Goals of Arthritis Therapy

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Goals of Arthritis Therapy

• Relieve pain/inflammation
• Minimize risks of therapy
• Retard disease progression
• Provide patient education
• Prevent work disability
• Enhance quality of life and functional
  independence

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• NSAID
• Corticosteroids
• Disease-modifying anti-rheumatic drugs (DMARDs)
  -- Hydroxychloroquine (Plaquenil/Geniquin)
  ????/??-- Salfasalazine ( Salazopyrine ) ??--
  D-penicillamine (Metalcaptase )
• Immunosuppressive agents ( Cytotoxic agnets )--
  Cyclophosphamide ( Endoxan ) ???-- Azathioprine
  ( Imuran ) ???/???-- Methotrexate ( MTX ) --
  Cyclosporine ( Sandimmun ) ???/??? -- Cellcept
  (Mycophenolate Mofetil) ???/ Myfortic
  (mycophenolic acid) ???

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• Biologic agents-- Tumor necrosis factor
  inhibitors a. Etanercept ( Enbrel ??)
  b. Infliximab ( Remicade ) c. Adalimumab
  (Humira ??)
• -- IL-1 antagonists -- Anakinra
• -- Endothelin receptor antagonist ( Bosentan )

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Mechanisms of NSAIDs
Arachidonic acid
Glucocorticoids
COX-1(constitutive)
COX-2(inducible)
Cox-2 inhibitor Celecoxib Etoricoxib Vioxx
Conventional NSAID
PGE2

• Inflammation
• Neoplasia
• Promotes tumor angiogenesis
• Induces tumor cell growth
• Inhibits apoptosis

Physiologicfunction
GI Mucosa Kidney Platelet
Dubois RN. FASEB J 1998
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Classification of NSAIDs By Selectivity for COX
Selectivity Drugs
Weak COX inhibitors COX-1/COX-2 inhibitors COX-2 preferential COX-2 selective inhibitors Acetaminophen,salsalate,salicylamide, sodium salicylate, choline-magnesium trisalicylate Piroxicam, indomethacin, sulindac, toletin, ibuprofen, naproxen, fenoprofen, meclofenamate, mefenamic acid, diflunisal, ketoprofen,diclofenac, ketolac, eyodolac, nabumetone, oxaprozin, flurbiprofen Nimesulide, meloxicam Celebrex, rofecoxib, valdecoxib, etoricoxib, parecoxib
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Risk Factors For Serious Upper GI Complications
Associated With NSAIDs

• Hx of
• PUD
• Upper GI bleeding
• Older age Arthritis-related disability

• High-dose or multiple NSAIDs
• Concurrent prednisone use
• Prior GI side effect

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????????????????Peptic Ulcer, Upper GI Bleeding,
Perforation

• ????NSAIDs??????????
• Simon LS et al. Arthritis Rheum.
  1998411591-1602.
• Goldstein JL et al. Aliment Pharmacol Ther.
  200318125-132.
• ???????NSAIDs????????
• Pérez Gutthann S et al. Epidemiology.
  1997818-24.
• ???????????????NSAIDs?????????????

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Glucocorticoids

• Mechanism -- binding to cytoplasmic
  receptor-- steroid/receptor complex regulate DNA
• Actions-- Lipocortin inhibit phospholipase A2
  to convert membrane phospholipid to arachidonic
  acid
• Effects -- Anti-inflammatory effects--
  Immunosuppressive effects

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Effects of Glucocorticoids

• Effects on leukocyte movementa. Lymphocytes
  c. Neutrophilsb. Monocyte-macrophages d.
  Eosinophils
• Effects on humoral factors a. ?? Ig levelsb.
  ?? RES ?? antibody-coated cellsc. ??
  prostaglandins and leukotrienesd. ?? actions of
  catecholaminesf. ?? histamine-induced
  vasodilationg. Probably no effects on complement
  metabolism.

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Glucocorticoid Equivalent oral dose ( mg) Plasma half-life (min) Relative anti-inflammatory effect Relative mineralcor-ticoid effect
Cortisol 20 90 1 1
Prednisolone 5 200 4 0.8
Methylprednisolone 4 200 5 0.5
Triamcinolone 4 200 5 0
Dexamethasone 0.75 300 25 0
Hydrocortisone ( solu-cortef, 100 mg/amp ) 1 amp
5 pred Prednisolone ( 5 mg )
Methylprednisolone ( solu-medrol. 40 mg/vial )
1 vial 10 Dexamethasone ( Decadron, 5 mg /
vial ) 1 vial 5 pred.
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Glucocorticosteroids

• Indications almost all autoimmune disease
• Sjogren syndrome only short term use
• A.S., Reiters syndrome only for active
  peripheral arthritis or enthesitis
• Adverse Reactions
• Peptic ulcer
• no definite clue of oral steroid alone increase
  rate of peptic ulcer
• Steroid increases NSAID GI toxicity
• Very rare nephrotoxicity report of steroid
• Infection ( 30mg/d gt 7 days)
• Osteoporosis ( 10mg/d gt 3 months)

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Methylprednisolone Pulse Therapy

• Infusion of large dose of corticosteroid in a
  short period of time
• Benefits
• rapid onset
• less puffy face/buffalo hump
• less impaction over hypothalamus-pituitary-adrenal
  axis

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Methylprednisolone Pulse Therapy

• Dosage
• Children 15-17mg/kg/day
• Adult 750-1000mg/day
• Major complications
• Ventricular arrhythmia cardiac arrest
• Thromboembolism Myocardial infarction, CVA,
  Mononeuritis multiplex, especially in APS
• Infection

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Methylprednisolone Pulse Therapy

• Minor adverse reactions
• Salt retention mild lower leg edema
• Hypertension
• Hyperglycemia
• peripheral vasodilatation facial flushing
• Hiccups
• Psychological reaction

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Methylprednisolone Pulse Therapy

• High risk group
• Old aged people children
• Antiphospholipid Ab syndrome ( APS )
• History of thromboembolism
• Monitoring
• BP management slower infusion rate, diuretic if
  lower leg edema
• HR lt60, management slower infusion rate

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Immunoregulatory agentsImmunomodulatory agents

• SAARDs
• Slow-Acting AntiRheumatic Drugs
• DMARDs
• Disease-Modificating AntiRheumatic Drugs

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Hydroxychloroquine

• Plaquenil Geniquin
• 200mg 200mg

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Hydroxychloroquine

• ?? lysosomal membranes, thereby inhibiting the
  release of lysosomal enzymes.
• Photoprotective effects
• ?? Ag-Ab interaction and immune complex formation
• ?? IL-1 production by monocytes
• Complexes with DNA ( blocking the reactions
  between DNA and anti-DNA Abs )

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Hydroxychloroquine

• Safe in pregnant mother and fetus
• Beneficial effects on lupus dyslipidemia with or
  without concomitant steroid administration (
  Borba and Bonfa )
• Dyslipidemia HDL-C,VLDL and TG are improved

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Hydroxychloroquine (Plaquenil)

• ?????????
• ??????????
• ???????????????
• Safe in pregnant mother and fetus?
• Photoprotective effects?
• -- Beneficial effects on lupus dyslipidemia with
  or without concomitant steroid administration (
  Borba and Bonfa )
• -- Dyslipidemia HDL-C,VLDL and TG are
  improved

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Hydroxychloroquine

• Applications
• SLE esp with skin rash and arthritis
• R.A. 60-80 responsive after 6-8 mons treatment
• Spondyloarthropathy except Psoriatic arthritis
• Sjogrens syndrome
• Dosage
• Usual dose 200mg (1 ) BID, PC
• Reduced dose Renal failure
• Maximal Hydroxychloroquine 6mg base/kg/day
  Chloroquine 4mg base/kg/day

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Hydroxychloroquine

• Contraindications
• Relatively Psoriasis
• Adverse Reactions
• Irreversible retinopathy( hyperpigmentation)
• dose-related
• Skin hyperpigmentation / hypopigmentation
• No life-threatening toxicity
• except marked overdose of chloroquine rapid
  onset cardiorespiratory failure

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Hydroxychloroquine

• Monitoring
• Oph. Exam. Baseline and every 6-12 months
• Sun-exposure protection
• Amsler grid ( self-testing )

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Skin rashes are the most common side effect
leading to cessation.
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Sulfasalazine (Salazopyrin)

• Mechanism unknown
• little absorption of intact Sulfasalazine
  insoluble
• cleaved by colonic bacteria to
• sulfapyridine antirheumatic effect
• 5-aminosalicytic acid anti-inflammatory effect
• Actions
• Onset 4 weeks
• RA as effective as gold or d-penicillamine, able
  to retard erosion of RA
• SAE including psoriatic arthritis

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Sulfasalazine(Salazopyrin)

• Indications
• R.A.
• Spondyloarthropathy
• Inflammatory colitis Ulcerative colitis, Crohns
  disease
• Prescriptions
• 500mg QD x 1 week, 500mg BID x 1 week,
• 500mg-1000mg BID x 2-4 weeks
• Maximal 1000mg TID

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Sulfasalazine(Salazopyrin)

• Major Adverse Reactions
• Hematologicala. Leukopenia 1-3, mostly in
  first 6 monthsb. Hemolysis
• Skin
• skin rash pruritic, maculopapule 1-5
• Steven-Johnsons syndrome ( rarely )
• Lung acute fibrosing alveolitis with
  eosinophilia, reversible

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Sulfasalazine (Salazopyrin)

• Minor Adverse Reactions
• GI upset nausea, abdominal pain
• enteric-coated is better
• CNS headache,lightheadedness, dizziness
• Hepatotoxicity
• close F/U if GPT lt4X elevation
• usually returning to normal within 3 months

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Sulfasalazine(Salazopyrin)
Common Adverse Effects Common Adverse Effects
GI Nausea, vomiting, anorexia, malasie, abdominal pain, indigestion, dyspepsia
CNS Headache, fever, lightheadness, dizziness
Less Common Adverse Effects Less Common Adverse Effects
Skin Rash ( Exanthemlike )
Hepatic Marginal enzyme elevations
Hematologic Leukopenia, Hemolysis, Methemoglobinemia
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Cytotoxic agents
Class Typical Agents Mechanisms
Alkylating agents -Cyclophosphamide -MMF Cross-linkage of DNA
Purine analogues -Azathioprine Inhibition of nucleic acid synthesis
Pyrimidine analogues -Leflulomide Inhibition of nucleic acid synthesis
Folic acid antagonists -Methotrexate Binds with high affinity to dihydrofolate reductase
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Azathioprine (Imuran)

• Mechanism inhibit adenine guanine
  ribonucleotides
• Actions
• reduce circulating B cells T cells (esp
  suppressor CD8)
• reduce IgM IgG synthesis
• reduce IL-2 synthesis

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Azathioprine (Imuran)

• Indications
• R.A.
• ITP
• Lupus nephritis
• SLE with refractory skin rash
• Prescription
• 25mg (0.5 ) QD, slowly increased (gt4wks) with
  increment 25mgQD (maxima 50mg BID)

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Azathioprine (Imuran)

• Adverse Reactions
• Bone marrow suppression
• not dose-related
• Hepatotoxicity usually reversible

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Cyclophosphamide (Endoxan)

• Mechanism
• cross-linked DNA, cytotoxic effect to resting
  dividing lymphocytes
• Actions
• decrease T-cell (esp Helper CD4 cell) activated
  T cells
• decrease B cell

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Cyclophosphamide (Endoxan)

• Indications
• Lupus nephritis
• SLE with CNS involvement
• Pulmonary involvement of autoimmune disease
• Vasculitis syndrome polyarteritis nodosa,
  Wegners granulomatosis
• Prescriptions
• IV pulse therapy start from 10mg/kg every time,
  reduced dose under CCr
• Increase dose by 50-100mg under WBC count 2 weeks
  after latest pulse therapy
• Oral 50mg QOD, slowly increased under therapeutic
  effect and WBC count more potent, more toxic

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Cyclophosphamide (Endoxan)

• Adverse Reactions
• Bone marrow suppression dose-related
• Leukopenia is most frequently
• reduced dose if WBC lt2500 DC if WBC lt2000
• Hemorrhagic cystitis
• due to urinary metabolite Acrolein
• related to duration of urine retention
• reduced by mesna
• less frequent by IV pulse therapy

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Cyclophosphamide (Endoxan)

• Infertility Azoospermia, Premature ovarian
  failure
• Female Age-related gt 24 y/o, child baring age
• Male cumulative dose gt18gm
• Carcinogenesis
• 12.8X of all cancers
• 10.9X for non-Hodgkins lymphoma
• 10X for bladder Ca
• our experience most common Cervical Ca
• Direct toxicity to skin skin necrosis

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Cyclophosphamide (Endoxan)

• Monitoring
• WBC best indicator
• WBC3000-3500 optimal dose
• WBClt2500 reduced dose
• WBClt2000 DC
• Close F/U any sign of malignancy

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Methotrexate (MTX)

• Mechanism
• Folic acid analogue
• inhibit dihydrofolate reductase, thymidylate
  synthetase, AICAR activity
• IL-1 IL-2 suppression
• Actions
• decreased RF-IgM production
• decreased IL-1 secretion, production binding
• decreased IL-6 activity

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Methotrexate (MTX)

• Indications
• R.A.
• Spondyloarthropathy esp. psoriatic arthritis
• SLE with active peripheral arthritis/Jaccouds
  deformity
• Myositis
• Bronchial asthma as steroid sparing agent
• Chronic recurrent urticaria as steroid sparing
  agent

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Methotrexate (MTX)

• Contraindications
• chronic renal failure
• relative age gt60
• Adverse Reactions
• Mucositis stomatitis dyspepsia most common
• Folic acid minimizes stomatitis
• Pulmonary fibrosis usually reversible
• Hepatotoxicity
• Bone marrow suppression

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Methotrexate (MTX)

• Prescription
• initial dose7.5mg/week(2-3/week)
• most recomand prescription serial q12h x3 doses
  in 1 week
• Monitoring
• WBC, Hb MCV, Platelet every 4-8 weeks
• decreased dose if MCV increased markedly
• make sure of Folic acid supplement
• close F/U renal function
• GOT/GPT every 4-8 weeks
• Chest X-ray at least every 6 months

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Cyclosporin

• Mechanism
• suppress IL-2 synthesis and release
• suppress T-cell response interaction
• Indications
• SLE with lupus nephritis
• R.A.
• Juvenile chronic arthritis
• Psoriasis Psoriatic arthritis
• Behcets disease
• Dermatomyositis, Polymyositis
• Progressive systemic sclerosis

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Cyclosporin

• Prescription contact with AIR fellow
• start from 2.5mg/kg/day in divided dose q12h
• Adverse Reactions
• Nephrotoxicity
• dose-related usually gt5mg/kg/day
• Hypertention
• avoid K-sparing diuretic possible hyperkalemia
• Calcium channel blocker might raise cyclosporin
  level
• Hepatotoxicity dose related

FK506 ( Tacrolimus ) Topic use in atopic
dermatitis
and cutaneous lupus
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Cellcept (Mycophenolate Mofetil)

• Mechanism
• Reversible inhibition of inosine-5-monophosphate
  dehydrogenase (IMPDH) by mycophenolic acid
• Indications
• SLE and Lupus nephritis
• Pemphigus/Pemphigoid
• Autoimmune hepatitis
• ITP

Cellcept 250mg
Myfortic 180mg
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Cellcept (Mycophenolate Mofetil)

• Prescription
• Start from 500mg BIDAC (2 BIDAC)
• Raised 250-500mg/1-2 weeks to optimal dose
• Adverse reaction
• GI abdominal pain, nausea, diarrhea
• Hepatotoxicity GPT elevation
• Bone marrow suppression
• Leukopenia
• Anemia esp renal insufficiency case
• Increased CMV infection in renal/heart
  transplantation cases

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Danazol

• Danazol a derivative of the synthetic steroid
  ethisterone, a modified testosterone
• Indication
• -ITP
• -Anti-phospholipid Ab syndrome
• Contra-indication
• -Pregnancy
• Adverse effect
• -Hirsutism, decreased breast, testis size
• -Body weight gain
• Prescription
• 600-900mg/day, in dividing dose, BID

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Dose Target Indication Side effect AP breastfeed
Antimalarial HCQ 200mgQD or BID Constitutional, cutaneous, musculoskeletal GI, Retina, skin AP (o) Feed (x)
Azathioprine 2-2.5mg/kg/D Both cellular and humoral immune function 1.Steroid-sparing /c mild-to moderate disease 2.Maintenance of CYC Acute myelotoxicity( esp. combine Allopurinol) AP(O) Feed (x)
Methotrexate 7.5-15mg/wk 1.GI mucositis, hepatotoxicity (esp. combine alchol) 2. Alopecia 3. MTX-induced pneumonitis AP (X) discontinue 6 months
Cyclosporine 2.5-5mg/kg/D Inhibit proliferation of T cell and selectively inhibits T-cell-mediated responses Proteinuria, leukopenia, thrombocytopenia, complement levels HTN, hepatic and renal toxicity, hypertrichosis, gingival hypertrophy AP (O) Feed (X)
Mycophenolate moferil 500-1500mg BID Both T and B cell Lupus nephritis GI (nausea, bloating, diarrhea),cytopenia AP (?) Feed (?)
Leflunomide Decrease T and B cell proliferation More favorable than CYC or MTX
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Thanks for your attention
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Dapsone

• ?sulfone?
• Indications
• SLE with refractory skin rash
• Some kinds of vasculitis
• Contraindication
• G6PD deficiency

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Dapsone

• Adverse Reactions
• Hemolytic anemia
• dose-related
• Allergic reaction pruritic skin rash, fever
• (1)?????????,?????????????
• (2)????? methemoglobinemia,??????????300mg?,??G6PD
  ??????,????????
• (3)????????sulfone-syndrome,?
  mononucleosis-like ???,???????????????????,???????
  ????????
• (4)????????????
• Monitoring
• CBC every 4-8 weeks,close F/U MCV

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Drugs for Gouty arthritis

• Confirming diagnosis is most important
• Synovial fluid aspiration is the only definite
  diagnosis
• Acute attack NSAID Steroid are most effective
• but never double NSAID IM oral
• Colchicine low dose usage 1 BID-TID
• Decreased or DC Colchicine after 1 year without
  attack

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Drugs for Gouty arthritis

• Uric acid lowering agents
• Never change (add or DC) 2 weeks within acute
  attack
• Xanthine oxidase inhibitor Allopurinol
• close F/U renal function
• start from 1 QD, increment 1 every 2-3 months
  till U.A lt5.0
• close F/U any sign of skin rash/oral ulcer

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Drugs for Gouty arthritis

• Uricosuic agent Benzbromarone
• only for undersecretion type 24hrs urine UAlt
  800-1000mg/day
• Contraindications
• Chronic renal failure, Crgt2.0
• Urolithiasis