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Management of rheumatoid arthritis .by Dr.Harmanjit Singh,GMC, Patiala
 

Management of rheumatoid arthritis .by Dr.Harmanjit Singh,GMC, Patiala

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    Management of rheumatoid arthritis .by Dr.Harmanjit Singh,GMC, Patiala Management of rheumatoid arthritis .by Dr.Harmanjit Singh,GMC, Patiala Presentation Transcript

    • MANAGEMENT OF RHEUMATOID ARTHRITIS Dr.Harmanjit Singh Department of Pharmacology Govt Medical College,Patiala.
    • INTRODUCTION
      • RA is chronic multisystem disease of unknown cause.
      • Characteristic feature is persistent inflammatory synovitis.
      • Usually involve peripheral joints in symmetric distribution.
      • Joint changes probably represent autoimmune reaction.
      • Etiology:
      • Cause is unknown .
      • Family studies indicate genetic predisposition.
      • HLA DR4, Dw16, DR10, DR9, DR3 associated with rheumatoid arthritis.
      • HLADR5, DR7, DR2 may protect against rheumatoid arthritis ( Frequency less).
      • . May be manifestation of response to infection by mycoplasma, EBV, CMV, Parvovirus & rubella virus.
      • .Cigarette smoking – triggering factor.
      • Pathology :
      • Hyperplasia & hypertrophy of synovial cells.
      • Infiltration with mononuclear cells, macrophages.
      • Production of IL-1, IL-6 TNF alpha, PGE2, Leukotriene B4.
      • TNF alpha : proliferation of inflammatory cells
      • IL-1 : cartilage proteoglycan resorption, bone erosion,destructive aspect of RA
      • IL-6 : mediates IL-1 & TNF alpha actions
      • stimulates B cells
    •  
    • Diagnosis of rheumatoid arthritis Morning stiffness  1h Three or more joints involved Arthritis of hand joints Symmetric arthritis Rheumatoid nodules ( over bony prominence , extensor surfaces) Rheumatoid factor (positive < 5% normal subjects) Radiographic changes (must show erosion/decalcification) Present for  6wk Any 4 of the following must be present to allow diagnosis of RA ( Patients with 2 or more clinical diagnoses are not excluded )
    • RA- joint involvement
      • Extraarticular manifestations
      • Pericarditis
      • Interstitial lung disease
      • Felty’s syndrome
      • Vasculitis
      • Neuropathy
      • INVESTIGATIONS
      • Rheumatoid Factor .   : +ve In about 80% of cases
      • - Also present in about 5% of normal individuals
      • - when it appears in patients with arthritic pain on both sides of the body, it is a strong indicator of RA.
      • ESR.   The higher the ESR the greater the inflammation., help determine how active the condition is.
      • C-Reactive Protein .  High levels of C-reactive protein (CRP) are also indicators of active inflammation..
      • Anti-CCP Antibody Test .  The presence of antibodies to cyclic citrullinated peptides (CCP) can identify RA years before symptoms develop.
      • Tests for Anemia .   normocytic normochromic
      • IMAGING TECHNIQES
      • X-Rays, Dexa Scans . Ultrasound.  Special ultrasound techniques called power Doppler ultrasonography (PDUS) or quantitative ultrasound (QUS) may be helpful in RA.
      • Magnetic Resonance Imaging .  Specially designed magnetic resonance imaging (MRI) equipment called extremity MRI may be able detect bone erosions in the hands of RA patients where x-rays cannot.
      • Above lab findings plus clinical features are important to make the diagnosis
      • Monitoring progression
      •   Disease Activity Score of 28 joints  (DAS28). It is widely used as an indicator of RA disease activity and response to treatment The joints included in DAS28 are PIP , MCP joints, wrists ,  elbows  ,  shoulders  and  knees  
      • When looking at these joints, both the number of joints with tenderness upon touching ( TEN28 ) and swelling ( SW28 ) are counted.
      • In addition, the   ESR is measured.
      • Score less than 3.2 means pt is inactive
      • 3.2-5.1 means moderately active patient
      • more than 5.1 means pt is active
    • Goals of therapy Alleviate pain Preservation of function Control disease activity Maximize quality of life Slow progression/rate of joint damage
    • MANAGEMENT
      • Physical Therapies
      • Diet
      • Pharmacologic Therapies
      • NSAIDS
      • Glucocorticoids
      • DMARDS
      • Biologics
      • Surgical treatment
      • Future trends
    • MANAGEMENT
      • Physical therapies
      • Splinting: prevents unwanted joint movement
      • Exercise: directed to maintain muscle strength & joint mobility
      • Diet  
      • .Some studies suggest that omega-3 fatty acids may reduce rheumatoid arthritis inflammation.
      • Some Herbal remedies also found to be useful
      • Pharmacologic measures:
      • NSAIDS
      • First line drugs in mild/early cases
      • Afford symptomatic relief in pain , swelling , morning stiffness
      • Do not arrest disease process
      • Non selective Cox inhibitors :
      • Naproxen - 500 mg bd.
      • Piroxicam -20 mg qid
      • Nabumetone 1000mg od
      • Aceclofenac , Etodolac upto 1000 mg/day
      • Indomethacin reserve dg when other NSAIDs don’t provide relief
      • Aspirin is rarely used now
      • Adverse effects :G I bleeding, ulcers, hepatoxicity, rash.
      • Selective cox-2 inhibitors :
      • Celecoxib100-200mg bd
      • Etoricoxib 90 mg od has highest selectivity ratio for inhibition of cox 2. & has superior efficacy compared with 500 mg naproxen bd over 12 weeks
      • Rafecoxib valdecoxib are obsolete now because of their cardiotoxicity
    • NSAID Therapy
      • Disadvantages
      • Does not affect disease progression
      • GI toxicity common
      • Renal complications (eg, irreversible renal insufficiency, papillary necrosis)
      • Hepatic dysfunction
      • Advantages
      • Effective control of inflammation and pain
      • Effective reduction in swelling
      • Improves mobility, flexibility, range of motion
      • Improve quality of life
      • Relatively low-cost
    • GLUCOCORTICOIDS
      • Second line agents
      • Mostly combined with NSAIDS
      • Pharmacological actions
        • Antiinflammatory & immunosuppressant action
        • Suppress signs & symptoms
        • Slow appearance of new bone erosions
    • GLUCOCORTICOIDS
      • PKs
      • Route:
        • Oral
        • Intraarticular- transient symptomatic therapy when systemic therapy fails, don’t repeat before 4-6 months
      • Dose
        • Prednisolone- 7.5 mg/d, or equivalent
        • Reduce dose gradually
    • GLUCOCORTICOIDS: ADRs
      • Cushing’s habitus
      • Infections
      • Delayed healing
      • Peptic ulcers
      • Cataract
      • Glaucoma
      • Growth retardation
      • Muscle weakness
      • Mood changes
      • Osteoporosis
      • Hyperglycemia
    • Corticosteroid Therapy
      • Disadvantages
      • 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
      • Advantages
      • Anti-inflammatory and immunosuppressive effects
      • Can be used to bridge gap between initiation of DMARD therapy and onset of action.
      • Intra-articular injections can be used for individual joint flares
      • Disease modifying anti rheumatic dgs (DMARDs):
      • - Current recommendation is to add DMARDs as soon as the diagnosis is confirmed
      • -Slow acting, take 6wks to 6 months to show the effects.
      • -They modify/ alter disease progression
      • Commonly used DMARDs are -:
      • - Mehotrexate
      • - Sulphasalazine
      • - Chloroquine & Hydroxychloroquine
      • - Leflunomide
      • - cyclosporine
      • - Azathioprine
    • Advantages of DMARDs
      • Slow disease progression
      • Improve functional disability
      • Decrease pain
      • Interfere with inflammatory processes
      • Retard development of joint erosions
    • Combination DMARD therapy
      • MTX + SSZ
      • MTX + Hydroxychloroquine
      • MTX + cyclosporine
      • MTX + Leflunomide
      • Excellent safety & improved efficacy over MTX alone
    • Who should be put on combination of DMARDs?
      • Failure to respond to > one DMARD / partial response
      • When to change?
      • - If response is not adequate / toxicity develops
    • How to combine two drugs?
      • 'step-up' approach : (easier to control ADR, may use only one drug in those who respond)
      • consisting of starting the patient on a first DMARD followed by the addition of a second if there is no adequate response
      • 'step-down' approach : (better control in early RA)
      • in which initial combination therapy is followed by a reduction of the dose or the abandonment of one or more of the DMARDs.
      • Methotrexate:
      • Considered first choice to treat RA
      • MOA: it probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase & thymidylate synthetase
      • It has secondary effects on PMN cells chemotaxis.
      • It has direct inhibitory effects on proliferation and stimulates apoptosis in immune - inflammatory cells
      • Orally 70% absorption
      • Dose 15-25 mg weekly, starting with 7.5 mg
      • Adverse effects of Methotrexate:
      • Nausea, mucosal ulcers.
      • Dose related hepatotoxicity.
      • Leucovorin used to reduce side effects.
      • Contraindicated in pregnancy.
      • Sulfasalazine:
      • It is metabolised to sulfapyridine & 5- aminosalicylic acid.
      • In treated arthritis patients, IgA & IgM rheumatoid factor production are decreased.
      • Suppression of T cell responses to concanavalin (glycoprotein that play role in cell cell interaction in inflammatory cell).
      • Inhibition of in vitro B cell proliferation.
      • Reduces radiologic disease progression.
      • Ad effects : N, V
      • headache
      • rash
      • Hemolytic anaemia
      • methemoglobinemia
      • Neutropenia
      • Pulmonary toxicity
      • Reversible infertility only in men.
      • Dose : 40 m g/kg/day
      • Chloroquine & Hydroxychloroquine
      • Proposed mech :
      • Suppresion of T lymphocytes response to mitogen
      • Decrease chemotaxis
      • Stablization of lysosomal enzymes
      • A/E: - N/V, abdominal pain, Rash
      • Retinitis : More with Chloroquine
      • CNS: convulsions
      • Cardiac depression
      • Dose :Chloroquine : 200 mg/day
      • Hydroxychloroquine : upto 6.4 mg/kg/day
      • Leflunomide:
      • MOA: its active metabolite ( A77-1726) inhibits dihydroorotate dehydrogenase and causes arrest of dividing T cells and inhibition of production of autoantibodies by B cells
      • in RA it is as effective as MTX
      • Inhibits bony damage
      • A/e diarrhoea, Hepatitis (FDA boxed warning), alopecia, wt gain, HTN
      • C/I : pregnancy
      • DOSE : 20mg/day
    • GOLD COMPOUNDS
      • MOA:
      • Alters morphology & functional capabilities of macrophages
      • Inhibiting monocyte chemotactic factor-1, IL-8, 1 β & VEGF
      • Additionally
      • Alter lysosomal enzyme activity
      • Reduce histamine release from mast cells
      • Formulations-
      • Oral: auranofin (29% elemental gold)
      • I/M: aurothiomalate, aurothioglucose (50% elemental gold)
    • GOLD COMPOUNDS
      • Dose : IM gold: Test dose of 5-25 mg & then 50 mg wkly for 20 wks
      • Oral gold: 6 mg daily in 1 or 2 doses
      • ADRs :-Pruritic skin rash, eosinophilia,Stomatitis & metallic taste,Aplastic anemia- rare, but fatal
      • Proteinuria (8-10% pts), nephrotic syndrome
      • Corneal gold deposition
      • Nitritoid rxns- sweating, flushing & headache, sp. with gold thiomalate
      • Rarely used now because of Questnable efficacy and high Toxicity
    • D-PENICILLAMINE
      • A copper chelating agents
      • Gold like action in RA
      • Dose: Start with 125-250 mg OD, then 250 mg BD
      • ADRs : Same as gold
      • Other: loss of taste, SLE & Myasthenia gravis
      • Rarely used because of toxicity
      • OTHER drugs approved are Chlorambucil, Cyclophosphamide , Cyclosporine, Azathioprine
      • Biologic therapies, or biologics
      • Newer drugs that reduce RA inflammation in a more highly targeted manner than the DMARDs. These are used when there is inadequate response with the DMARDS
      • Biologics are made through biotechnology and target very specific proteins or cells that are involved in the inflammatory process.
      • Biologics have also been shown to help reduce the progression of joint damage in RA.
      • The currently available biologic therapies for RA must either be injected under the skin [etanercept, adalimumab, anakinra] or infused [infliximab, abatacept, and rituxumab]).
      • TNF α inhibitors
      • Etanercept:
      • MOA: it is recombinant fusion protein consisting of two soluble TNF p75 receptor moieties linked to Fc portion of human IgG1, it binds TNF α molecule
      • It decreases rate of formation of new erosion
      • DOSE: 25 mg twice weekly given s.c.
      • A/E
      • - Opportunistic infections, Activation of latent TB
      • Adalimumab
      • MOA: it is fully human IgG1 anti TNF monoclonal antibody complexes with soluble TNF α and prevents its interaction with cell surface receptors causing down regulation of macrophages and Tcell function
      • DOSE: 40 mg given every 2 weely given s.c.
      • Respiratory infection is a common a/e
      • Comb with MTX to improve response
      • Infliximab
      • MOA: it is chimeral IgG1 monoclonal antibody that binds with TNF α
      • DOSE: 3-10 mg/kg as an i.v. infusion every 8 weekly
      • Comb with MTX improves response and decreases rate of formtion of new erosions more than MTX alone
      • A/E: URTI, nausea, headache, sinusitis, rash, activation of latent TB
      • C/I: multiple sclerosis as demyelinating syndromes have been reported
    • TNf-  blocking agents More effective in combination with methotrexate Drug Primary action ROA Usual dose Half life Infliximab Chimeric anti TNF- Ab I/V inj. 3 mg/kg at 0,2,6 wks, then 8 wkly. Gradual ↑ to 10 mg/kg if incomplete response 9 days Etanercept Soluble TNF fusion protein, Binds TNF- α & β S/C inj. 25 mg twice/wk or 50 mg once/wk 4 days Adalimumab Human anti- TNF- α Ab S/C inj. 40 mg every 2 nd wk 2 wks
      • IL-1 ANTAGONIST
      • Anakinra - It is recombinant human IL-1 receptor antagonist.
      • Used in cases who have failed on others drugs.
      • A/e local reaction on s/c inj. & chest infection
      • Do not use in combination with TNF-alpha antagonists
    • IL-1R antagonists: ANAKINRA
    • IL-6 BLOCKING AGENT : TOCILIZUMAB
      • IL-6 activation leads to systemic inflammatory manifestations and abnormal lab findings in patients with RA.
      • Tocilizumab is a Humanized anti IL-6 monoclonal Ab that specifically inhibits the action of 1L-6
      • It is reserved for Resistant RA
      • Abatacept:
      • It is recombinant fusion protein.
      • MOA: inhibits activation of T cell
      • DOSE: depends on body wt it is given as i.v inj.
      • <60 kg: 500mg
      • 60-100 kg: 750 mg
      • >100kg: 1000mg.
      • Used when there is inadequate response to DMARDS
      • A/e :
      • Risk of infections
      • Hypersensitivity reaction
      • Unfortunately not all patients respond sufficiently to TNF blockade and some of the patients become unresponsive to TNF-blocking agents.
    • B CELL DEPLETION THERAPY
      • Targeting B-lymphocytes in these patients has opened a new therapeutic window
      • Rituximab
      • Chimeric monoclonal Ab, targets CD20 B cells
      • Used in resistant RA . Benefit in treatment of RA refractory to antiTNF agents
      • Combination therapy with methotrexate
      • Dose: 2 IV infusions 2 wks apart
      • ADRs: Mild infusion reactions (infrequent)
    • BIOLOGICS : FUNCTION AT A GLANCE
    • Adverse Effects of Biologics
      • Infusion related : dyspnoea , chest pain , rash, hypotension
      • Serious Infections
        • TB : Activation of latent TB
        • Skin and soft tissue
      • Malignancy ? Lymphoma,? Solid Tumors
      • OTHERS
      • Optic neuritis, demyelination , Cytopenias, Increase LFT, ILD, Vasculitis;
      • Pregnancy: stop before 3 months
      • No live vaccines should be given
    • SURGICAL TREATMENT
      • Reserved for pts with severely damaged joints
      • Includes
      • Arthroplasty/Total joint replacement
      • Open/arthroscopic synovectomy
      • Reconstructive hand surgery
    • FUTURE PROSPECTIVES compound MOA Development phase USA EU TNF inhibitors CDP-870 Anti-TNF Ab fragment III III Pegsunercept Pegylated soluble TNF R type 1 II ISIS-104838 TNF-  antisense inhibitors II AGIX4207 TNF inhibitor (oral) II II IL based therapies Atlizumab Humanized anti-IL6 R monoclonal Ab II I HuMAX-IL-15/AMG-714 Anti-IL-15 monoclonal Ab II II ABT-874/J-695 Anti-IL-12 monoclonal Ab II II
    • FUTURE PROSPECTIVES Compound MOA Development phase USA EU Cell adhesion molecule inhibitors Natalizumab Humanized monoclonal Ab II II Co-stimulation inhs CTLA4-Ig CD27/B7 pathway inhibitor III Alefacept CD2 antagonist II
    • FUTURE PROSPECTIVES Immunoadsorption Apheresis – new technique used in pts who are not responding to drug therepy Compound MOA Development phase USA EU Other therapies CCI-779/ Temsirolimus Cell cycle inhibitor II Belimumab Ab against B cell stimulator protein II AT-001/dnaJp1 Heat shock derived protein II
      • FDA Adds Boxed Warning To Leflunomide For Severe Liver Injury
      • July 13, 2010 — The rheumatoid arthritis drug leflunomide has received a boxed warning about the risk for severe liver injury.
      • The FDA identified 49 cases of severe liver injury associated with the drug, including 14 cases of fatal liver failure.
    •  
      • Summary
      • Rheumatoid arthritis is a common autoimmune disease that can lead to serious functional limitations, joint destruction, extra-articular disease, poor quality of life, and premature death
      • Early recognition of arthritis and speedy referral to a rheumatologist are essential
      • Treatment should start early and aggressively to prevent functional limitations and structural damage
      • Innovations in treatment and monitoring have resulted in patients achieving early and sustained clinical and radiographic remission
      • Methotrexate is the first line drug, but in high risk patients early combination of methotrexate with prednisone or a tumour necrosis factor inhibitor improves outcomes
      • Thanks……