulfasalazine • If uncontrolled-combination of DMARD

Drug therapy… • Severe cases: steroids in large doses ⇨ tapered to maintenance doses • Methotrexate (+folic acid) currently favored – – – –

Relative rapid onset of action Maintains sustained improvement Relative safety High level of patient compliance