Cause of disability.

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Rheumatoid Arthritis

• Cause of disability.
• Changes in the joint
• inflammation,
• proliferation of the synovium,
• errosion of cartilage bones.

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• 1 in every 100 people suffer from rheumatoid
  arthritis .
• 31 female preponderance.

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Disease Modifying Drugs

• Drugs with different chemical structure
  mechanism of action.
• DMARDs improve symptoms ? disease reactivity .
• Measurment of improvement

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Methotrxate

• A folic acid antagonist with cytotoxic
  immunosuppressive activity.
• It is a first choice DMARD .
• It is active in this condition at much lower
  doses than those needed in cancer chemotherapy.
• Mechanism of action.

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• 70 absorbed after oral administration.
• t½ 69 hours.
• Methotrexate's concentration is increased in the
  presence of hydroxychloroquine.

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• A potent anti rheumatoid drug, with a more rapid
  onset of action than other DMARD less adverse
  effects.
• ADR- pulmonary fibrosis, progressive
  dose-related hepatotoxicity.
• It is contraindicated in pregnancy.

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Sulfasalazine

• Rheumatoid arthritis, chronic inflammatory bowel
  disease.
• It is split into its components sulphapyridine
  5-aminosalicylic acid by bacteria in the colon.

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• ? IgA and IgM rheumatoid factor production are
  decreased.
• ½ T cell responses to concanavalin
• ? B cell proliferation.
• Only 1020 of orally administered sulfasalazine
  is absorbed.

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• Sulfapyridine is excreted after hepatic
  acetylation and hydroxylation.
• t½ 617 hours.
• ADR- GIT disturbances, malaise, headache, skin
  rash, leukopenia, impairment of folic acid
  absorption.
• Reversible infertility in men.

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Chloroquine and hydroxychloroquine

• It causes remission of rheumatoid arthritis but
  it does not retard the progression of bone damage.

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• Mechanism of action-suppression of T lymphocyte
  responses to mitogens,
• Decreased leukocyte chemotaxis,
• Stabilization of lysosomal enzymes,
• Inhibition of DNA and RNA synthesis,
• Trapping of free radicals.
• Pharmacokinetics-rapidly absorbed but only 50
  protein-bound in the plasma.

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• Extensively tissue-bound.
• Deaminated in the liver , t½ 45 days.
• Used in systemic discoid lupus ereythematosus.

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• Half the patients treated respond, effects appear
  after a month.
• ADR-ocular toxicity may occur at high dosages.
• Dyspepsia, nausea, vomiting, abdominal pain,
  rashes, and nightmares.

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Anticytokine Therapy

• Wide range of cytokines are expressed in the
  joints of rheumatoid arthritis patients, the most
  important isTNFa.
• TNF a effects cellular function via activation of
  specific membrane-bound TNF receptors (TNFR1,
  TNFR2).
• Administered soluble TNF receptors, by combining
  with soluble TNF a, can inhibit the effects of
  the endogenous cytokine.

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Infliximab

• Infliximab is a chimeric (25 mouse, 75 human)
  monoclonal antibody that binds with high affinity
  to soluble and possibly membrane-bound TNF-a.
• Is given as an intravenous infusion every 8
  weeks.
• The terminal half-life is 912 days.

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• Infliximab elicits up to a 62 incidence of human
  antichimeric antibodies.
• methotrexate ? human antichimeric antibodies.
• Infliximab is effective-
• in rheumatoid arthritis
• ulcerative colitis
• psoriasis,
• psoriatic arthritis,
• juvenile chronic arthritis.

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• Infliximab plus methotrexate.
• ADR-Upper respiratory tract infections, nausea,
  headache, sinusitis, rash, and cough, activation
  of latent tuberculosis, infusion site reactions

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Quiz?

• Infliximab produces its antirheumatic effects by
  direct
• (A) Inhibition of cAMP phosphodiesterase in
  monocytic leukocytes
• (B) Selective inhibition of COX-2
• (C) Enhancement of leukotriene synthesis at the
  expense of prostaglandin synthesis
• (D) Reduction of circulating active TNF-a levels
• (E) Inhibition of the production of autoantibodies

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Case
A 54-year-old woman presented with signs and
symptoms consistent with an early stage of
rheumatoid arthritis. The decision was made to
initiate NSAID therapy.
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Q1

• Which of the following patient characteristics is
  a possible reason for the use of celecoxib in the
  treatment of her arthritis?
  
• (A) A history of a severe rash after treatment
  with a sulfonamide antibiotic
  
• (B) A history of gout
  (C)
  A history of peptic ulcer disease
  
• (D) A history of sudden onset of bronchospasm
  after treatment with aspirin
• (E) A history of type 2 diabetes

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Q2

• Although the patient's disease was adequately
  controlled with an NSAID and methotrexate for
  some time, her symptoms began to worsen and
  radiologic studies of her hands indicated
  progressive destruction in the joints of several
  fingers. Treatment with a new second-line agent
  for rheumatoid arthritis was considered. This
  drug is available only in a parenteral
  formulation its mechanism of anti-inflammatory
  action is antagonism of tumor necrosis factor.
  The drug being considered is-
  
  
• (A) hydroxychloroquine
  
• (B) infliximab
  
• (C) methotrexate
  
• (D) chloroquine
  
• (E) Sulfasalazine