Rheumatoid Arthritis

Pharmacotherapy of rheumatoid arthritis

Contributed By:Dr. Preethi G Pai MD

Department of Pharmacology

KMC, 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

• Symptomatic drugs: NSAIDs• Disease modifying agents: Gold, d-

Penicillamine, Chloroquine or Hydroxychloroquine, Sulfasalazine, Leflunomide, Immunosuppressants-Methotrexate, Azathioprine, Cyclosporine

• Biologic response modifiers:Infliximab, Adalimumab, Etanercept, Anakinra

• Adjuvant drugs: Corticosteroids

classification

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

Chloroquinehydroxychloroquine

• Milder non erosive disease refractory to methotrexate/sulfasalazine; especially when only a few joints are involved

• Reduce monocyte IL-1⇛inhibit B-lymphocytes; also interfere with antigen processing

• 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

Hydroxychloroquine…

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 blocker-Anakinra

• 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 1997

•Abatacept:

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

PD

AT

E

- 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 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.

Abatacept: Mechanism of Action

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 intra-articular 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 DMARD-methotrexate, 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