Treatment of Rheumatoid Arthritis in the New Millennium. Neal I. Shparago, D.O., FACP, FACR

Transcription

1 Treatment of Rheumatoid Arthritis in the New Millennium Neal I. Shparago, D.O., FACP, FACR

2 What is RA? Symmetric inflammatory polyarthritis Rheumatoid factor positive in 80% Anti-CCP positive in approximately 60% Systemic illness can involve multiple organ systems Female predominance-2.5:1 Average age is between 30 and 55 years Heritable factors account for 50-65% of the risk for developing RA (HLA-DR4, DR1, and DR14)

3 Criteria For the Diagnosis of Rheumatoid Arthritis Target Population Patients with at least one joint with definite clinical synovitis (swelling) Synovitis not better explained by another disease

4 2010 American College of Rheumatology/European League Against Rheumatism Rheumatoid Arthritis Diagnostic Criteria 1 large joint large joints 1 Joint Involvement 1-3 small joints, with or without large joint involvement 4-10 small joints, with or without large joint involvement 2 3 > 10 joints 5 Labs:1 result in each category required Serology Negative RF and Negative CCP 0 Low positive RF or low positive CCP 2 High-positive RF or high positive CCP 3 Acute Phase Reactants Normal CRP and normal ESR 0 Abnormal CRP or abnormal ESR 1 Duration Symptoms < 6 weeks duration 0 Symptoms > 6 weeks duration 1 Total Score of > 6 required for definite diagnosis of Rheumatoid Arthritis

5 Rational For Early Treatment

6 Large body of evidence shows that joint damage is an early phenomenon of RA

7 Joint erosions occur in up to 90% of patients within the first 2 years of disease activity

8 Disability occurs early. Up to 50% of patients will be work-disabled at 10 years

9 Severe Disease is associated with increased mortality

10 Traditional DMARD s Methotrexate 10-25mg weekly (oral or sq) Leflunomide (Arava), 10-20mg daily Sulfasalzine 2-3 grams per day Hydroxycholoquine 400mg per day in divided doses Prednisone Low dose, used as a bridge for other therapies Azathioprine 1.5-2mg/kg per day-not used very much Cyclosporine (rarely used) Gold (rarely used)

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12 Biologic Medications

13 Tumor Necrosis Factor Alpha Inhibitors Monoclonal antibodies (binds to soluble and cell bound TNF) Adalimumab (Humira)- 40mg sq qowk Infliximab (Remicade)- 3-10mg/kg IV q 8 weeks Certolizumab (Cimzia)- 400mg sq q month or 200mg qowk Golimumbab ( Simponi)- 50mg sq once monthly TNF receptor bound to an IgG-1 antibody (binds to soluble TNF) Etanercept (Enbrel)- 50mg sq once weekly

14 Adverse Effects of TNF Inhibitors Infection (usually mild, but serious infections can occur) Injection site reactions (very common) Drug induced autoimmune diseases SLE, Psoriasis, Guillain-Barre Syndrome, Sarcoidosis Vasculitis Reactivation of TB or viral hepatitis Anaphylaxis ( mostly seen with Infliximab) Malignancy Avoid live vaccines (Varicella zoster)

15 Selective Costimulation Modulator Inhibits T-lymphocyte activation by binding to CD-80 and CD-86 on antigen presenting cells (APC s), thus blocking the required CD-28 interaction between the APC and T cells Activated T lymphocytes are found in the synovium of Rheumatoid Arthritis patients

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17 Abatacept (Orencia) Used in combination with a traditional DMARD IV or SQ IV Dosing based on weight <60mg-500mg per infusion mg-750mg per infusion >100mg-1000mg per infusion SQ dosing-125mg sq once weekly Adverse effects Infection Headache Skin rash Malignancy has been noted in clinical trials

18 B Cell Depletion

19 B-Cell Depletion Therapy in RA How does B-Cell Depletion work? B-Cells cannot act as antigen presenting cells to activate T- Cells B-Cells cannot produce Rheumatoid Factor B-Cells cannot release cytokines B-Cell Antibodies Rheumatoid Factor Plasma Cell

20 Rituximab (Rituxan) Anti-CD-20 antibody (chimeric) Used in combination with a traditional DMARD 1000mg IV on day #1 and 1000mg on day #15 Given over 4-5 hours to prevent infusion reactions May be infused every 4-6 months Must pre-medicate with IV corticosteroid (Solumedrol, 100mg prior to infusion) Adverse effects Infusion reactions Infection Cytopenias Reactivation of Hepatitis B Progressive multifocal leukoencephalopathy (very rare in RA patients)

21 IL-6 Inhibition

22 IL-6 is Produced by Multiple Cell Types and Is Associated with Numerous Biologic Activities 1,2 Monocytes/ macrophages Endothelial cells Mesenchymal cells, fibroblasts/ synoviocytes T-cell activation IL-6 Hepatocytes Maturation of megakaryocytes B-cells Acute-phase response Hepcidin, CRP CYP450 Osteoclast activation Bone resorption Thrombocytosis Auto-antibodies (RF) Hyper- -globulinemia Adapted from 1 Firestein GS. Nature. 2003; 423: Smolen JS, et al. Nat Rev Drug Disc. 2003; 2: P 22

23 IL-6 Has Numerous Articular Effects in RA 1,2 Synoviocytes Antibody production B-cell Macrophage IL-6 VEGF Endothelial cells Pannus formation T-cell Neutrophil Mediation of chronic inflammation Osteoclast activation bone resorption Joint destruction Adapted from 1 Choy E. Rheum Dis Clin North Am. 2004;30: Gabay C. Arthritis Res Ther. 2006;8(suppl 2):S3. P 23

24 Tocilizumab (IL6-R blocker) Humanized mab IgG1 (MW ~150 kd) Heavy chain Light chain CDR region Key Features: Binds soluble and membrane bound IL-6R Weak/no CDC* or ADCC** effector functions (in vitro) *CDC: complement-dependent cytotoxicity **ADCC: antibody-dependent cellular cytotoxicity P 24

25 Actemra (Tocilizumab) May be used in combination with a DMARD or as monotherapy Used in moderate to severe RA Should never be used with other biologics Adverse effects can include Elevation of liver function tests Hyperlipidemia Neutropenia Thrombocytopenia Infection

26 Actemra (Tocilizumab) Dosing Infusion First infusion is at 4mg/kg Subsequent infusions at 8mg/kg per month May reduce dose to 4mg/kg per month if patient has frequent infection or if LFT s elevated >1-3X normal Subcutaneous <100kg- 162mg every other week >100kg-162mg once weekly

27 Janus Kinase Inhibition (JAK)

28 JAK Family Tyrosine kinase proteins Family includes 4 JAK proteins and 7 STAT proteins (signal transducer and activator of transcription) JAK1 JAK2 JAK3 TYK2 Plays an important role in mediating the intracellular signal transduction of cytokines

29 JAK Proteins Acting in pairs, JAK proteins facilitate the phosphorylation of intracellular proteins Phosphorylation of the signal transducer and activator of transcription (STAT) leads to altered gene transcription STAT controls autoimmune and inflammatory responses 2 9

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31 Tofacitinib (Xeljanz) Selective JAK inhibitor with functional selectivity for JAK 1 and 3 over JAK 2 Only oral biologic for the treatment of RA Used as monotherapy only at this time (Studies ongoing) Dosed at 5mg BID Adverse effects include Infection-20% (Serious infection-2%) Elevated liver functions Diarrhea Headache Lymphocytopenia

32 IL-1 Inhibition

33 Anakinra (Kineret) Recombinant human IL-1 receptor antagonist RA dosing is 100mg sq daily Used as monotherapy and in combination with a DMARD Found not to work very well in RA Works well in Adult Still s and Systemic onset JIA Used in the treatment of periodic syndromes Cryopyrin-associated periodic syndrome Adverse effects Injection site reaction Infection Headache

34 The Future

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36 In Conclusion Rheumatoid arthritis should be treated as early, and as aggressively as possible to avoid permanent damage to the joints. Delays in treatment increase both morbidity and mortality.

37 Thank You