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

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  • 1. MANAGEMENT OF RHEUMATOID ARTHRITIS Dr.Harmanjit Singh Department of Pharmacology Govt Medical College,Patiala.
  • 2. 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.
  • 3.
    • 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.
  • 4.
    • 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
  • 5.  
  • 6. 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 )
  • 7. RA- joint involvement
    • Extraarticular manifestations
    • Pericarditis
    • Interstitial lung disease
    • Felty’s syndrome
    • Vasculitis
    • Neuropathy
  • 8.
    • 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
  • 9.
    • 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
  • 10.
    • 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
  • 11. Goals of therapy Alleviate pain Preservation of function Control disease activity Maximize quality of life Slow progression/rate of joint damage
  • 12. MANAGEMENT
    • Physical Therapies
    • Diet
    • Pharmacologic Therapies
    • NSAIDS
    • Glucocorticoids
    • DMARDS
    • Biologics
    • Surgical treatment
    • Future trends
  • 13. 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
  • 14.
    • 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.
  • 15.
    • 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
  • 16. 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
  • 17. GLUCOCORTICOIDS
    • Second line agents
    • Mostly combined with NSAIDS
    • Pharmacological actions
      • Antiinflammatory & immunosuppressant action
      • Suppress signs & symptoms
      • Slow appearance of new bone erosions
  • 18. 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
  • 19. GLUCOCORTICOIDS: ADRs
    • Cushing’s habitus
    • Infections
    • Delayed healing
    • Peptic ulcers
    • Cataract
    • Glaucoma
    • Growth retardation
    • Muscle weakness
    • Mood changes
    • Osteoporosis
    • Hyperglycemia
  • 20. 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
  • 21.
    • 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
  • 22. Advantages of DMARDs
    • Slow disease progression
    • Improve functional disability
    • Decrease pain
    • Interfere with inflammatory processes
    • Retard development of joint erosions
  • 23. Combination DMARD therapy
    • MTX + SSZ
    • MTX + Hydroxychloroquine
    • MTX + cyclosporine
    • MTX + Leflunomide
    • Excellent safety & improved efficacy over MTX alone
  • 24. 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
  • 25. 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.
  • 26.
    • 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
  • 27.
    • Adverse effects of Methotrexate:
    • Nausea, mucosal ulcers.
    • Dose related hepatotoxicity.
    • Leucovorin used to reduce side effects.
    • Contraindicated in pregnancy.
  • 28.
    • 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.
  • 29.
    • Ad effects : N, V
    • headache
    • rash
    • Hemolytic anaemia
    • methemoglobinemia
    • Neutropenia
    • Pulmonary toxicity
    • Reversible infertility only in men.
    • Dose : 40 m g/kg/day
  • 30.
    • 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
  • 31.
    • 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
  • 32. 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)
  • 33. 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
  • 34. 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
  • 35.
    • 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]).
  • 36.
    • 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
  • 37.
    • 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
  • 38.
    • 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
  • 39. 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
  • 40.
    • 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
  • 41. IL-1R antagonists: ANAKINRA
  • 42. 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
  • 43.
    • 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.
  • 44.
    • 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.
  • 45. 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)
  • 46. BIOLOGICS : FUNCTION AT A GLANCE
  • 47. 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
  • 48. SURGICAL TREATMENT
    • Reserved for pts with severely damaged joints
    • Includes
    • Arthroplasty/Total joint replacement
    • Open/arthroscopic synovectomy
    • Reconstructive hand surgery
  • 49. 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
  • 50. 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
  • 51. 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
  • 52.
    • 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.
  • 53.  
  • 54.
    • 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
  • 55.
    • Thanks……