KAJIAN MOLEKULER PENYAKIT DAN PENGOBATAN

Arthritis
arthr = joint ; itis = inflammation

Arthritis can affect babies and children, as well as people in the prime of their lives

Osteoarthritis Rheumatoid Arthritis Systemic Lupus Erythematosus Gout Childhood Arthritis (Juvenile Idiopathic Arthritis)

Joint pain is an early symptom of Arthritis The joint is the area where bones meet! Synovial joints are responsible for movement The joint is the area most commonly targeted by inflammation

Rheumatoid Arthritis A chronic autoimmune disease characterized

by the inflammation of the synovial joints
Has a symmetrical bilateral effect on joints Results in joint deformity and immobilization

Multiple factors increase ones risk

Symptoms Morning stiffness lasting more than half an hour

Simultaneous symmetrical joint swelling Not relieved by rest Fever Weight loss Fatigue Anemia Lymph node enlargement Nodules Raynauds phenomenon

1. Morning stiffness Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement at any time inthe disease course. 2. Arthritis in at least three joint Areas* Soft tissue swelling or fluid observed by a physician, with swelling at current examination or deformity and a documented history of swelling. 3.Arthritis of hands Swelling of wrist, MCP, or PIP with swelling at current examination or deformity and a documented history of swelling. 4. Symmetric arthritis Simultaneous involvement of the same joint areas (defined in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute symmetry) with swelling at current examination or deformity and a documented history of swelling.

5. Rheumatoid nodules Over bony prominences or extensor surfaces, or in periarticular regions

6.Rheumatoid factor Detected by a method positive in less than 5% normal controls at current examination or documented to have been positive in the past by any assay method. 7. Radiographic changes Typical of RA on posteroanterior hand and wrist radiographs which must include erosions or unequivocal bony decalcification localized to or most marked adjacent to the involved joints (osteoarthritis changesalone do not qualify).
*Note: At least four criteria must be fulfilled for classification as RA.

Autoimmune/Genetic factors?

Other factors Silica Dust Exposure

Increased risk for RA in smokers
Infections?-(EBV) Dietary Factors-

? red meat ? intake of fruit and oily fish may protect against RA (Mediterranean diet)
?Interactions between genes and environment

and stochastic factor contributions

Other nutrient factors

Lower intakes of vitamin C, fruit and vegetables (high consumption of the antioxidants cryptoxanthin and zeaxanthin) increased the risk of inflammatory polyarthritis

Pathogenesis of Rheumatoid Arthritis

Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

Inflammed synovial tissue (synovitis) Villous hyperplasia Intimal cell proliferation Inflammatory cell infiltration T cells, B cells, macrophages and plasma cells Production of cytokines and proteases Increased vascularity Self-amplifying process

Multiple Cell Types and Cytokine Signaling Pathways Involved in Chronic Inflammatory Arthritis
Modified from Choy, E. H.S. et al. N Engl J Med 2001;344:907-916

Key cytokines in Chronic Inflammatory Arthritis: TNF-a IL-1 IFN-g IL-6 OPGL (RANK-ligand) IL-17

Multiple T cell Subsets Contribute to the Development of Arthritis

adapted from McInnes and Schett, Nat. Rev. Immunol., 7:429-442, 2007

Key Factors that Regulate Osteoclast Differentiation in Arthritis

Nature Reviews Immunology, 2007

Th17 Cells Contribute to Cartilage Distruction in Additional Ways

Nature Reviews Immunology, 2007

Factors that Predispo se an Individual to Rheumatologic Diseases

I. Susceptibili ty Ge nes
A. MHC class I (i.e., HLA-B27 in spond yloarthropathies) B. MHC class II (i.e. HLA-DR4 in RA) C. Complement d eficienc y states (i.e., C2 or C4 d eficiency in SLE) D. Fc Receptor Polymorphisms d eficiency in SLE) (i.e., FcR

E. PTPN22, a tyrosine phosphatase, po lymorphism associated with rheumatoi d arth ritis, SLE, others F. Gende r (female:m ale cases of SLE ar e 9:1) G. Others (48 susceptib ilit y loci for SLE in th e genome)

II. Environmental Factors

A. Viral infect ions (hepati tis B, hepatitis C, others) B. Bacterial infecti ons (Shigella, Salmonella, gp A strep., etc.) C. Drugs (procainamide, dilan tin, others) D. Toxins (heavy metals, others) E. UV -light (i.e., in SLE)

III. Status of the Immune System

A. Relative state of

activation

B. Relative balance of Th1 and Th2 C. History of previous respo nses

IV. Status of Targ et Organ/Tissue

A. Visibi lity of autoantigen (privileged sites, intra- vs extra-cellular, etc) B. Expression level of autoantigen C. Expression level of MHC D. Costim ulatory molecules E. Ongoing inflamma tion

Multiple Factors Contribute to the Development of Arthritis

Newly Diagnosed
The major goal is to relieve pain and inflammation and

prevent further joint damage Anxiety, depression, and a low self esteem commonly accompanies Rheumatoid Arthritis

Articular and Peri-articular Manifestations

Duration of signs and symptoms at more than 3

months was the strongest predictor of RA Duration of signs and symptoms at more than 3 months was the strongest predictor of RA Slow, insidious disease onset (70%) Intermediate onset (20%) Sudden acute onset (10%) Complain of pain, stiffness, and swelling of their peripheral joints

Extra-Articular Manifestations
Rheumatoid Nodules
Anemia of chronic disease, lymphadenopathy Vasculitis- sensorimotor neuropathy, nail-fold infarcts,

leg ulcers, purpura, and digital gangrene

Treatment of Early Arthritis

Nonsteroidal Anti-Inflammatory Drugs- do not alter

the course of the arthritis and its outcome GlucocorticoidsDisease-Modifying Antirheumatic Drugs Methotrexate- favorable riskbenefit ratio, is (as in established RA) regarded to be the drug of first choice hydroxychloroquine or sulfasalazine

medication
There are four types of medications used to treat RA:
Non-steroidal anti-inflammatory drugs (NSAIDs) Disease-modifying anti-rheumatic drugs(DMARDS). Corticosteroids Biologic Response Modifiers (Bioligics)

Non-steroidal anti-inflammatory drugs (NSAIDs)

Examples Aspirin, ibuprofen, naproxen, COX-2 inhibitors, propionic acid, phenylacetic acid General Use anti-inflammatory: Used in the management inflammatory conditions Antipyretic: used to control fever Analgesic: Control mild to moderate pain

Side Effects Nausea, Vomiting, Diarrhea , constipation, Dizziness ,Drowsiness Edema , Kidney failure , Liver failure , Prolonged bleeding ,Ulcers.

Nursing Considerations Use cautiously in patients with hx of bleeding disorders Encourage pt to avoid concurrent use of alcohol NSAIDs may decrease response to diuretics or antihypertensive therapy

Examples Cortisone, hydrocortisone, prednisone, betamethasone,dexa-methasone

General Use Used in the management inflammatory conditions When NSAIDS may be contraindicated Promptly improve symptoms of RA

Side Effects Increased appetite, Weight gain ,Water/salt retention ,Increased blood pressure, Thinning of skin, Depression ,Mood swings ,Muscle weakness Osteoporosis ,Delayed wound healing ,Onset/worsening of diabetes.
Nursing Considerations Take medications as directed (adrenal suppression) Used with caution in diabetic patients Encourage diet high in protein, calcium, potassium and low in sodium and carbohydrates Discuss body image Discuss risk for infection

Disease-modifying anti-rheumatic drugs(DMARDS

Examples Methotrexate (the gold standard) , gold salts, cyclosporine, sulfasalazine, azathioprine General Use immunosuppressive activity Reduce inflammation of rheumatoid arthritis Slows down joint destruction Preserves joint function

Side Effects Dizziness, drowsiness, headache, Pulmonary fibrosis ,Pneumonitis Anorexia ,Nausea ,Hepatotoxicity ,Stomatitis ,Infertility ,Alopecia Skin ulceration ,Aplastic anemia ,Thrombocytopenia ,Leukopenia Nephropathy ,fever ,photosensitivity. Nursing Considerations May take several weeks to months before they become effective Discuss teratogenicity, should be taken off drug several months prior to conception Discuss body image

Specific drugs: Methotrexate

Anti folic acid- inhibition of proliferation of cells responsible for synovial inflammation Decreases markers of inflammation, including the erythrocyte sedimentation rate and c-reactive protein (CRP) Adverse Effects-low-dose weekly-7.5 to 10 mg anorexia, nausea, vomiting, and diarrhea(10%) Hematologic-leukopenia (3%) ? cirrhosis and liver failure (1/1000) acute interstitial pneumonitis

MTX is currently considered a first-line agent in the treatment of RA, and the anchor drug for combination therapy with other DMARDs and biologic agents. It has become the standard of care and the most widely used drug in the treatment of RA.

Leflunomide
A second choice DMARD to be used after methotrexate
has a long half-life (2 wks) dose:20 mg daily leflunomide, sulfasalazine, radiologic progression and methotrexate reduced

Biologic Response Modifiers

Examples Etanercept, anakinra, abatacipt, adalimumab, Infliximab (Remicade)

General Use Used in the management inflammatory conditions When NSAIDS may be contraindicated Promptly improve symptoms of RA
Side Effects Increased appetite ,Weight gain ,Water/salt retention ,Increased blood pressure Thinning of skin ,Depression ,Mood swings ,Muscle weakness ,Osteoporosis Delayed wound healing ,Onset/worsening of diabetes

Nursing Considerations Take medications as directed (adrenal suppression) Encourage diet high in protein, calcium, potassium and low in sodium and carbohydrates Discuss body image Discuss risk for infection

Other Drugs
Antimalarials Sulfasalazine Tetracyclines Gold Salts D-penicillamine Azathioprine Cyclosporine

Alternative Medicine
Olive leaf extract Aloe Vera

Green Tea
Omega 3 Ginger Root Extract Cats Claw

Omega 3 interferes with blood clotting drugs!

Pain
Pain is subjective and influenced by multiple factors Helpless Lack of control Stressful events can increase symptoms of arthritis

Nutrition
The most commonly observed vitamin and mineral deficiencies in patients with RA are: folic acid , vitamin C , vitamin D , vitamin B6 , vitamin B12 vitamin E , calcium , magnesium , zinc , selenium.

Therapeutic Strategies
Reagents that blunt inflammation but dont have effects on disease progression: Aspirin Nonsteroidal anti-inflammatory drugs (NSAIDs) Non-selective and selective COX-2 antagonists Steroids (prednisone) Disease Modifying Anti-Rheumatic Drugs (DMARDs): Broad Acting: Methotrexate Hydroxychloroquin Azathoprine Cyclophosphamide Cyclosporin More selective biologics: TNF antagonists IL-6R antagonists IL-1R antagonists anti-B cell (CD20) therapy costimulatory inhibitors (CTLA4-Ig) Intravenous Immunoglobulin (iv Ig)

Methods of Blocking the Activity of an Inflammatory Cytokine

Blocking CD28-dependent Costimulation

Abatacept is a fusion of the extracellular domain of CTLA-4 (similar to CD28 but with higher affinity for CD80 and CD86) with the Fc fragment of IgG1 (for effector function and to prolong half-life)

Biological Therapeutics :Targets, Rationale, Status