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+prednisoloneonly SSZ PARALLEL :multiple DMARDS continued on long term basis FINRACO TRIAL –SSZ+MTX+HCQ+low dose prednisolone for 2yrs
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
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.
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.
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.
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
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
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.
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.
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.
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.
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.
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
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
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.
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.
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.
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.
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.
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.
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
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.
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.
When to start DMARD therapy Before onset of erosion by US/MRI Within 3-6 months
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.
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
How to initiate DMARD therapy? SSZ,HCQ -in mild cases MTX,LEF OR cyclosporine-in severe cases MTX +biologicals –very severe cases
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
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
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
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
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
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
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
TARGETS OF TREATMENT IN RA. Biological agents are divided into -- monoclonal ab small molecules
MONOCLONAL AB s FUNCTION BY neutralizing target cytokine/receptor blocking co stimulation moleculescytolysis depletion of target cell molecule or apoptosis.
TNF ALPHA INHIBITORS Infliximab,etanercept,adalimumab –being used. Golimumab ;certolizumab likely to be approved
IL -1 INHIBITORS ANAKINRA Canakinumab is on clinical trails
IL -6 inhibitors Tocilizumab now approved for the mod to severe RA.
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
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.
SMALL MOLECULES Molecular wts do not exceed 1kDa. GOAL is to develop orally effective agents and increased selectivity.