Drugs for Osteoarthritis Revise 2010

7/28/2019 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 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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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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Treatment

goal of treatment reduce inflammation and pain,

preservation of function, and

prevention of deformity.


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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

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Drugs for Osteoarthritis Revise 2010

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