Download - Drugs for Osteoarthritis Revise 2010
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Drugs for Arthritis
Dr. Nicolaski Lumbuun, SpFKDepartment of Pharmacology
Faculty of Medicine
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Arthritis
Arthritis is derived from the Greek words
arthronmeaning joint and i t ismeaning
inflammation.
There are more than 100 types of arthritis.
Some types of arthritis are caused from
inflamation.
Some types are caused from viruses,
bacteria, injury, or sodium urate crystals.
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Osteoarthritis
Syndrome of joint pain + loss of join form & function
caused by a progressive loss of articular cartilage
accompanied by attempted repair of articular cartilage,
remodeling and sclerosis of subchondral bone(formation of subchondral bone cysts & osteophytes)
Joint degeneration Structural Changes :
articular cartilage fibrillation & erosion
Subchondral bone thickening
Osteophytes
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Normal jointcartilage
Osteoarthritis
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Osteoarthritis: Symptoms & Causes
Symptoms
Swelling, stiffness,
and pain. Joints ache after
physical activity.
Stiffness or pain in
the neck or lowerback which can
result in numbness
of the legs or arms.
Causes
Trauma to joints suchas repetitivemovements over along time.
Acute injury can leadto osteoarthritis years
later. Age.
Metabolic disordersthat can causecartilage deterioration.
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Common places osteoarthritis :Lower back
knees
hips
neck
thumbs
ends of fingers
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Diagnosis
No single test can diagnose osteoarthritis.
The doctor will review the medical history, ask the
patient to describe symptoms, conduct a physical
exam, check reflexes, and check the patients ability
to bend and walk.
X-rays may show cartilage or bone damage.
Fluid from the joint may be extracted to check for
pieces of bone or cartilage.
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(Event of morning Stiffness)
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, stiffness and swelling
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Management of OA
1. Patient education (avoid physical stress ,avoid injury)
2. Physiotherapy (physical therapy and rehabilitation): muscle strengthening, joint stability & mobility exercise
Prevent debilitation as aging progresses
Appropriate exercise and conditioning
3. Occupational Therapy : Assistive devices for ambulation (canes, walkers)
Patellar taping (for knee OA), appropriate footwear andbracing
Assistive devices for activities of daily living
4. Dietary consideration : - Maintain optimal weight- Nutritional supplementation
5. Early and adequate drugs treatment
6. Surgery
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OBESITY
Risk of OA with obesity BMI > 30 4 fold greater risk of OA
Weight reduction lowers risk of OA
5 Kg weight loss 56% reduction in risk of knee
OA if BMI > 25
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TREATMENT OF OA
Confirm diagnosis exclude tendonitis or
bursitis adjacent to joint
Initial treatment Muscle strengthening exercises and
reconditioning walking program
Appropriate footwear Weight loss
Local heat/cold and topical agents
Paracetamol
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OA: Management Summary (contd)
Second-line approach
NSAIDs if paracetamol fails
Intra-articular agents Opioids
Third-line -SURGERY
Arthroscopy
Osteotomy
Total joint replacement
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American College of Rheumatology
American College of Rheumatology Subcommitteeon Osteoarthritis Guidelines. Recommendationsfor the medical management of osteoarthritis of
the hip and knee: 2000 update. Arthritis andRheum 2000;43(9):1905-15.
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Drugs Therapy for OA
Symptomatic (Fast Effect)
Per oral :
Analgesic
Simple Analgesic : Paracetamol (acetaminophen)
Combination Analgesic : - Paracetamol + Codeine
- Paracetamol + Ibuprofen
NSAID :Conventional : Aspirin, Sodium Diclofenac, Ketoprofen
Cox 2 selective inhibitor : Celecoxib, Etoricoxib, Valdecoxib, Parecoxib
Rofecoxib, Lumiracoxib (Withdrawal from market)
- Opioid Analgesic
Intra-articular injection
Corticosteroid : triamcinolone, dexamethasone, methylprednisolone
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Symptomatic (Slow Effect)= SYSADOA (Symptomatic slow acting Drugs for OA)
Per Oral : Glucosamine, Chondroitin, Diacerein
Intra-articular : Hyaluronic Acid
Structure/Disease Modifying Osteoarthitis Drugs (S/DMOAD)
Glucosamine
Chondroitin Diacerein
Hyaluronic Acid
Drugs Therapy for OA
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Making Sense of Oral Medications
Recommendations Continuous versus As Needed
Preferable on a periodic basis in patientswith non-inflammatory OA; continuous only
if this regimen is inadequate. Medications normally take 2 to 4 weeks to
assess; if inadequate, the dose should beincreased.
If not effective after 2 to 4 weeks, then anotheragent should be tried.
If there is a history of GI disease, a selectiveCOX2 inhibitor or a nonselective agent withanti-ulcer prophylaxis may be used.
Opioids may be used for severe breakthroughpain, patients who have failed other therapies,and where surgery is not an option.
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Who Deserves an Injection?
AAOS(American Acad of Orthopaedic Surgeons)
Inflamed knees respond best to injections.
Localized knee pain felt only with weight-
bearing is less likely to respond.
ACR (American College of Rheumatology)
Intraarticular glucocorticoid injections are of
value in the treatment of acute knee pain in
patients with, and may be particularly
beneficial in patients who have signs of localinflammation with a joint effusion.
EULAR (European League Against Rheumatism)
Intra-articular injection of long acting steroid
is indicated for acute exacerbation of knee
pain, especially if accompanied by effusion
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Chondroitin sulfate (CS) belongs to the group ofglycosaminoglycans, important constituents of cartilageextracellular matrix.
Chondroitin sulfate is a symptomatic slow acting drug for osteoarthritis(SYSADOA) in Europe, where it has been approved as a drug for morethan ten years in several countries.
OX
CH OX2 O
OHO
O
COOR O
NHCOCH3
R: Na, H
OHn
X: SO3R, H
Chondroitin sulfate
Hardingham T. Osteoarthritis Cart (1998) 6, (Supplement A), 3-5.Lequesne M. G. Rev Rhum (Eng/Ed) 1994; 61: 69-73.
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STIMULATES: proteoglycans HAEFFECT:-anti-inflammatoryactivity
-Membranestabilising action
INHIBITS: cartilage degradative enz. (collagenase,elastase, proteoglycanase, fosfolipaseA2, N-acetylglucosaminidase, etc.) cartilage damaging substances (freeradicals) apoptosis NO Stromelysin (MMP-3) NF-kB
CHONDROITIN SULFATE ACTION MECHANISMS
(3) Ronca F et.al. Osteoarthritis Cart (1998) 6, (Supplement A), 14-21. (4) Blanco FJ. et. al. Rev. Esp.
Reumatol 2001; 28, 1: 12-17.
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9 randomized, controlled, clinical trials have been conducted in Europewith Condrosan / Condrosulf (CS),comparing its effect againstplacebo (PBO) and sodium diclofenac (SD) (150 mg) in 1163patients with knee and hand osteoarthritis (OA)
The results from these clinical trials conclude that CS is as effective asSD and around 50% more effective than PBO (p < 0.05) in thereduction of OA symptoms. Besides, its efficacy lasts for at least 3months after treatment suppression (carry-over effect).
CLINICAL EVIDENCE
Morreale, et al. J. Rheumatol. 1996, 23: 1385-1391. Kissling R. et al. Osteoarthritis Cart 1997, 5 (Supplement A), 9: 70. BucsiL, et.al. Osteoarthritis Cart 1998, 6 (supplement A):31-36. Pavelka K, et al. Litera Rheumatologica1998, 24:21-30. UebelhartD, et.al. Osteoarthritis Cart 1998, 6, (Supplement A), 39-46. Uebelhart D, et al. Osteoarthritis Cart 2004, 12:269-276. Michel B,et al.. Osteoarthritis Cart 2001, 9 (supplement B), LA2. (12) Verbruggen G, et al. Osteoarthritis Cart (1998) 6, (Supplement
A), 37-38. Vebruggen G. et al. Clinical Rheumatology 2002, 21: 231-241. Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211.du Souich P, Vergs J. Clin. Pharm. Ther. 2001; 70: 5-9.
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Condroitin Sulfate may act as a structure
disease modifying OA drug (S/DMOAD), it
may slow down disease progression.
3 clinical trials in knee OA have evidenced astabilization of joint space width with CStreatment as opposed to a narrowing of jointspace with PBO.
2 clinical trials in hand OA concluded thatdisease progression was lower in CS-treated patients and less patients from thisgroup developed erosive OA.
S/DMOAD
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The tolerance of Chondroitin Sulfate is very welldocumented; equivalent to PBO and much higherthan that of SD.
It isnot metabolized by enzymes from cytochrome P450.It can not present drug interactions at this level.
Pharmacosurveillance data from Europe, where no
serious adverse events have been reported formore than 10 years, support the safety of the product.
SAFETY PROFILE
Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211.
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Clinical efficacy on symptom reduction and improvementof functional capacity
Persistent clinical effect after treatment suppression(evidenced for at least 3 months)
Greater safety than conventional therapy (analgesics,
NSAIDs). It does not cause drug interactions.
Chondroitin Sulfate Advantages
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Glucosamine
Glucosamine sulfate (+ chondroitinsulfate) are particularly populartreatments for osteoarthritis.
Several early studies demonstratedthat glucosamine was superior toplacebo and comparable to NSAIDsfor knee OA. (manufacturersupported)
Other studies measuring changes injoint space narrowing suggested achondroprotective effect againstarticular cartilage loss.
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STIMULATES: proteoglycansEFFECT:-anti-inflammatoryactivity-Membrane stabilising
activity
INHIBITS: cartilage degradative enz.(collagenase, aggrecanase, fosfolipase A2, etc.)
Stromelysin (MMP-3), MMP-2, MMP-9 free radicals PGE2 IL-1NF-kB
GLUCOSAMINE SULFATE ACTION MECHANISMS
Studies of radiolabeled glucoasmine do demonstrate uptake in the jointarticular cartilage.
Thought to stimulate chondrocytes to make proteoglycans.
Real mechanism of action is largely unknown.
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Glucosamine
Cochrane Review 2005:WOMAC outcomes of pain, stiffness and function did not showa superiority of glucosamine over placebo. Glucosamine was assafe as placebo
NIH multi-centered trial: Glucosamine and chondroitin alone or in combination did not
reduce pain effectively in the overall group of patients
Exploratory analyses suggest that the combination of glucosamine
and chondroitin may be effective in the subgroup of patients withmoderate-to-severe knee pain
European trials that showed a benefit with glucosamine used asglucosamine sulfate; most of the American trialsincludingGAITused glucosamine hydrochloride
Clegg DO et al. (2006), N Engl J Med 354(8):795-808
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Glucosamine
Using Glucosamine: Safe, however, questions exist
as to adverse effects, purityand efficacy.
Not recommended in patientswith seafood allergy;chondroitin may haveanticoagulant effect.
No studies demonstratingconsistent benefit of addingchondroitin.
Trial of 1500 mg/d for 6 to 8weeks
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Hyaluronic Acid
Synovial fluid is an ultrafiltrate of
plasma modified by the addition
of hyaluronic acid (HA), which is
produced by the synovium.
In osteoarthritis, the HA is
decreased and compromised.
Exogenous supplementation of
intraarticular HA is thought to
support changes in the character
of synovial fluid.
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STIMULATES:Hyaluronic acidGlucosaminoglicans
Tissue inhibitor ofmetalloproteinases
(TIMPs)
EFFECT:
-anti-inflammatory activity-Improve synovial fluidviscosity
INHIBITS: Apoptosis Stromelysin (MMP-3) free radicals PGE2 NO
Leucocyte proliferation, migration
and phagocytosis- Counteract some IL-1 effect
HYALURONIC ACID ACTION MECHANISMS
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Hyalgan
Whats the Evidence? Cochrane Review 2005
Viscosupplementation is aneffective treatment for OA of theknee with beneficial effects: onpain, function and patient globalassessment; and at different postinjection periods but especially atthe 5 to 13 week post injection
period. Questions?
Is HA superior to corticosteroidinjections or saline injections?
Do HA injections result in lower
utilization of NSAIDs?
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Hyalgan
Using Hyalgan: Indications: indicated for the
treatment of osteoarthritis notresponsive to non-pharmacologic
measures and to simple analgesics. Requires sterile technique, remove
joint effusion if present prior toinjection.
Three to five weekly injectionsrecommended.
Is it safe? No concern of inhibition of
prostaglandins.
Post-injection synovitis is described,and can last up to three weeks.
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Rheumatoid Arthritis
Rheumatoid arthritis is caused from inflammation.
The primary site of inflammation is the synovial
membrane.
Inflamed synovial tissue may fill the joint cavity and
invade articular cartilage and bone.
The inflamed synovial tissue may cause erosion of
bone and cartilage.
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Rheumatoid Arthritis Continued
Eventually irreversible damage may occur such as
total destruction of the joint with fusion of adjacent
bony surfaces.
In milder forms joints may withstand inflammation for
months or years before irreversible damage occurs.
For all types of arthritis early detection and treatment
produce the most favorable results.
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Rheumatoid Arthritis
Rheumatoid Arthritis is common ~1%
Damage occurs very early
Mortality rates increased in poorlycontrolled disease
DMARDS improve clinical outcome if used
in early RAdelay is detrimental
Identify, refer, treat EARLY
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Rheumatoid Arthritis: Symptoms & Causes
Symptoms
Stiffness, pain,
redness, warmth, &swelling over the joint.
Loss of appetite, fever,
& lack of energy.
Rheumatoid nodules,
psoriasis of the skin &
nail bed, dry eye
syndrome, & scleritis.
Causes
Rheumatoid arthritis is
an autoimmune
disease.
For unknown reasons
the immune system
attacks the individuals
own cells inside the
joint.
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Rheumatoid Arthritis
1987 American College of Rheumatology Revised criteria for
the diagnosis of Rheumatoid Arthritis:
At least four of the following Morning stiffness > 1hour
Synovitis in three joints simultaneously
Synovitis in wrist or hand MCP or PIP joints
Symmetrical arthritis (some joint areas on both sides of
the body)
Rheumatoid nodules
Serum rheumatoid factor
Radiographic changes typical of Rheumatoid Arthritis
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Rheumatoid Arthritis
Treatment
goal of treatment reduce inflammation and pain,
preservation of function, and
prevention of deformity.
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Rheumatoid Arthritis
Treatment
Nonpharmacologic treatment
Education and emotional factors
Physical and occupational therapies
Systemic and articular rest
Exercise
Heat and cold
Assistive devices like splints, canes, raised
toilet seat and/or crutches or walker
Weight loss
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Drugs Management of
Rheumatoid Disease
NSAIDS and analgesics and corticosteroid
DMARDS - methotrexate
- sulfasalazine
- hydroxychloroquine
- leflunomide
Biologics
- TNF inhibition: infliximab,
etanercept, adalimumab
- Inhibitor T cell activation: abatacept
- B cell inhibition: rituximab
- IL 1 inhibition: anakinra
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DMARDS
Early mild disease
Anti-malarials eg hydroxychloroquine mechanism - decrease protease function
- inhibit Ag processing
- decrease cytokine release
dose - < 6.5 mg/ kg/ day
toxicity - ocular, neuromyopathy, rash
Sulfasalazine mechanism - unknown; scavenge O2 radicals
dose - 2 - 3 gm/day
toxicity - hypersensitivity, granulocytopenia,
headache, G-I
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Moderate - Severe disease
Methotrexate / Leflunomide
Mechanism - inhibit purine/pyrimidinebiosynthesis
Dose - MTX 7.5 - 25 mg/wk
oral/sc/IM
- Leflunomide 10-20 mg/d
Toxicity - hepatic, pulmonary, heme,
infection, GI, skin, mm ulcer
Caution - teratogenetic
DMARDS
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Combination DMARD therapy
MTX + SSZ + OH-Chloroquine
MTX + Corticosteroid
MTX + Etanercept MTX + Remicade
MTX + Adalimumab
MTX + Leflunomide
Excellent safety & improved efficacyover MTX alone
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Indications for Biologic Drugs
Failure or Intolerance to :
MTX 20mg/week sc or po x 3months
Leflunomide 20 mg po x 3months
Any combination DMARD
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Biologic Drugs
Tumor Necrosis Factor (TNF) Inhibitors
Infliximab (Remicade)
Etanercept (Enbrel)
Adalimumab (Humira)
Interleukin-1 Receptor antagonist (IL-1Ra)
Anakinra (Kineret)
Fusion protein blocks T cell activation
Abatacept (Orencia)
CD 20 (B cell) Chimeric Antibody
Rituximab
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Mechanisms in Rheumatology 2001
Proinflammatory and anti-inflammatory cytokines in
RA
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Mechanisms in Rheumatology 2001
Matrix metalloproteinases in RA
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Effectiveness of Biologic Drugs
Decrease symptom s/s igns ofinf lammat ion
ACR criteria, Eular criteria, DAS
Inh ib i t radio log ic prog ression
Modified Sharp score
Improve Funct ional outcome
Health Assessment Questionnaire,SF36S
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Adverse Effects of TNF Inhibitors
Serious Infections TB
Intracellular organisms Skin and soft tissue
Malignancy ? Lymphoma
? Solid Tumors
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Adverse Effects of TNF Inhibitors
Autoantibodies
Optic neuritis, demyelination
Cytopenias Increase LFT
Interstitial Lung Disease
Vasculitis; 39 cases reported Pregnancy: ? no increased risk
No live vaccines
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TNF Drugs in Rheumatoid Arthritis
70% response; 30% non response
Best clinical & radiological outcome in RApatients failed Methotrexate - early in course of
disease
Improved symptom control does not equate toreduction in disease progression or disability
Different mechanism responsible for symptomsand structural damage in TNF IL-1ra drugs
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Drugs & Pregnancy
NSAIDS: safe until week 34 (patent ductus)
OH-chloroquine: safe, ?cleft palate
Sulfasalzine: continue if on it; safe
Azathioprine: continue if on it; safe
Methotexate: teratogen ??? ok in small doses; stop 3
months before conception
Leflunomide: teratogenmay be present for 2 yrs
Cyclophosphamide:? teratogen ? Safe > 2nd trimester
Biologic agents: unknown; stop 3 months before
conception
Steroids: non-fluorinated do NOT cross placenta
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Summary
Biologic Agents are:
Effective in decreasing inflammation
Effective in decreasing structural change in RA
TNF inhibitors are effective in RA plus PS, PSA, AS
Effective in improving health outcomes
No head to head trials; limited comparison to combination Rx
? change paradigm; treat in very early disease; step down Clarify malignancy/infection risk with post market surveillance
30% of patients have no clinical response;
Need to identify those patients with rapidly progressive disease
that will respond to biologic therapy
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Thank
You