Drugs for Arthritis

Dr. Nicolaski Lumbuun, SpFK

Department of Pharmacology Faculty of Medicine

The Case
A 61 year old woman with new onset inflammatory, large and small joint, somewhat asymmetric polyarthritis
What What

is the diagnosis? is the treatment?

Arthritis

Arthritis is derived from the Greek words

arthron meaning joint and itis meaning 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.

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

Normal jointcartilage

Osteoarthritis

Osteoarthritis: Symptoms & Causes

Symptoms Swelling, stiffness, and pain. Joints ache after physical activity. Stiffness or pain in the neck or lower back which can result in numbness of the legs or arms.

Causes Trauma to joints such as repetitive movements over a long time. Acute injury can lead to osteoarthritis years later. Age. Metabolic disorders that can cause cartilage deterioration.

Common places osteoarthritis :

Lower back

knees
hips neck

thumbs
ends of fingers

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.

(Event of morning Stiffness)

, stiffness and swelling

Management of OA
1. 2.

Patient education (avoid physical stress ,avoid injury) 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 and bracing Assistive devices for activities of daily living
- Nutritional supplementation

4. 5. 6.

Dietary consideration : - Maintain optimal weight Early and adequate drugs treatment Surgery

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

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

OA: Management Summary (contd)

Second-line approach

NSAIDs if paracetamol fails Intra-articular agents Opioids

Third-line -SURGERY

Arthroscopy Osteotomy Total joint replacement

American College of Rheumatology

American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis and Rheum 2000;43(9):1905-15.

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

Drugs Therapy for OA

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

Making Sense of Oral Medications

Recommendations
Continuous versus As Needed Preferable on a periodic basis in patients with non-inflammatory OA; continuous only if this regimen is inadequate. Medications normally take 2 to 4 weeks to assess; if inadequate, the dose should be increased. If not effective after 2 to 4 weeks, then another agent should be tried. If there is a history of GI disease, a selective COX2 inhibitor or a nonselective agent with anti-ulcer prophylaxis may be used. Opioids may be used for severe breakthrough pain, patients who have failed other therapies, and where surgery is not an option.

Who Deserves an Injection?

AAOS (American Acad of Orthopaedic Surgeons)

Inflamed knees respond best to injections. Localized knee pain felt only with weightbearing 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 local inflammation 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

Chondroitin sulfate

Chondroitin sulfate (CS) belongs to the group of glycosaminoglycans, important constituents of cartilage extracellular matrix.
OX COOR O HO R: Na, H X: SO3R, H O OH NHCOCH 3 O CH 2OX O

Chondroitin sulfate is a symptomatic slow acting drug for osteoarthritis (SYSADOA) in Europe, where it has been approved as a drug for more than ten years in several countries.
Hardingham T. Osteoarthritis Cart (1998) 6, (Supplement A), 3-5. Lequesne M. G. Rev Rhum (Eng/Ed) 1994; 61: 69-73.

CHONDROITIN SULFATE ACTION MECHANISMS

STIMULATES:
proteoglycans HA

EFFECT:
-anti-inflammatory activity -Membrane stabilising action

INHIBITS: cartilage degradative enz. (collagenase ,elastase, proteoglycanase, fosfolipase A2, N-acetylglucosaminidase, etc.) cartilage damaging substances (free radicals) apoptosis NO Stromelysin (MMP-3) NF-kB

(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.

CLINICAL EVIDENCE

9 randomized, controlled, clinical trials have been conducted in Europe with Condrosan / Condrosulf (CS), comparing its effect against placebo (PBO) and sodium diclofenac (SD) (150 mg) in 1163 patients with knee and hand osteoarthritis (OA) The results from these clinical trials conclude that CS is as effective as SD and around 50% more effective than PBO (p < 0.05) in the reduction of OA symptoms. Besides, its efficacy lasts for at least 3 months after treatment suppression (carry-over effect).

Morreale, et al. J. Rheumatol. 1996, 23: 1385-1391. Kissling R. et al. Osteoarthritis Cart 1997, 5 (Supplement A), 9: 70. Bucsi L, et.al. Osteoarthritis Cart 1998, 6 (supplement A):31-36. Pavelka K, et al. Litera Rheumatologica 1998, 24:21-30. Uebelhart D, 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.

S/DMOAD

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 a stabilization of joint space width with CS treatment as opposed to a narrowing of joint space with PBO. 2 clinical trials in hand OA concluded that disease progression was lower in CStreated patients and less patients from this group developed erosive OA.

SAFETY PROFILE
The tolerance of Chondroitin Sulfate is very well documented; equivalent to PBO and much higher than that of SD.

It is not 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 for more than 10 years, support the safety of the product.

Leeb F, et al. J. Rheumatol. 2000; 27: 1: 205 211.

Chondroitin Sulfate Advantages

Clinical efficacy on symptom reduction and improvement of 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.

Glucosamine

Glucosamine sulfate (+ chondroitin sulfate) are particularly popular treatments for osteoarthritis. Several early studies demonstrated that glucosamine was superior to placebo and comparable to NSAIDs for knee OA. (manufacturer supported) Other studies measuring changes in joint space narrowing suggested a chondroprotective effect against articular cartilage loss.

GLUCOSAMINE SULFATE ACTION MECHANISMS

STIMULATES:
proteoglycans

EFFECT:
-anti-inflammatory activity -Membrane stabilising activity

INHIBITS: cartilage degradative enz.(collagenase , aggrecanase, fosfolipase A2, etc.) Stromelysin (MMP-3), MMP-2, MMP-9 free radicals PGE2

IL-1 NF-kB

Studies of radiolabeled glucoasmine do demonstrate uptake in the joint articular cartilage. Thought to stimulate chondrocytes to make proteoglycans. Real mechanism of action is largely unknown.

Glucosamine

Cochrane Review 2005:

WOMAC outcomes of pain, stiffness and function did not show a superiority of glucosamine over placebo. Glucosamine was as safe 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 with moderate-to-severe knee pain European trials that showed a benefit with glucosamine used as glucosamine sulfate; most of the American trialsincluding GAITused glucosamine hydrochloride
Clegg DO et al. (2006), N Engl J Med 354(8):795-808

Glucosamine

Using Glucosamine:
Safe, however, questions exist as to adverse effects, purity and efficacy. Not recommended in patients with seafood allergy; chondroitin may have anticoagulant effect. No studies demonstrating consistent benefit of adding chondroitin. Trial of 1500 mg/d for 6 to 8 weeks

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.

HYALURONIC ACID ACTION MECHANISMS

STIMULATES: Hyaluronic acid Glucosaminoglicans Tissue inhibitor of metalloproteinases (TIMPs)
EFFECT: -anti-inflammatory activity -Improve synovial fluid viscosity

INHIBITS:

Apoptosis Stromelysin (MMP-3) free radicals PGE2 NO Leucocyte proliferation, migration and phagocytosis - Counteract some IL-1 effect

Hyalgan

Whats the Evidence?

Cochrane Review 2005
Viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period.

Questions?
Is HA superior to corticosteroid injections or saline injections? Do HA injections result in lower utilization of NSAIDs?

Hyalgan

Using Hyalgan:
Indications: indicated for the treatment of osteoarthritis not responsive to non-pharmacologic measures and to simple analgesics. Requires sterile technique, remove joint effusion if present prior to injection. Three to five weekly injections recommended.

Is it safe?
No concern of inhibition of prostaglandins. Post-injection synovitis is described, and can last up to three weeks.

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.

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.

Rheumatoid Arthritis

Rheumatoid Arthritis is common ~1% Damage occurs very early

Mortality rates increased in poorly controlled disease

DMARDS improve clinical outcome if used in early RA delay is detrimental Identify, refer, treat EARLY

Rheumatoid Arthritis: Symptoms & Causes

Symptoms
Stiffness, pain, redness, warmth, &

Causes
Rheumatoid arthritis is an autoimmune disease. For unknown reasons the immune system attacks the individuals own cells inside the joint.

swelling over the joint.

Loss of appetite, fever, & lack of energy. Rheumatoid nodules, psoriasis of the skin & nail bed, dry eye syndrome, & scleritis.

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

Rheumatoid Arthritis
Treatment

goal of treatment reduce inflammation and pain, preservation of function, and prevention of deformity.

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

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

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

DMARDS

Moderate - Severe disease

Methotrexate / Leflunomide
Mechanism - inhibit purine/pyrimidine biosynthesis 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

Combination DMARD therapy

MTX + SSZ + OH-Chloroquine

MTX + Corticosteroid MTX + Etanercept MTX + Remicade MTX + Adalimumab MTX + Leflunomide

Excellent safety & improved efficacy over MTX alone

Indications for Biologic Drugs Failure or Intolerance to :

MTX 20mg/week sc or po x 3 months Leflunomide 20 mg po x 3 months

Any combination DMARD

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

Proinflammatory and anti-inflammatory cytokines in RA

Mechanisms in Rheumatology 2001

Matrix metalloproteinases in RA

Mechanisms in Rheumatology 2001

Effectiveness of Biologic Drugs

Decrease symptoms/signs of inflammation ACR criteria, Eular criteria, DAS

Inhibit radiologic progression Modified Sharp score

Improve Functional outcome Health Assessment Questionnaire, SF36S

Adverse Effects of TNF Inhibitors

Serious Infections TB Intracellular organisms Skin and soft tissue
Malignancy ? Lymphoma ? Solid Tumors

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

TNF Drugs in Rheumatoid Arthritis

70% response; 30% non response
Best clinical & radiological outcome in RA patients failed Methotrexate - early in course of disease Improved symptom control does not equate to reduction in disease progression or disability Different mechanism responsible for symptoms and structural damage in TNF IL-1ra drugs

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: teratogen may 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

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

Thank You