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Rheumatoid arthritis management

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  • 1. RHEUMATOID ARTHRITIS
    MANAGEMENT
  • 2. RHEUMATOID ARTHRITIS
    MANAGEMENT
    Dr.S.AISHWARYA
  • 3. Dr .Augustin Jacob Landré-Beauvais documented first case of r.a.
    SUFFERED FROM R.A.
    PETER PAUL RUBENS
    DOROTHY MARY HODGKIN
    CHRISTIAAN BERNARD
    ALFRED BARING GARROD
  • 4. RHEUMATOID ARTHRITIS
    Chronic inflammatory autoimmune and systemic disease.
    Target tissue is SYNOVIAL TISSUE.
    PREVALENCE -0.8% adult population worldwide.
    Age 4th -5th decades (80% 35-50 yrs ).
  • 5.
  • 6. GENARAL PRINCIPLES
    Pain relief
    Reduce inflammation
    Protection of articular surfaces
    Maintenance of function
    Control of systemic involvement
  • 7. MANAGEMENT OF R.A.
    Medications are divided into three main classes
    1.NSAIDs
    2.corticosteroids
    3.DMARDs
    4.BIOLOGICS
    5.Surgery
  • 8. Outline of current management of RA
    Non biologics
    biologics
  • 9. CURRENT THERAPEUTIC APPROACH IS EARLY AGGRESSIVE INTERVENTION.
  • 10. DMARDs
    METHOTREXATE;HYDROXYCHLOROQUINE;SALFASALAZINE;LEFLUNAMIDE .
    other DMARDS
    • GOLD;CYCLOSPORINE-A;
    • 11. AZATHIOPRINE;CYCLOPHOSPHAMIDE;
    • 12. CHLORAMBUCIL;
    • 13. D-PENICILLAMINE;
    • 14. MINOCYCLINE ,DOXYCYCLINE.
  • 15. TYPES OF COMBINATION THERAPYOF DMARDS
    STEP –UP
    TICORAtrial-SSZ ESCALATING MTX ,HCQ if it fails cycloph and MTX NEXT LEF ,INJ GOLD
    STEP-DOWN: 3or 4DMARDS deescalated to 1 DMARD
    COBRAtrial –SSZ+MTX+prednisoloneonly SSZ
    PARALLEL :multiple DMARDS continued on long term basis
    FINRACO TRIAL –SSZ+MTX+HCQ+low dose prednisolone for 2yrs
  • 16. DISEASE ACTIVITY SCORE (DAS)
    Is a composite score
    Tender and swollen joint count
    ESR
    PATIENT global assessment of disease activity using a 100 mm visual analogue scale.
    Assessess suitability for biological therapies and response to treatment.
    DAS28 = 0.56  (number of tender joints )+ 0.28 (number of swollen joints ) + 0.70 In (ESR)+0.014 global assessment in mm
  • 17.
  • 18. METHOTREXATE
    gold std of treatment
    7.5 to 25 mg orally, IM, or SC per week given at least 3-6 months
    One to two months
    Nausea, diarrhea; fatigue; mouth ulcers; rash, alopecia; abnormal LFTsRare: low WBC and platelets; pneumonitis; sepsis; liver disease; Epstein-Barr virus–related lymphoma; nodulosis
    CBC, creatinine, and LFTs monthly for six months, then every one to two months; repeat AST or ALT in two to four weeks if initially elevated, and adjust dose as needed; liver biopsy if no resolution on discontinuation.
    Rapid onset (six to 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 newer DMARDs.
  • 19. HYDROXYCHLOROQUINE (Plaquenil)
    200 to 400 mg orally per day(6.5mg/kg)
    Immunomodulatory effect
    Two to six months
    Nausea; headachesRare: abdominal pain; myopathy; retinal toxicity
    Eye examinations every 12 months in patients older than 40 years and those with previous eye disease
    In combination with MTX ,SSZ,corticosteroids.
  • 20. SULFASALAZINE(Azulfidine)
    2 to 3 g orally per day in divided doses
    48 (14 to 31)
    One to three months
    Nausea, diarrhea; headache; mouth ulcers; rash, alopecia; contact lens staining; reversible oligospermia; abnormal LFTsRare: leukopenia
    CBC every two to four weeks for three months, then every three months
    Rapid onset (eight to 13 weeks); enteric, coated forms available; can be used when diagnosis uncertain; modest effects compared with other medications.
  • 21. LEFLUNOMIDE (Arava)
    (100 mg orally per day for three days loading dose earlier) 10 to 20 mg orally per day
    Four to 12 weeks (tending toward four)
    Nausea, diarrhea; rash; alopecia; highly teratogenic, even after discontinuationRare: leukopenia; hepatitis; thrombocytopenia
    Hepatitis B and C serology in high-risk patients; CBC, creatinine, and LFTs monthly for six months, then every one to two months; repeat AST or ALT in two to four weeks if initially elevated, and adjust dose as needed.
    Inhibits pyrimidine synthesis and may suppress T-cell activation;
    LEF toxicity ;cholestyramine 8gms -11days or activated charcoal 50gm qid-11days
  • 22. AZATHIOPRINE (Imuran)
    50 to 150 mg orally per d
    Two to three months
    NauseaRare: leukopenia; sepsis; lymphoma
    CBC every one to two weeks until dose is stable, then every one to three months
    Has greater toxicity and is used less commonly than other DMARDs
  • 23. CYCLOSPORINE (Gengraf, Neoral, generic)
    2.5 to 5 mg per kgorally per day
    Two to four months
    Nausea; paresthesias, tremor; headaches; gingival hypertrophy; hypertrichosisRare: hypertension; renal disease; sepsis
    Creatinine every two weeks until dose is stable, then monthly; consider CBC, LFTs, and potassium level tests
    Significant clinical benefit up to one year; adverse effects limit use.
  • 24. D-PENICILLAMINE
    D-Penicillamine (Cuprimine)
    250 to 750 mg orally per day
    Three to six months
    Nausea; loss of taste; rash; reversible platelet decreaseRare: proteinuria; late autoimmune disease
    CBC and urinary protein by dipstick every two weeks until dose is stable, then every one to three months
    Used less commonly than other DMARDs.
  • 25. AURANOFIN
    Auranofin (Ridaura)
    3 mg orally twice per day or 6 mg orally per day
    Four to six months
    ADV :DiarrheaRare: leukopenia
    Monitor ---CBC and urine protein (by dipstick) every one to three months
    Has modest effects compared with other DMARDs.
  • 26. IM GOLD
    Gold sodium thiomalate (Myochrysine)Aurothioglucose (Solganal)
    25 to 50 mg IM every two to four weeks
    Six to eight weeks
    Mouth ulcers; rash; vasomotor symptoms after injectionRare: leukopenia; thrombocytopenia; proteinuria; colitis
    CBC and urinary protein by dipstick every two weeks until dose is stable, then with each injection
    Has significant withdrawal rate in trials because of toxicity.
  • 27. MINOCYCLINE (Minocin)
    100 mg orally twice per day
    One to three months
    Dizziness; skin pigmentation
    None needed
    Effective in combination with prednisone for management of new-onset rheumatoid arthritis.
  • 28. GUIDELINES FOR USE OF BIOLOGICS
    Must have failed to response with atleast two DMARDs including MTx (20-25mg/wk)
    Must have ACTIVE disease.
    Have no major infections in the preceding six months.
    Have no malignancies
    Non pregnant,non breast feeding women
  • 29. INFLIXIMAB
    Infliximab(Remicade)
    3 mg per kg IV at weeks zero, 2, and 6, then every eight weeks
    A few days to four months
    Infusion reactions; increased infection risk, including TB reactivationRare: demyelinating disorders
    Monitor for TB, histoplasmosis, and other infections; CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.
    A chimeric(mouse and human) monoclonal antibody to TNF-3; reduces disease activity with acceptable safety.
    Always used n conjunction w MTX 10-25mg/wk
  • 30. Chimeric monoclonal antibody against TNFα
  • 31. Monoclonal antibody against TNFα
  • 32. ETARNERCEPT
    Etanercept (Enbrel)
    25 mg SC twice per week or 50 mg SC per
    A few days to 12 weeks
    Contraindicated in infection; mild injection site reactionsRare: demyelination
    CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.
    Combination fusion protein of TNF receptor and portion of IgG1; inhibits TNF-3; slows joint damage.
  • 33. ADALIMUMAB
    DMARDs for Treatment of Rheumatoid Arthritis
    Adalimumab (Humira)
    40 mg SC every two weeks
    A few days to four months
    Adv reactions :Infusion reactions; increased infection risk, including TB reactivationRare: demyelinating disorders
    Monitor for TB, histoplasmosis, and other infections; CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.
    Recombinant monoclonal antibody to TNF-3; shown to reduce disease activity with acceptable safety.
  • 34. Recombinant TNFα Soluble Receptor
  • 35. ANAKINRA
    100 to 150 mg SCper day
    Within 12 weeks; lasting effects by 24 weeks
    ADV REACTIONS :Infections and decreased neutrophil counts; headaches, dizziness; nauseaRare: hypersensitivity
    MONITOR :CBC at baseline, monthly for three months, then every three months
    Interleukin-1 receptor antagonist; used when treatment with another DMARD has failed.
  • 36. TNFα and it’s Receptor
  • 37. TOCLIZUMAB
    First IL-6receptor inhibiting monoclonal antibody.
    Dose :8mg/kg i.v. every 4wks given as i. v. infusion over an hour.
    Moderate to severe RA
    CONTRA INDICATIONS :infusion reactions,active infections.
  • 38. RITUXIMAB(anti CD20 therapy)
    Genetically engineered human mouse chimeric monoclonal antibody.
    CD 20 antagonist and B cell ACTION depletor
    Dose:1000mg /infusion on days 1 and 15(over sevaeral hrs ) with 100mg i.v. methyl prednisolone.
    Contraindications :hypersensitivity,activeinfection,severe HF.
  • 39. ABATACEPT (T cells CTLV-4 Ig)
    Prevents co-stimulatory binding of CD28 on naïve T-cells and attenuating T-cell function.
    Dose:10mg/kg i.v. every 2wkly for 3 doses ,followed by every 4wkly.
    Contraindications: hypersensitivity,activeinfections,COPD.
  • 40. ADVERSE REACTIONS OF BRMs
    1.injection site/infusion reactions
    2.infections (activation of latent TB or new TB)
    3.neutropenia,aplastic anemia
    4.mild reversible lupus like syndrome
    5.CCF
    6.malignancy
    7.ANA postivity
    8.demyelinating neurological diseases
  • 41. PARADIGM SHIFT
    1.early use of DMARDs --initiated early within 3months-3yrs.
    -- to avail window of oppurtunity,replacing’ Go low,go slow.
    --’inverting pyramid’ concept
    2.REMISSION :instead of relief.
    3.MTX :anchor drug -as monotherapy or combination therapy.
  • 42. Contd….
    4.Combination therapy—DMARD combination
    triple therapy-of MTX+SSZ+HCQ
    MTX+biologicals --better outcome
    5.Reappraisal of glucocorticoids:low dose+DMARDS
    6.Evolution of strategy trials :like COBRA,CAMERA,FINRACO,TICORA.
    Sub group of Best trails.
  • 43. When to start DMARD therapy
    Before onset of erosion by US/MRI
    Within 3-6 months
  • 44. Who to Treat?
    Consider DMARD therapy for all patients with early inflammatory polyarthritis where persistent disease is likely
    Most important determinant of chronicity is disease duration > 12 weeks.
  • 45. Whom to treat with DMARDS?
    Early n severe synovitis
    Strogly +ve ACPA and RF
    Extra articular features
    Joint erosion –US/MRI
    Functional impairment
    Lower educational status
  • 46. How to initiate DMARD therapy?
    SSZ,HCQ -in mild cases
    MTX,LEF OR cyclosporine-in severe cases
    MTX +biologicals –very severe cases
  • 47. In pregnancy DMARDS ?
    SSZ ,HCQ are safe
  • 48. Follow up?
    Every6 wks or earlier.
  • 49. Combination DMARD therapy
    MTX + SSZ + OH-Chloroquine
    O’Dell 1995
    MTX + CSA
    Tugwell 1995
    MTX + Etanercept
    MTX + Remicade
    MTX + Adalimumab
    MTX + Leflunomide
    excellent safety & improved efficacy over MTX alone
  • 50. Rationale for TNFα Blockade
    Cytokines are small molecules whose function is to communicate between cells
    Tumor necrosis factor α = gatekeeper of inflammatory cascade
    Cytokines can be either pro-inflammatory or anti-inflammatory
  • 51. Mechanisms in Rheumatology ©2001
    Proinflammatory and anti-inflammatory cytokines in RA
  • 52. Matrix metalloproteinases in RA
    Mechanisms in Rheumatology ©2001
  • 53. TNF inhibitors and TB
    Mycobacterium tuberculosis currently infects approximately one third of the world's population (close to 2 billion people).
    Approximately 2 million people die of TB each year and there are 8 million new cases reported annually.
    TNF is essential for formation and sustainment of granuloma, which sequester mycobacteria and prevent their dissemination.
    The calculated risk ratio of TB in infliximab-treated patients with RA versus patients with RA not exposed to this agent was 19.9 (95% confidence interval [CI], 16.2–24.8) in the year 2000 and 11.7 (95% CI, 9.5–14.6) in the year 2001.
    Screening has almost eliminated this increased risk in Spain and Germany
  • 54.
  • 55. Quality of Life in Rheumatoid Arthritis
  • 56.
  • 57.
  • 58.
  • 59.
  • 60.
  • 61.
  • 62.
  • 63.
  • 64.
  • 65.
  • 66. SURGERY IN RA
    Tenosynovectomy.
    Decompression of carpal tunnel
    Reconstructive arthroplasty
    Corrective artrotomies of matatarsals
    Stabilization of cervical spine
    Tendon release and transfer
    Arthrodesis of ankle
  • 67. CORTICOSTEROIDS IN RA
    ACCORDING TO EULAR COMMITTEE RECOMMONDATIONS
    NOMENCLATURE OF CORTICOSTEROID DOSING :
    Low dose:<7.5mg prednisolone/day
    Medium dose:>7.5 but <30mg /day
    High dose:.>30 but <100mg/day
    Very high dose:>100mg/day
    Pulse therapy:>250mg/day for 1 or few days
  • 68. corticosteroids
    Current indications are---
    1.bridge therapy inacute cases
    2.acute ocular emergencies
    3.rheumatoid vasculitis
    4.combin therapy with DMARDs
    5.active disease in pregnancy
    6.intra articular use in monosynovitis
  • 69. Modes of use of CS
    Oral prednisolone 10mg/d with tapering to 2.5-5mg/d over few months.
    Inj.methylprednisolone acetate 80-120mg i.m. every 4 wks for 2-3 months.
    Intra articular steroids in monosynovitis
  • 70. RECENT ADVANCES CS
    NOVEL MODIFIED RELEASE( MR) prednisolone formulation given at bedtime -better clinical effects
    CAPRA -1(circadian administration ofpradnisolone in RA trail).
    SEGRAs :Selective glucocorticoid receptor agonists (NEW CLASS OF STEROIDS)
    Compound A(CpdA)
    Botschanzev
  • 71.
  • 72. TARGETS OF TREATMENT IN RA.
    Biological agents are divided into --
    monoclonal ab
    small molecules
  • 73. MONOCLONAL AB s
    FUNCTION BY neutralizing target cytokine/receptor blocking co stimulation moleculescytolysis depletion of target cell molecule or apoptosis.
  • 74. TNF ALPHA INHIBITORS
    Infliximab,etanercept,adalimumab –being used.
    Golimumab ;certolizumab likely to be approved
  • 75. IL -1 INHIBITORS
    ANAKINRA
    Canakinumab is on clinical trails
  • 76. IL -6 inhibitors
    Tocilizumab now approved for the mod to severe RA.
  • 77. IL-15 INHIBITOR :HUMANISED MONOCLONAL AB AGAINST IL-15(HuMaxIL-15) proved
    IL-17 inhibitor :clinical trial in progress.
    IL-12/IL-23 inhibitor :ustekinumab–on going trails.
    Inhibitors of osteoclastogenesis :Danosumab in phase 3 clnical trail.
    Inhibitors of TNF superfamily members :baminercept,belimubab ,atacicept –in trails
  • 78. Inhibitors of chemokines and angiogenesis :bevacizumab –ab against VEGF.
    APOPTOSIS regulators :anti FAS IgMab under trails.
    T-cell inhibitors :alemtuzumab ,keliximab,clinoliximab --discontinued trails due to lymphopenia and skin rash.
    B-cell inhibitors :RITUXIMAB approved ;clinical trails in progress by ocrelizumab,ofatumumab.
  • 79. SMALL MOLECULES
    Molecular wts do not exceed 1kDa.
    GOAL is to develop orally effective agents and increased selectivity.
  • 80. INHIBITORS OF
    1. intracellular signalling molecules
    2. mitogen activated protein (MAP)
    3. transcription factors
    4. cytokines/chemokines
    5. cell surface markers
  • 81. OTHER TARGET FUTURE Rx of RA
    Regulatory t cells (treg cells)
    Toll like receptors
    RNA epigenetic alterations
    Gene therapy
    UNDER TRIALS.
  • 82. With the help of these newer drugs,the future may well see rheumatologists talking not about symptomatic relief but potencial cure for RA.
  • 83. Aim of management of r.a .case
  • 84.
  • 85. THANK YOU