RHEUMATOID ARTHRITIS (2) By Ahmed M. Ali, PhD.

The Mediators of Joint Destruction Immune Destruction Cytokines TNFα Chemokines IL-1, IL-6 MMP VEGF VEGF = Vascular Endothelial Growth Factor MMP = Matrix Metalloproteinase

The Natural Course of RA Undifferentiated Polyarthritis Early RA – Mild Disease Severe RA with Deformities

Management of RA

Goals of Treatment To relieve pain and inflammation. To prevent joint destruction and deformity. To preserve or improve functional activities. To control systemic involvement. To slow disease progression. To restore patients’ normal lifestyle.

Non-Drug Treatment

I. Diet and weight control

II. Physiotherapy Physiotherapy help to reduce pain and swelling, improve joint movement, strengthen joints, prevents disuse atrophy and minimizes deformity. Physiotherapy includes flexibility/stretching exercise, heat therapy, cold therapy, electrotherapy and hydrotherapy.

III. Occupational therapy This therapy involves joint protection using appliances and splints (supportsجبائر) that reduce inflammation and maintain normal joint alignment (normal position).

IV. Surgical intervention Surgery can be effective in relieving pain, restoring function and repairing damaged joints when drug therapy fails to achieve these goals. Surgical procedures include major joint replacement (artificial joints) and carpal tunnel decompression. Surgical interventions are required in 25% of RA cases.

Keypoints Erosive changes occur early in disease. A brief delay of therapy can have a harmful impact on the course of disease years later. Early DMARD therapy is required to arrest disease progression. Bridge the gap initially with NSAIDs and glucocorticoids. Use biologics only for refractory cases (cautions; ↑cost). Surgical treatment options in selected patients. The Therapeutic Window of Opportunity Recent research has confirmed that early, aggressive treatment with disease-modifying antirheumatic drugs (DMARDs) is critical for optimizing long-term results in patients with rheumatoid arthritis.1 Among the findings leading to this conclusion are those showing that approximately 75% RA patients show evidence of joint erosions during the first 2 years of their disease. The rate of progression, expressed as newly eroded joints or increased radiographic damage, is highest during the early years of the disease.2 Others studies have shown that even a brief delay (as little as 8 to 9 months) in starting DMARD therapy can have a significant impact on disease parameters many years later. Research suggests that:2 Early and aggressive DMARD therapy suppresses the inflammatory response can reset the rate of radiographic progression. Reliance on the traditional “pyramid approach” to therapy, which involved the initial prescription of aspirin and NSAIDs and then individual DMARDs is no longer recognized as effective. Moreover, combination therapy is not necessarily more toxic than monotherapy. O’Dell JR. Treating rheumatoid arthritis early: A window of opportunity? Arthritis Rheum. 2002;46:283-285. Van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheum. 1995;34 (suppl 2):74-78.

Drug Treatment of RA

Fast-acting agents (simple analgesics, NSAIDs and corticosteroids) are used to relieve symptoms of RA (pain & inflammation) in combination with Slow-acting agents or the disease-modifying antirheumatic drugs (DMARDs) to control disease progression.

DMARDs suppress inflammatory markers of disease activity (e. g DMARDs suppress inflammatory markers of disease activity (e.g., ESR, CRP) and improve joint function but do not necessarily prevent long-term disability. Early use of DMARDs preserves joint function and reduces bone erosion. C-reactive protein (CRP) is a good indicator of disease activity and used to monitor response to drug therapy. CP*

Medical Management – Drug Classes NSAIDs: Cox-1 & Cox-2 inhibitors Glucocorticoids: Prednisolone, Methylprednisolone IAS: Intra articular steroids DMARDs: MTX, SSZ, HCQ, Leflunomide Immunosuppressive Rx: Azathioprine (AZT), CyS Cytotoxic agents: Cyclophosphamide Biologics: TNF-α antibodies, IL-1 R antagonist Old drugs: Gold salts, D-Penicillamine

Renal and GI homeostasis NSAIDS in RA NSAIDs COX 1 COX2 Selective COX 2 Inhibitors (COXIBs) Improved GI tolerability Reduced effects on RBF No effect on platelets May have CV adverse effects Examples: Celecoxib, Etoricoxib, Meloxicam Constituent pathway Renal and GI homeostasis Inducible pathway Inflammation

NSAIDs Class of Drugs Non-Selective (COX1/COX2) Ibuprofen Ketoprofen Diclofenac Aceclofenac Piroxicam Lornoxicam Naproxen Indomethacin NSAIDs used as analgesics Ketorolac Aspirin Selective COX-2 inhibitors Celecoxib, Etoricoxib Meloxicam Analgesics Tramadol Paracetamol

Pros and Cons of NSAID Therapy Effective control of inflammation and pain Effective reduction of tissue swelling Improve mobility, flexibility, range of motion Improve quality of life Relatively low-cost CONS Does not affect disease progression GI toxicity common Renal complications (e.g. Irreversible renal insufficiency, papillary necrosis) Hepatic dysfunction CNS toxicity

NSAIDs with short half-life HOURS)) HALF-LIFE TIME DRUG NSAIDs with short half-life 0.25 Aspirin 1.1 Diclofenac 3 Etodolac 2.1 Ibuprofen 4.6 Indomethacin 1.8 Ketoprofen NSAIDs with long half-life 15 Azapropazone 20 Meloxicam 28 Piroxicam 60 Tenoxicam 7 Sulindac 16 Sulindac sulphide (active metabolite) 11 Celecoxib

Renal Excretion of some NSAIDs DRUG % < 2 Aspirin < 1 % Diclofenac %1 Ibuprofen % < 15 Indomethacin % 62 Azapropazone Meloxicam %10 Piroxicam % 7 Sulindac

Relative risk of GI complications with various NSAIDs Ibuprofen 1.0 Diclofenac 2.3 Naproxen 7.0 Indomethacin 8.0 Piroxicam 9.0 Azapropazone 11.7

------------------------------------------------------------- NSAIDs Dose ------------------------------------------------------------- Aspirin 650 mg/4 hrs Diclofenac Sodium (Voltaren) 75 mg bid Diclofenac Potassium (Cataflam) 75 mg bid Indomethacin (Indocid) 50-200 mg/day Ibuprofen (Brufen) 400 mg bid Naproxen (Naprosyn) 500 mg bid Tolmetin (Tolectin) 400 mg bid Sulindac (Hi Dac) 200 mg bid Piroxicam (Feldene) 20 mg qd Celecoxib (Celebrex) 100-200 mg bid Etoricoxib 30-120 mg/day

Corticosteroids Corticosteroids can be given orally or injected systemically or locally (intra-articularly) into joints and surrounding tissues. They are more effective than NSAIDs in reducing inflammation and restoring joint mobility. Corticosteroids are useful for short-term use during severe flares of disease activity in patients not responding to NSAIDs. Long-term use of high-dose steroids should be avoided because of serious side effects.

Corticosteroids has immunosuppressant effect with increased risk of infection. Corticosteroids should be discontinued gradually as the patient’s condition improves by tapering the doses. Abrupt discontinuation can lead to flares of the disease.

Side effects of Corticosteroids Weight gain. Oedema. Cataract. Osteoporosis. Hypertension. Hyperglycemia. Muscle wasting Glaucoma. Peptic ulceration. Dermal thinning. Sodium retention. Easy bruising. Depression. Facial puffiness. Destruction of large joints Infection. Hypokalemia. Delayed wound healing. Hyperlipidemia. Avascular necrosis. Acne.

Pros and Cons of Corticosteroid Therapy Anti-inflammatory and immunosuppressive effects Can be used to bridge gap between initiation of DMARD therapy and onset of action Intra-articular steroid (IAS) injections can be used for individual joint flares CONS Does not conclusively affect disease progression Tapering and discontinuation of use often unsuccessful Low doses result in skin thinning, ecchymoses, and Cushingoid appearance Significant cause of steroid-induced osteopenia An ecchymosis is a subcutaneous spot of bleeding with a diameter >1 Cm 

Methotrexate (MTX) MTX is given 10 to 30 mg/week (orally, IM, or SC). It is DHF reductase inhibitor – Supplemental folic acid is required. The clinical improvement takes 1-2 months. Rapid onset (6-10 weeks); tends to produce more sustained results over time than other DMARDs and lowers all-cause mortality. Can be used when cause of polyarthritis uncertain. Often combined with other DMARDs like Leflunomide, SSZ, HCQ. ADRs: Nausea, diarrhea; mouth ulcers; rash, alopecia; Abnormal LFT. Rare ADRs: low WBC & platelets; pneumonitis; sepsis; liver disease; EBV related lymphoma. Monitoring: CBC, creatinine, and LFTs monthly for 6 months, then every 1- 2 months. Repeat AST or ALT in 2-4 weeks if initially elevated, and adjust dose as needed.

Drug Therapy of RA

Biological Agents in RA TNFα antagonists Adalimumab (Humira) Etanercept (Enbrel) Infliximab (Remicade) Interleukin-1 antagonist Anakinra (Kineret) Suppressors of T-Cell activation Abatacept (Orencia) Anti B-Cell monoclonal antibody Rituximab (Rituxan)

Characteristics of Biologicals used in RA Etanercept Enbrel® Infliximab Remicade® Adalimumab Humira® Anakinra Kineret® Abatacept Orencia® Rituximab Rituxan® Target TNF IL-1 Receptor T-Cell Activation B-Cell Half Life 3-5 Days 8-10 Days 10-20 Days 4-6 Hrs 13-16 Days 19 Days Construct Human Chimeric Dosing Once Biweekly-weekly Once every 4-8 weeks Once every 1-2 weeks Once Daily Once Monthly Twice every 6-12 months Route SC I.V.

Biologics: Relative Contraindications Active Hepatitis B Infection Multiple sclerosis, optic neuritis Active serious infections Chronic or recurrent infections Current neoplasia History of TB Congestive heart failure (Class III or IV)

Early & Established RA Early RA: Rheumatoid arthritis with duration of disease/symptoms of < 6 months (duration denotes the length of time the patient has had symptoms/disease, not the length of time since RA diagnosis). Established RA: RA with duration of disease/symptoms of ≥ 6 months or meeting 1987 ACR RA classification criteria.

ACR Guidelines for the Treatment of Rheumatoid Arthritis