Rheumatoid Arthritis Update Beth Valashinas, DO, FACOI, FACR Disclosures Speaker for AbbVie Pharmaceuticals Learning Objectives Upon completion of this session, participants should be able to discuss: The paradigm shift in treatment of RA Recent changes in classification criteria for RA Treat-to-target (T2T) Recommendations 2015 ACR recommendations for treatment of RA DMARDs, Biologics, and other novel RA therapies 1
Clinical Case #1 47 y.o. female with recently diagnosed RA is currently maintained on oral methotrexate at 20mg once weekly in addition to prednisone 5mg daily. Recent labs included an ESR of 12mm/hr and elevated CRP at 10mg/L. She has 2 tender joints and 2 swollen joints on exam, global health evaluation of 10/100, and DAS 28 score of 3.06 indicating moderate disease activity. Recent hand XR reveal marginal erosions on bilateral 2 nd MCPs. Clinical Case #1 Question Which of the following would be the best treatment option at this time? A.) Increase methotrexate to 25mg once weekly B.) Increase prednisone to 10mg daily C.) Add sulfasalazine or hydroxychloroquine D.) Add a TNF inhibitor E.) Change to parenteral methotrexate Clinical Case #2 67 y.o. female with history of long-standing RA and HTN presents for a routine follow up and inquires about immunizations. Her RA has been well controlled on Enbrel, parenteral methotrexate 25mg once weekly, and prednisone 5mg daily. 2
Clinical Case #2 Question All of the following vaccines are appropriate to give as indicated EXCEPT: A.) Pneumococcal B.) Hepatitis B C.) Herpes Zoster D.) Influenza (IM) Clinical Case #3 64 y.o. female presents with an inflamed left PIP joint as well as tenderness of all PIPs, DIPs, and bilateral knees. She relates long-standing joint discomfort and laboratory evaluation reveals a negative RF and anti-ccp Ab. Both ESR and CRP are normal. Clinical Case #3 Question Does she meet criteria for diagnosis of RA based on the 2010 ACR/EULAR Criteria? A.) Yes B.) No 3
Clinical Case #4 53 y.o. male with history of RA and NYHA Class III CHF presents for routine follow up visit. He has been maintained on oral methotrexate 20mg once weekly for his RA and relates recurrent flare activity. He has multiple tender and swollen joints on exam and DAS28 score is 4.7, consistent with moderate disease activity. Clinical Case #4 Question All of the following would be potential treatment options EXCEPT: A.) Change to parenteral methotrexate for better bioavailability B.) Add Abatacept (Orencia) C.) Add a TNF inhibitor D.) Add sulfasalazine and hydroxychloroquine for triple therapy Clinical Case #5 42 y.o. male who presents with a 4 week history of polyarticular joint pain. On exam, he has tenderness and synovitis involving bilateral 2 nd -4 th MCPs. Laboratory evaluation reveals negative RF and anti-ccp Ab. ESR is normal, but CRP is elevated. 4
Clinical Case #5 Question Does he meet criteria for RA according to the 2010 ACR/EULAR Criteria? A.) Yes B.) No Rheumatoid Arthritis Affects 1% of population worldwide Risk increases with age as affects ~6% of Caucasian population >65 years of age Higher prevalence in women 3.6% female vs. 1.7% male lifetime risk Morbidity/Mortality associated with RA >1/3 of patients with RA experience work disability due to their disease RA is associated with a 50% increased risk for MI and >2-fold increased risk for CHF RA shortens life expectancy by 3-5 years Includes extra-articular disease as well as treatment-related adverse effects 5
Evidence of early radiographic progression contributes to paradigm shift Studies in very early RA indicate early radiographic progression 63.6% of patients developed erosive disease within 3 years 74.3% in first year 97.2% by second year Strongly associated with positive ACPA, RF, and high long-term disease activity K.P. Machold, et al. Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of the disease. Rheumatology. 2007; 46:342-349. 2010 ACR/EULAR Classification Criteria for RA Established by an international task force Designed to be used in patients with clinical synovitis in at least one joint Classification criteria, not diagnostic criteria Serves as a guide 6
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Treating RA to target: The T2T International Task Force 2014 Update Principles Treatment must be based on shared decision between patient and rheumatologist Primary goal is to maximize long-term healthrelated quality of life Abrogation of inflammation most important way to achieve goal T2T by measuring disease activity and adjusting therapy to optimize outcomes in RA 9
10 recommendations of T2T committee 1. Primary target in treatment of RA should be state of clinical remission 2. Clinical remission is defined by absence of signs and symptoms of significant inflammatory disease activity 3. While remission is goal, low disease activity may be acceptable alternative, especially in longstanding disease 10 recommendations of T2T committee 4. Until desired target met, drug therapy should be adjusted at least every 3 months 5. Measures of disease activity must be obtained frequently (monthly for moderate/high disease activity or every 3-6 months for low disease activity/clinical remission) 6. Use of validated composite measures of disease activity, including joint assessment, needed to guide treatment decisions 10 recommendations of T2T committee 7. Structural changes and functional impairment should be considered in treatment decisions 8. Desired treatment target should be maintained throughout course of disease 9. Choice of composite measure of disease activity and level of target value may be influenced by comorbidities, patient factors, and drug-related risks 10. Patient should be informed of target and strategy planned to reach target under supervision of rheumatologist 10
Composite Disease Activity Measurement Disease activity score (DAS 28) Simplified disease activity index (SDAI) Clinical disease activity index (CDAI) Tender joint count (0-28) Swollen joint count (0-28) ESR or CRP Patient s global assessment on VAS(0-100) Tender joint count (0-28) Swollen joint count (0-28) CRP Patient s global assessment on VAS(0-100) Physician s global assessment on VAS(0-100) Tender joint count (0-28) Swollen joint count (0-28) Patient s global assessment on VAS(0-100) Physician s global assessment on VAS(0-100) Remission score <2.6 Remission score </= 3.3 Remission score </= 2.8 Novel measure of disease activity Vectra DA Blood test which measures 12 biomarkers linked to RA inflammation and produces a composite score between 1-100 indicating low, moderate, or high disease activity Clinical validation in both RF, ACPA positive and seronegative RA patients DMARDs (Disease modifying antirheumatic drugs) Methotrexate Approved in 1988 Remains cornerstone of RA therapy Often used in combination with other DMARDs, biologic therapies Leflunomide (Arava) Hydroxychloroquine (Plaquenil) Sulfasalazine Triple therapy (methotrexate, hydroxychloroquine, and sulfasalazine) 11
Potential side effects/adverse effects of DMARDs Methotrexate Nausea, fatigue, alopecia, hepatotoxicity, lowered blood counts, pneumonitis, immunosuppression Hydroxychloroquine Rash, increased sun sensitivity, skin discoloration, rare eye toxicity Leflunomide (Arava) Nausea, diarrhea, alopecia, hepatotoxicity, lowered blood counts, immunosuppression Sulfasalazine Nausea, vomiting, lowered blood counts, rash Triple therapy vs. Etanercept+MTX Biologic therapy for RA Tumor necrosis factor (TNF) inhibitors Etanercept (Enbrel) Approved in 1998 Soluble TNF receptor fusion protein Infliximab (Remicade) Chimeric monoclonal antibody Adalimumab (Humira) Fully monoclonal antibody 12
Biologic therapy for RA Tumor necrosis factor (TNF) inhibitors Golimumab (Simponi) Human monoclonal antibody Certolizumab pegol (Cimzia) Pegylated Fab fragment of a humanized monoclonal antibody Mechanism of action in anti-tnf therapy Potential side effects/adverse effects of TNF inhibitors Injection site reactions, upper respiratory tract infections, immunosuppression, reactivation of TB/latent fungal infections, malignancy, infusion reactions (Remicade) Avoid in CHF (especially NYHA Class III-IV), previously treated or untreated skin cancer (nonmelanoma or melanoma), and previously treated lymphoproliferative disorders 13
Biologic therapy for RA Abatacept (Orencia) Selective T cell costimulation modulator which inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28 Activated T lymphocytes are implicated in the pathogenesis of RA and are found in the synovium of patients with RA. Orencia decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. Biologic therapy for RA Abatacept (Orencia) Potential adverse effects Headache, immunosuppression, serious infections, infusion reactions, malignancy, COPD exacerbations Biologic therapy for RA Tocilizumab (Actemra) Humanized monoclonal antibody that binds to interleukin-6 (IL-6) receptors and inhibits IL-6 mediated signaling IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by RA 14
Biologic therapy for RA Tocilizumab (Actemra) Potential adverse effects Serious infections, immunosuppression, lowered blood counts, elevated LFTs, gastrointestinal perforation, reactivation of TB/fungal infections, hyperlipidemia Biologic therapy for RA Rituximab (Rituxan) Chimeric monoclonal antibody against CD20 antigen present on surface protein of B cells which mediates B-cell lysis. B cells believed to play a role in pathogenesis of RA and associated synovitis, thus Rituxan may interfere with production of autoantibodies, antigen presentation, T-cell activation, and/or cytokine production Biologic therapy for RA Rituximab (Rituxan) Potential adverse effects Serious infections, infusion reactions, reactivation of JC virus causing incurable progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation, cardiovascular events 15
Janus kinase (JAK) inhibitor Tofacitinib (Xeljanz) Modulates the signaling pathway of JAKs (intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on cell membranes influencing immune cell function) by preventing phosphorylation and activation of Signal Transducers and Activators of Transcription (STATs), which modulate intracellular activity including gene expression. Janus kinase (JAK) inhibitor Tofacitinib (Xeljanz) Potential adverse effects Serious infections, reactivation of TB/fungal infections, malignancy, lowered blood counts, elevated LFTs, hyperlipidemia, gastrointestinal perforation 2015 American College of Rheumatology Guidelines for treatment of early RA 16
2015 ACR recommendations for treatment of established RA 2015 ACR recommendations for treatment of established RA Clinical Case #1 revisited 47 y.o. female with recently diagnosed RA is currently maintained on oral methotrexate at 20mg once weekly in addition to prednisone 5mg daily. Recent labs included an ESR of 12mm/hr and elevated CRP at 10mg/L. She has 2 tender joints and 2 swollen joints on exam, global health evaluation of 10/100, and DAS 28 score of 3.06 indicating moderate disease activity. Recent hand XR reveal marginal erosions on bilateral 2 nd MCPs. 17
Clinical Case #1 Question Which of the following would be the best treatment option at this time? A.) Increase methotrexate to 25mg once weekly B.) Increase prednisone to 10mg daily C.) Add sulfasalazine or hydroxychloroquine D.) Add a TNF inhibitor E.) Change to parenteral methotrexate Clinical Case #1 Question Which of the following would be the best treatment option at this time? A.) Increase methotrexate to 25mg once weekly B.) Increase prednisone to 10mg daily C.) Add sulfasalazine or hydroxychloroquine D.) Add a TNF inhibitor E.) Change to parenteral methotrexate Clinical Case #2 revisited 67 y.o. female with history of long-standing RA and HTN presents for a routine follow up and inquires about immunizations. Her RA has been well controlled on Enbrel, parenteral methotrexate 25mg once weekly, and prednisone 5mg daily. 18
Clinical Case #2 Question All of the following vaccines are appropriate to give as indicated EXCEPT: A.) Pneumococcal B.) Hepatitis B C.) Herpes Zoster D.) Influenza (IM) Clinical Case #2 Question All of the following vaccines are appropriate to give as indicated EXCEPT: A.) Pneumococcal B.) Hepatitis B C.) Herpes Zoster D.) Influenza (IM) Clinical Case #3 revisited 64 y.o. female presents with an inflamed left PIP joint as well as tenderness of all PIPs, DIPs, and bilateral knees. She relates long-standing joint discomfort and laboratory evaluation reveals a negative RF and anti-ccp Ab. Both ESR and CRP are normal. 19
Clinical Case #3 Question Does she meet criteria for diagnosis of RA based on the 2010 ACR/EULAR Criteria? A.) Yes B.) No Clinical Case #3 Question Does she meet criteria for diagnosis of RA based on the 2010 ACR/EULAR Criteria? A.) Yes B.) No (She appears to meet criteria for RA, but this is a case of erosive OA) Clinical Case #4 revisited 53 y.o. male with history of RA and NYHA Class III CHF presents for routine follow up visit. He has been maintained on oral methotrexate 20mg once weekly for his RA and relates recurrent flare activity. He has multiple tender and swollen joints on exam and DAS28 score is 4.7, consistent with moderate disease activity. 20
Clinical Case #4 Question All of the following would be potential treatment options EXCEPT: A.) Change to parenteral methotrexate for better bioavailability B.) Add Abatacept (Orencia) C.) Add a TNF inhibitor D.) Add sulfasalazine and hydroxychloroquine for triple therapy Clinical Case #4 Question All of the following would be potential treatment options EXCEPT: A.) Change to parenteral methotrexate for better bioavailability B.) Add Abatacept (Orencia) C.) Add a TNF inhibitor D.) Add sulfasalazine and hydroxychloroquine for triple therapy Clinical Case #5 42 y.o. male who presents with a 4 week history of polyarticular joint pain. On exam, he has tenderness and synovitis involving bilateral 2 nd -4 th MCPs. Laboratory evaluation reveals negative RF and anti-ccp Ab. ESR is normal, but CRP is elevated. 21
Clinical Case #5 Question Does he meet criteria for RA according to the 2010 ACR/EULAR Criteria? A.) Yes B.) No Clinical Case #5 Question Does he meet criteria for RA according to the 2010 ACR/EULAR Criteria? A.) Yes B.) No (This patient may have early seronegative RA and be classified prospectively) Summary RA is more common in women, affects ~1% of the worldwide population, and risk increases with age RA leads to disability in >1/3 of patients, decreases life expectancy, and increases cardiovascular risks Studies in very early RA indicate radiographic progression with evidence of erosive disease common within 2 years of diagnosis 22
Summary A paradigm shift in treatment of RA 2010 ACR/EULAR changes in classification criteria for RA 2014 update on treat-to-target (T2T) recommendations 2015 ACR recommendations for treatment of both early and established RA The primary target of treatment is clinical remission by employing early intensive therapies Summary The development of novel treatments including biologics often used in conjunction with DMARDs has transformed RA therapy and positively impacted the outcome of patients Balancing new developments with patient safety will remain important along with continued communication between the patient and rheumatologist regarding treatment strategy References 1. Helmick C.G., Felson D.T., Lawrence R.C., National Arthritis Data Workgroup Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part I. Arthritis Rheum. 2008;58(1):15 25. [PubMed] 2. Crowson C.S., Matteson E.L., Myasoedova E. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011;63(3):633 639. [PMC free article] [PubMed] 3. Allaire S., Wolfe F., Niu J., Lavalley M.P. Contemporary prevalence and incidence of work disability associated with rheumatoid arthritis in the US. Arthritis Rheum. 2008;59(4):474 480. [PMC free article] [PubMed] 4. Sokka T., Kautiainen H., Pincus T., QUEST-RA Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study. Arthritis Res Ther. 2010;12(2):R42. [PMC free article] [PubMed] 5. Turesson C., O'Fallon W.M., Crowson C.S., Gabriel S.E., Matteson E.L. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol. 2002;29(1):62 67. [PubMed] 6. Gabriel S.E., Crowson C.S., Kremers H.M. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003;48(1):54 58. [PubMed] 7. Lindhardsen J., Ahlehoff O., Gislason G.H. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis. 2011;70(6):929 934. [PubMed] 8. Semb A.G., Kvien T.K., Aastveit A.H. Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoproteinrelated Mortality RISk (AMORIS) Study [published online ahead of print June 15, 2010] Ann Rheum Dis. 2010;69(11):1996 2001. [PubMed] 9. Maradit-Kremers H., Crowson C.S., Nicola P.J. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a populationbased cohort study. Arthritis Rheum. 2005;52(2):402 411. [PubMed] 10. Nicola P.J., Crowson C.S., Maradit-Kremers H. Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis. Arthritis Rheum. 2006;54(1):60 67. [PubMed] 11. Nicola P.J., Maradit-Kremers H., Roger V.L. The risk of congestive heart failure in rheumatoid arthritis: a population-based study over 46 years. Arthritis Rheum. 2005;52(2):412 420. [PubMed] K.P. Machold, et al. Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of the disease. Rheumatology. 2007; 46:342-349. 12. J.A. Singh, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care and Research. 2015 13. Smolen, J. S. et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann. Rheum. Dis. 69, 631 637 (2010). 14. Smolen, J. S. et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann. Rheum. Dis. 23
Questions/Comments? 24