KAJIAN MOLEKULERPENYAKIT DAN PENGOBATAN

Arthritis

“arthr” = joint ; “itis” = inflammation

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

OsteoarthritisRheumatoid ArthritisSystemic Lupus ErythematosusGoutChildhood Arthritis (Juvenile Idiopathic

Arthritis)

Joint pain is an early symptom of ArthritisThe joint is the area where bones meet! Synovial joints are responsible for movementThe 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 one’s risk

SymptomsMorning stiffness lasting more than half an hourSimultaneous symmetrical joint swellingNot relieved by restFeverWeight lossFatigueAnemiaLymph node enlargementNodulesRaynaud’s phenomenon

1. Morning stiffness1. Morning stiffnessMorning stiffness in and around the joints, lasting at least 1 Morning stiffness in and around the joints, lasting at least 1 hour before maximal improvement at any time inthe disease hour before maximal improvement at any time inthe disease course.course.

2. Arthritis in at least three joint Areas*2. Arthritis in at least three joint Areas*Soft tissue swelling or fluid observed by a physician, with Soft tissue swelling or fluid observed by a physician, with swelling at current examination or deformity and a swelling at current examination or deformity and a documented history of swelling.documented history of swelling.

3.Arthritis of handsArthritis of handsSwelling of wrist, MCP, or PIP with swelling at current Swelling of wrist, MCP, or PIP with swelling at current examination or deformity and a documented history of examination or deformity and a documented history of swelling.swelling.

4. Symmetric arthritis4. Symmetric arthritisSimultaneous involvement of the same joint areas (defined Simultaneous involvement of the same joint areas (defined in 2) on both sides of the body (bilateral involvement of in 2) on both sides of the body (bilateral involvement of PIPs, MCPs, or MTPs is acceptable without absolute PIPs, MCPs, or MTPs is acceptable without absolute symmetry) with swelling at current examination or symmetry) with swelling at current examination or deformity and a documented history of swelling.deformity and a documented history of swelling.

5. Rheumatoid5. Rheumatoid nodulesnodulesOver bony prominences or extensor surfaces, or in Over bony prominences or extensor surfaces, or in peri-articular regionsperi-articular regions

6.Rheumatoid6.Rheumatoid factorfactorDetected by a method positive in less than 5% Detected by a method positive in less than 5% normal controls at current examination or normal controls at current examination or documented to have been positive in the past by documented to have been positive in the past by any assay method.any assay method.

7. Radiographic7. Radiographic changeschangesTypical of RA on posteroanterior hand and wrist Typical of RA on posteroanterior hand and wrist radiographs which must include erosions or radiographs which must include erosions or unequivocal bony decalcification localized to or unequivocal bony decalcification localized to or most marked adjacent to the involved joints most marked adjacent to the involved joints (osteoarthritis changesalone do not qualify).(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 environmentand stochastic factor contributions

Other nutrient factorsLower 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 ChronicInflammatory Arthritis:

TNF- IL-1

IFN-IL-6OPGL (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 Differentiationin Arthritis

Nature Reviews Immunology, 2007

Th17 Cells Contribute to Cartilage Distructionin Additional Ways

Nature Reviews Immunology, 2007

Factors that Predispose an Individual to Rheumatologic Diseases

I. Susceptibility Genes

A. MHC class I (i.e., HLA-B27 in spondyloarthropathies) B. MHC class II (i.e. HLA-DR4 in RA) C. Complement deficiency states (i.e., C2 or C4 deficiency in SLE) D. Fc Receptor Polymorphisms (i.e., FcR deficiency in SLE) E. PTPN22, a tyrosine phosphatase, polymorphism associated with rheumatoid arthritis, SLE, others F. Gender (female:male cases of SLE are 9:1) G. Others (48 susceptibility loci for SLE in the genome)

II. Environmental Factors

A. Viral infections (hepatitis B, hepatitis C, others) B. Bacterial infections (Shigella, Salmonella, gp A strep., etc.) C. Drugs (procainamide, dilantin, 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 responses

IV. Status of Targ et Organ/Tissue

A. Visibility of autoantigen (privileged sites, intra- vs extra-cellular, etc) B. Expression level of autoantigen C. Expression level of MHC D. Costimulatory molecules E. Ongoing inflammation

Multiple Factors Contribute to the Development of Arthritis

Newly DiagnosedThe 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-articularManifestations• 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-ArticularManifestationsRheumatoid NodulesAnemia of chronic disease, lymphadenopathyVasculitis- 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•Glucocorticoids- •Disease-Modifying Antirheumatic Drugs•Methotrexate- favorable risk–benefit ratio, is (as in established RA) regarded to be the drug offirst choice

•hydroxychloroquine or sulfasalazine

medicationThere 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”)

ExamplesAspirin, ibuprofen, naproxen, COX-2 inhibitors,

propionic acid, phenylacetic acid

General Useanti-inflammatory:Used in the management inflammatory conditions Antipyretic: used to control feverAnalgesic:Control mild to moderate pain

Non-steroidal anti-inflammatory drugs (NSAIDs)

Side EffectsNausea, Vomiting, Diarrhea , constipation, Dizziness ,DrowsinessEdema , Kidney failure , Liver failure , Prolonged bleeding ,Ulcers.

Nursing ConsiderationsUse cautiously in patients with hx of bleeding disordersEncourage pt to avoid concurrent use of alcoholNSAIDs may decrease response to diuretics or antihypertensive therapy

ExamplesCortisone, hydrocortisone, prednisone, betamethasone,dexa-methasone

General UseUsed in the management inflammatory conditions When NSAIDS may be contraindicatedPromptly improve symptoms of RA

Side EffectsIncreased appetite, Weight gain ,Water/salt retention ,Increased blood pressure, Thinning of skin, Depression ,Mood swings ,Muscle weaknessOsteoporosis ,Delayed wound healing ,Onset/worsening of diabetes.

Nursing ConsiderationsTake medications as directed (adrenal suppression)Used with caution in diabetic patientsEncourage diet high in protein, calcium, potassium and low in sodium and carbohydratesDiscuss body imageDiscuss risk for infection

Disease-modifying anti-rheumatic drugs(DMARDS

ExamplesMethotrexate (the gold standard), gold salts, cyclosporine, sulfasalazine, azathioprine

General Useimmunosuppressive activityReduce inflammation of rheumatoid arthritisSlows down joint destructionPreserves joint function

Side EffectsDizziness, drowsiness, headache, Pulmonary fibrosis ,PneumonitisAnorexia ,Nausea ,Hepatotoxicity ,Stomatitis ,Infertility ,AlopeciaSkin ulceration ,Aplastic anemia ,Thrombocytopenia ,LeukopeniaNephropathy ,fever ,photosensitivity.

Nursing ConsiderationsMay take several weeks to months before they become effectiveDiscuss teratogenicity, should be taken off drug several months prior to conceptionDiscuss body image

Specific drugs: MethotrexateAnti 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.”

LeflunomideA second choice DMARD to be used after methotrexate

has a long half-life (2 wks)

dose:20 mg daily

leflunomide, sulfasalazine, and methotrexate reduced radiologic progression

ExamplesEtanercept, anakinra, abatacipt, adalimumab, Infliximab (Remicade)

General UseUsed in the management inflammatory conditions When NSAIDS may be contraindicatedPromptly improve symptoms of RA

Side EffectsIncreased appetite ,Weight gain ,Water/salt retention ,Increased blood pressureThinning of skin ,Depression ,Mood swings ,Muscle weakness ,OsteoporosisDelayed wound healing ,Onset/worsening of diabetes

Biologic Response Modifiers

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 DrugsAntimalarialsSulfasalazineTetracyclinesGold SaltsD-penicillamineAzathioprineCyclosporine

Alternative MedicineOlive 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

HelplessLack of controlStressful 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 StrategiesReagents that blunt inflammation but don’t have effects on disease

progression:AspirinNonsteroidal anti-inflammatory drugs (NSAIDs)

Non-selective and selective COX-2 antagonistsSteroids (prednisone)

Disease Modifying Anti-Rheumatic Drugs (DMARDs):Broad Acting:

MethotrexateHydroxychloroquinAzathoprineCyclophosphamideCyclosporin

More selective biologics:TNF antagonistsIL-6R antagonistsIL-1R antagonistsanti-B cell (CD20) therapycostimulatory 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