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

►
►
►
►
NSAID
Corticosteroids
Disease-modifying anti-rheumatic drugs (DMARDs)
-- Hydroxychloroquine (Plaquenil/Geniquin) 必賴克廔 / 殲瘧
-- Salfasalazine ( Salazopyrine ) 斯樂
-- D-penicillamine (Metalcaptase )
Immunosuppressive agents ( Cytotoxic agnets )
-- Cyclophosphamide ( Endoxan ) 癌得星
-- Azathioprine ( Imuran ) 壓彼迅 / 移護寧
-- Methotrexate ( MTX )
-- Cyclosporine ( Sandimmun )
環孢靈
/
新體睦
-Cellcept (Mycophenolate Mofetil) 山喜多 /
Myfortic (mycophenolic acid)
睦體康

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

Mechanisms of NSAIDs
Arachidonic acid
Glucocorticoids
COX-1
(constitutive)
COX-2
(inducible)
PGE
2
Physiologic function
GI Mucosa
Kidney
Platelet
Conventional
NSAID
Cox-2 inhibitor
Celecoxib
Etoricoxib
Vioxx
Inflammation
Neoplasia
 Promotes tumor angiogenesis
 Induces tumor cell growth
 Inhibits apoptosis
Dubois RN. FASEB J 1998

Classification of NSAIDs By Selectivity for COX
Selectivity
Weak COX inhibitors
COX-1/COX-2 inhibitors
COX-2 preferential
COX-2 selective inhibitors
Drugs
Acetaminophen ,salsalate,salicylamide, sodium salicylate, cholinemagnesium trisalicylate
P iroxicam, indomethacin, sulindac, toletin, ibuprofen, naproxen , fenoprofen, meclofenamate, mefenamic acid, diflunisal, ketoprofen, diclofenac , ketolac, eyodolac, nabumetone, oxaprozin, flurbiprofen
N imesulide, meloxicam
Celebrex , rofecoxib, valdecoxib, etoricoxib , parecoxib

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
►
►

消化性潰瘍、上消化道出血或胃穿孔
Peptic Ulcer, Upper GI Bleeding, Perforation
► 服用傳統 NSAIDs 僅一週即造成胃腸毒性
 Simon LS et al. Arthritis Rheum. 1998;41:1591-1602.
 Goldstein JL et al. Aliment Pharmacol Ther. 2003;18:125-132.
► 高或低劑量傳統 NSAIDs 均會引起胃腸毒性
 P é rez Gutthann S et al. Epidemiology. 1997;8:18-24.
► 許多骨關節炎患者因長期服用傳統
NSAIDs
而進駐胃腸科門
診或住院治療

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

Effects of Glucocorticoids
►
Effects on leukocyte movement a. Lymphocytes b. Monocyte-macrophages c. Neutrophils d. Eosinophils
►
Effects on humoral factors : a. 減少 Ig levels b. 減少 RES 清除 antibody-coated cells c. 減少 prostaglandins and leukotrienes d. 加強 actions of catecholamines f. 抑制 histamine-induced vasodilation g. Probably no effects on complement metabolism.

Glucocorticoid
Cortisol
Prednisolone
Methylprednisolon e
Triamcinolone
Dexamethasone
Equivalent oral dose
( mg)
20
5
4
4
0.75
Plasma half-life
(min)
90
200
200
200
300
Relative antiinflammator y effect
1
4
5
5
25
Relative mineralcor
-ticoid effect
1
0.8
0.5
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.
0
0

Glucocorticosteroids
►
►
Indications: almost all autoimmune disease
 Sjogren syndrome: only short term use
 A.S., Reiter ’ s 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 > 7 days )
 Osteoporosis ( 10mg/d > 3 months )

►
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-pituitaryadrenal axis

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

►
Methylprednisolone Pulse
Therapy
Minor adverse reactions:
 Salt retention: mild lower leg edema
 Hypertension
 Hyperglycemia
 peripheral vasodilatation: facial flushing
 Hiccups
 Psychological reaction

Methylprednisolone Pulse
►
High risk group
Therapy
 Old aged people & children
 Antiphospholipid Ab syndrome ( APS )
 History of thromboembolism
►
Monitoring
 BP management: slower infusion rate, diuretic if lower leg edema
 HR <60, management: slower infusion rate

►
SAARDs:
 Slow-Acting AntiRheumatic Drugs
►
DMARDs:
 Disease-Modificating AntiRheumatic Drugs

Hydroxychloroquine
Plaquenil ®
200mg
Geniquin ®
200mg

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

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

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

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

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

Skin rashes are the most common side effect leading to cessation.

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

Sulfasalazine(Salazopyrin ® )
►
Indications:
 R.A.
 Spondyloarthropathy
 Inflammatory colitis: Ulcerative colitis,
Crohn ’ s disease
►
Prescriptions:
 500mg QD x 1 week, 500mg BID x 1 week,
 500mg-1000mg BID x 2-4 weeks
 Maximal: 1000mg TID

Sulfasalazine(Salazopyrin ® )
►
Major Adverse Reactions:
 Hematological: a. Leukopenia 1-3%, mostly in first 6 months b. Hemolysis
 Skin:
► skin rash: pruritic, maculopapule; 1-5%
►
Steven-Johnson ’ s syndrome ( rarely )
 Lung: acute fibrosing alveolitis with eosinophilia, reversible

Sulfasalazine (Salazopyrin ® )
►
Minor Adverse Reactions:
 GI upset: nausea, abdominal pain
► enteric-coated is better
 CNS: headache,lightheadedness, dizziness
 Hepatotoxicity
► close F/U if GPT <4X elevation
► usually returning to normal within 3 months

GI
CNS
Sulfasalazine(Salazopyrin
)
Skin
Hepatic
Common Adverse Effects
Nausea, vomiting, anorexia, malasie, abdominal pain, indigestion, dyspepsia
Headache, fever, lightheadness, dizziness
Less Common Adverse Effects
Rash ( Exanthemlike )
Marginal enzyme elevations
Hematologic Leukopenia, Hemolysis,
Methemoglobinemia

Class
Alkylating agents
Purine analogues
Pyrimidine analogues
Folic acid antagonists
Cytotoxic agents
Typical Agents Mechanisms
-Cyclophosphamide
-MMF
Cross-linkage of
DNA
-Azathioprine
-Leflulomide
Inhibition of nucleic acid synthesis
Inhibition of nucleic acid synthesis
-Methotrexate Binds with high affinity to dihydrofolate reductase

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

Azathioprine (Imuran ® )
►
Indications:
 R.A.
 ITP
 Lupus nephritis
 SLE with refractory skin rash
►
Prescription
 25mg (0.5# ) QD , slowly increased (>4wks) with increment 25mgQD (maxima: 50mg BID)

Azathioprine (Imuran ® )
►
Adverse Reactions:
 Bone marrow suppression
► not dose-related
 Hepatotoxicity: usually reversible

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

Cyclophosphamide (Endoxan ® )
►
►
Indications:
 Lupus nephritis
 SLE with CNS involvement
 Pulmonary involvement of autoimmune disease
 Vasculitis syndrome: polyarteritis nodosa,
Wegner ’ s 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

Cyclophosphamide (Endoxan ® )
►
Adverse Reactions:
 Bone marrow suppression: dose-related
►
Leukopenia is most frequently
► reduced dose if WBC <2500; DC if WBC <2000
 Hemorrhagic cystitis
► due to urinary metabolite: Acrolein
► related to duration of urine retention
► reduced by mesna
► less frequent by IV pulse therapy

Cyclophosphamide (Endoxan ® )
 Infertility: Azoospermia, Premature ovarian failure
►
Female: Age-related > 24 y/o, child baring age
►
Male: cumulative dose >18gm
 Carcinogenesis
►
12.8X of all cancers
►
10.9X for non-Hodgkin ’ s lymphoma
►
10X for bladder Ca
►
* our experience: most common: Cervical Ca
 Direct toxicity to skin: skin necrosis

Cyclophosphamide (Endoxan ® )
►
Monitoring:
 WBC: best indicator
►
WBC: 3000-3500 : optimal dose
►
WBC<2500: reduced dose
►
WBC<2000: DC
 Close F/U any sign of malignancy

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

Methotrexate (MTX ® )
►
Indications:
 R.A.
 Spondyloarthropathy esp. psoriatic arthritis
 SLE with active peripheral arthritis/Jaccoud ’ s deformity
 Myositis
 Bronchial asthma: as steroid sparing agent
 Chronic recurrent urticaria: as steroid sparing agent

Methotrexate (MTX ® )
►
Contraindications:
 chronic renal failure
 relative: age >60
►
Adverse Reactions:
 Mucositis : stomatitis & dyspepsia: most common
►
Folic acid minimizes stomatitis
 Pulmonary fibrosis: usually reversible
 Hepatotoxicity
 Bone marrow suppression

Methotrexate (MTX ® )
►
►
Prescription:
 initial dose: 7.5mg/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

►
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
 Behcet ’ s disease
 Dermatomyositis, Polymyositis
 Progressive systemic sclerosis

►
Prescription: contact with AIR fellow
 start from 2.5mg
/kg/day in divided dose: q12h
►
Adverse Reactions:
 Nephrotoxicity :
► dose-related: usually >5mg/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

►
• 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

• 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

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

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

Dapsone
► 屬 sulfone 類
►
Indications:
 SLE with refractory skin rash
 Some kinds of vasculitis
►
Contraindication:
 G6PD deficiency

Dapsone
►
Adverse Reactions:
 Hemolytic anemia
► dose-related
 Allergic reaction: pruritic skin rash, fever
(1) 最常見為腸胃道不適，包括噁心、嘔吐、食慾不振。
(2) 溶血反應及 methemoglobinemia ，可發生於每日劑量超過
300mg 時，但在 G6PD 缺乏病患身上，少劑量亦可發生。
(3)
開始用藥時可發生” sulfone-syndrome ” ，即 mononucleosis-like 症候群，臨床表現有黃疸、發燒、皮疹
及淋巴結腫大，但繼續增加劑量後可減緩其症狀。
(4) 嚴重肝功能障礙病患需減量
►
Monitoring
 CBC every 4-8 weeks,close F/U MCV

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

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: <5.0
 close F/U any sign of skin rash/oral ulcer

Drugs for Gouty arthritis
►
Uricosuic agent: Benzbromarone
 only for undersecretion type: 24hrs urine UA<
800-1000mg/day
 Contraindications:
►
Chronic renal failure, Cr>2.0
►
Urolithiasis