RHEUMATOID ARTHRITIS (VK)

What is Arthritis? There are 127 different kinds of

arthritis!

Osteoarthritis: progressive degeneration of joint cartilage. Minor degree of inflammation.

Rheumatoid arthritis: Severe inflammation that involves many joints and moves beyond musculoskeletal system.

Gout: Very painful form of arthritis characterized by the formation of uric acid crystals and severe inflammation.

Rheumatoid arthritis-

Chronic progressive, autoimmune disease in which there is joint inflammation, synovial proliferation, and destruction (crippling) of articular cartilages with waxing and waning course.

INFLAMMATORY MEDIATORS-

Cytokines

Interleukin 1

TNF-alpha

Autoimmune

IgM activates complements and release infl. Mediators

Neutrophil infiltration

Release of Lysosomal enzymes PGs

Damage to cartilage, bone errosion

vasodilatationedema & pain

• Diagnosis– Early diagnosis is the first step to easy control– History– Physical examination

• Findings 1.Morning stiffness >1hour 2.Symetrical joint swelling for 6 weeks. 3.Swelling in 3 or more joint areas lasting for

6 weeks or more. 4.Rheumatoid nodule. 5.Positve RF. 6.Radiographic erosions.

The treatment approach:1. Aims to reduce & possibly prevent damage to the joints & other

organs.2. Relief of pain –primary aim.3. Rx of pathology-

- Arrest of disease process- Modification of disease process

Nonpharmacological therapy:o Traditional physical therapy includes-heat & cold therapyo Motion exercises, Aerobic exercise with muscle strength.

Pharmacological therapy:o NSAIDso DISEASE MODIFYING ANTIRHEUMATIC DRUGS

[DMARDs]o Adjuvant: GLUCOCORTICOIDS

NSAIDs-

• Used in first; they afford symptomatic relief of

pain, swelling, morning stiffness, immobility.

• Donot arrest disease process.

Diclofenac sodium (75-100mg BD) Ibuprofen (200-400mg TDS) Naproxen (500mg single dose) Aspirin (3-5g/day) Indomethacin

Special precautions

- Peptic ulcer -Bleeding disorder

DISEASE MODIFYING ANTIRHEUMATIC DRUGS [DMARDs]

• Suppress the rheumatoid process i.e. arrest the basic process of joint destruction

• Bring about remission.

• Also called as SAARDs

»Contd.,

DMARDs• 1.Methotrexate (Mtx.)

• 2. Agents used in mild disease or in combination with MTX.• Hydroxychloroquine • Sulfasalazine• Minocycline

• 3.Traditional DMARDs -(limited used currently)• Gold salts (Aurothiomalate sodium)…..X• d-Penicillamine………………………..X• Azathioprine

• 4. Biological agents • Cyclosporine Leflunomide• Infliximab

• Methoterxate, Azathioprine, Cyclosporine are IMMUNOSUPPRESANT• Leflunomide IMMUNO MODULATOR

METHOTREXATE (Mtx)

• An anti metabolite (inhibit dihydrofolate reductase) inhibits folic acid synthesis.

• 1st line DMARD at present• RA-Primary MOA is anti-inflammatory rather than

antimetabolites -Inhibit cytokine production, cell mediated immune reaction, chemotaxis.

• Dose-7.5-10 mg oral weekly.• Onset of symptom relief is relatively rapid –

preferred for initial treatment

»Contd.,

• PK- - Oral BV of Mtx is variable, may effected by food

- Excretions is dec. in renal disease pt.

• S/E- -GIT distress (parenteral therapy effective to reduce

30mg/wk. i.v, less expensive.)

-Oral ulcer

-Hair loss

-Pneumonia (dec. By use of FA)

-Dose dependent progressive liver damage

Hydroxychloroquine• Antimalarial• Antirheumatic-found to induce remission in 50% patients.• MOA-inhibit inflammatory cells: monocytes interleukins,

B lymphocytes.• RA- long periods• Dose-200mg bd• Combined with MTX.• S/E- Retinal damage Corneal opacities Neuropathy, Myopathy Rash

Graying of hairsIrritable bowel syndrome

Sulfasalazine

• Combination of sulphapyridine and 5 aminosalicylic acid

• Inhibits generation of superoxides and cytokines by the inflammatory cells.

• Efficacy is equal to chloroquine.• 1-3g/day (3divided dose)• Few adverse effect / good alternative for Mtx

Minocycline• Group III broad spectrum antibiotic inhibit

arthritic inflammation.• Used in com. With MTX.

Gold salts (Aurothiomalate sodium)

• Introduced in 1929.• Gold is most effective agent for arresting

rheumatic process and preventing involvement of additional joints.

• It reduce chemotaxis, phagocytosis, macrophages and lysosomal activity and inhibit cell mediated immunity

• Benefit - 4-6wks• Starting dose10mg im/wk gradually inc. to

50mg/im/wk up to 1g.then maintain 50mg /im/ for few months.

»Contd.,

• PK:-Gold is heavily bound to plasma and tissue proteins, specially in kidney, stay in the body for years

• Toxicity:-– Vasodilatation, postural hypotension– Dermtitis, pruritic rash, – Albuminuria– Hepatitis, peripheral neuritis, pulmonary

fibrosis – Eosinophilia , bone marrow suppression

D-Penicillamine

• Copper chelating agent

• Gold compound like action but less efficacious.

• Toxicity is similar like gold

• Toxicity: Rash, Proteinurea, Kidney damage, bone marrow depression

• Dose: Start with 125-250mg OD, then 250mg BD.

Azathioprine

• Purine antimetabolite • Potent suppressant of cell mediated

immunity• Affect differentiation and function of T-cells

and natural killer cells• Remission in RA is less but some cases

not responding to gold may respond to it.• Given along with corticosteroid • Dose: 2.5-5mg/kg/day

Infliximab-• Chimeric IgG1-kappa monoclonal antibody• Anti TNF antibodies• Binds to soluble, bound both the forms of TNF

and thus causes dose dependent neutralization of TNF alpha.

• Useful in patients resistant to DMARDs and Methotrexate.

• Given IV, half life 8-12 days.• A/E: N,V,H and coughing.

other use-Crohn’s disease.

4.Biological agents

»Contd.,

Entanercept• Dimer consisting of TNF receptor joined to Fc

domain of human IgG…..binds to TNFα & β.• Given by SC route thrice a wk.• Effective in juvenile RA where Infliximab is found

ineffective.

Levamisole• Antihelminthic in a dose of 150 mg.• MOA-unknown• A/E- Agranulocytosis

Leflunomide:

• Recently introduced immunomodulator

• It inhibits proliferation of activated lymphocytes in

patients with active RA.

• Arthritic symptoms are suppressed and radiological

progression is retarded

• It is rapidly converted in the body to active

metabolite, which inhibits dihydroorotate

dehydrogenase and pyrimidine synthesis in actively

growing cells.

»Contd.,

23

• It is alternative for MTX or Sulfasalazine

• Dose: Loading dose of 100mg daily for

3days followed by 20mg OD (t1/2 2 wks)

• S/E: Elevation of liver enzymes, renal

impairment and teratogenic effect

• Adverse effects:- D, H, N, rashes, loss of

hair, thrombocytopenia, chest infection

• C/I:children, pregnant and lactating

women.

Corticosteriods

• Potent immunosuppressants and antiinflammatory drugs.

• Inducted at any stage in RA.• They do not arrest the rheumatoid process nor

prevent erosions.• Long term use of corticosteroid carries serious

disadvantages.. Low dose 5-10mg • High dose employed over short periods in cases

with severe systemic manifestations.