rheumatoid arthritis
DESCRIPTION
Theory for MBBS undergraduatesDr.U.P.Rathnakarhttp://www.pharmacologyfordummies.blogspot.com/TRANSCRIPT
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