1.Rheumatoid Arthritis Early Diagnosis and Treatment Swamy Venuturupalli MD, FACR Clinical Chief, Division of Rheumatology, Cedars Sinai Medical Center Associate Clinical Professor of Medicine, UCLA Editor-in-Chief, Current Rheumatology Reviews www.drswamy.com

2. Overview What is the pathogenesis of RA? How do you diagnose RA? What clinical manifestations must one be aware of? Is there a window of opportunity to make a difference? Current treatment principles: Medications used Treat to target When to introduce newer agents Complications of therapy 3. Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation and destruction in association with serological evidence of autoreactivity. Affects approximately 1% of the population and causes significant morbidity and mortality, with accelerated atherosclerosis impairing life expectancy. In the past two decades, the therapy of RA has undergone revolutionary change, reflecting a paradigm shift in treatment approach as well as the introduction of new disease-modifying antirheumatic drugs (DMARDs), most prominently the biological agents, including the tumor-necrosis-factor (TNF) blockers. 4. Pathogenesis of Rheumatoid Arthritis.Choy EH, Panayi GS. N Engl J Med 2001;344:907-916. 5. Pathogenesis of RA 2: Trigger 1: Pre-articular phase GenesAutoantibodiesCitrullination 4: Early RA phenotypeE.g: Minor trauma Infection Hormones PsychologicalProgressive, erosive RAT-cell Immunosenescence 3: SynovitisEnvironmentImpaired thymic selection Smoking Infections (gingival disease, gut flora changes)Altered lymphocytesignaling thresholdsB S I O ? M A R K E ? RGood-prognosis RADMARD-responsive RAAnti-cytokine-responsive RADeregulated TLR/cytokine signalingAnti-lymphocyte-responsive RASelf-limiting IPLegend: TLR: Toll like receptor; DMARD: Disease-modifying anti-rheumatic drug; IP: Inflammatory polyarthritisAdapted from Best Pract Res Clin Rheumatol. 2009 February; 23(1): 3748. 6. Model for the Etiology of RA Autoreactivity/genetics Joint damageActivation of innate immunity PeripheryDCFL SSynovial inflammation/cytokinesAdaptive ImmunityMRecruitment autoantibodiesMigrationDCTTT TAdapted from Vibeke Strand, Medscape.BLegend: DC= dendritic cell; FLS= fibroblast-like synoviocyte; M= macrophage; T= T cell 7. Severity of ArthritisClinical Course of RA 4 Type 1 Type 2 Type 33 2 1 0 0 0.5 123468 16YearsType 1 = Self-limited5% to 20% Type 2 = Minimally progressive5% to 20% Type 3 = Progressive60% to 90% Pincus. Rheum Dis Clin North Am. 1995;21:619. 8. Clinical Spectrum of RAImages courtesy of J. Cush, 2002. 9. Overview of joints affected Joints most frequently affected in RA include: The proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands The wrists The shoulders The elbows The knees The ankles, and The metarsophalangeal (MTP) joints of the feet Distal interphalangeal (DIP) joints are typically spared in RA. 10. RA: Its not just the joints CVD Osteoporosis10 Years Earlier6-9x serious infection rateJoint Destruction Disability Index2x rate malignancy Pulmonary disease GI Bleeding 11. RA is a systemic disease with extraarticular manifestations Secondary Sjgrens syndrome Heart Pericarditis Myocarditis Endocarditis Valvular fibrosis Liver Enzyme abnormalities due to drug reactions or Sjgrens syndromeBlood / blood vessels Mild anemia Vasculitis Feltys syndromeEyes Keratoconjunctivitis Sicca syndrome Scleritis Episcleritis Keratitis corneal ulceration Choroiditis Retinal vacuities Episcleral nodulesLungs Pleuritis pleural effusions Pulmonary nodules Interstitial pulmonary fibrosis Skin Rheumatoid nodules Vasculitis Interstitial granulomatous dermatitis Firestein. ACP Medicine, Rheumatology II 12. Poor prognostic factors Extra-articular signs and symptoms (e.g. Cutaneous ulcers, vasculitic rash, neuropathy, scleritis, subcutaneous nodules) Female gender Shared epitopes Poor functional status Involvement of multiple joints Early radiographic evidence of erosive changes Advanced age at onset of disease High RF titer Sustained elevation of acute-phase reactants (e.g. ESR) Low socioeconomic status/educational level High titre CCP antibody Smoking Anaya JM, et al. Ann Rheum Dis. 1994;53:782783; Pincus T, Callahan LF. Ballieres Clin Rheumatol. 1992;6:161191; Furst DE. Rheum Dis Clin North Am. 1994;20:309319. 13. Cardiovascular Disease (CVD) in RA Increased incidence of CVD and mortality in RA: 2-4 times Not only traditional CVD risk factors (smoking, lipids, hypertension, DM) increased Inflammation involved in pathogenesis of atherosclerosis High index of suspicion; atypical, silent chest pain, CHF, and sudden death common CVD accounts for much excess mortality in RA 14. Malignancy in RA 2-3x lymphoproliferative disease, in particular, diffuse large B-cell lymphoma EBV-associated lymphomas increased in patients on methotrexate (MTX) Chronic inflammation may be responsible for increased lymphoma Lung cancer more common in RA, but may be due to cigarette smoking, a common risk factor Anti-TNF medications may be associated with increased risk of lymphoma and skin cancer 15. Diagnosing RA 16. 1987 Revised ACR Classification of RA CriterionDefinitionMorning stiffnessLasting 1 hour before maximal improvementArthritis 3 jointsClinical evidence of soft tissue swelling or fluid in right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP jointsArthritis of hand joints1 or more swollen areas in wrist, MCP, or PIP jointSymmetric arthritisSimultaneous involvement of same joint areas on both sides of body (bilateral involvement of PIP, MCP, or MTP joints is acceptable without absolute symmetry)Rheumatoid nodulesClinical evidence of subcutaneous nodules over bony prominences, extensor surfaces, or in juxtaarticular regionsSerum RFElevated rheumatoid factor measured by any method in which positive results are found in < 5% of normal subjectsRadiographic changesErosions or unequivocal body decalcification localized in or adjacent to involved joints on posteroanterior hand and wrist radiographsClassification of RA is fulfilled when 4 of 7 criteria are present (first 4 criteria must be present for at least 6 weeks); another clinical diagnosis does not exclude RA.Arnett FC et al. Arthritis Rheum. 1988;31:315-324. 17. 2010 ACR/EULAR classification criteria for RA A score of 6/10 is needed to classify RA A. Joint involvement 1 large joint 2-10 large joints 1-3 small joints (with or without involvement of large joints) 4-10 small joints (with or without involvement of large joints) >10 joints (at least 1 small joint)Score 0 1 2 3 5B. Serology (at least 1 test result is needed) Negative RF and negative ACPA Low-positive RF or low-positive ACPA High-positive RF or high-positive ACPA0 2 3C. Acute-phase reactants (at least 1 test result is needed) Normal CRP and normal ESR Abnormal CRP or abnormal ESR0 1D. Duration of symptoms 2.8 to 10.0> 10.0 to 22.0> 22.0RAPID 3 (range, 0-30)0 to 3.0> 3.0 to 6.0> 6.0 to 12.0> 12.0 to 30.0SDAI (range, 0-86) 3.3> 3.3 to 11.0> 11.0 to 26.0 > 26.0 36. BeSt: Treatment Strategies Group 1 MonotherapyGroup 2 Step-Up TherapyGroup 3 Combo TherapyGroup 4 MTX + INFMTXMTXMTX + SSZ + PREDMTX + INFSSZMTX + SSZMTX + CsA + PREDSSZLEFMTX + SSZ + HCQMTX + INFLEFMTX + INFMTX + SSZ + HCQ + PREDMTX + CsA + PREDMTX + INFLegend: CsA = cyclosporin A; HCQ = hydroxychloroquine; INF = infliximab; LEF = leflunomide; MTX = methotrexate; PRED = predinisone; SSZ = sulfasalazine 37. BeST Study Treatment Strategies in Early Rheumatoid Arthritis: Clinical and Radiological Outcomes After 2-year Follow-Up 2.5 Seq. mono n=126 12Step-up combo n=1211.5Initial combo w/prednisone n=1331Initial combo w/IFX n=1280.5 0 TSS change from baseline 38. Triple Therapy: Proportion of Patients with Sustained ResponsePatients with 50% improvement in modified Paulus criteria (%)100 All 3 drugs 8024/31 (77%) Sulfasalazine and hydroxychloroquine6014/35 (40%) 12/36 (33%)40 Methotrexate 200 06121824Months P = 0.003, triple therapy vs. other treatment armsO'Dell. N Engl J Med. 1996. 39. Combination Methotrexate, Sulfasalazine, and Hydroxychloroquine (FIN-RACo Study) 75%Patients with ACR50 Responses (%)80 70 60Single DMARD Combination DMARDs60%71% 58%P = .028 at 1 year P = .058 at 2 years50 40 30 20 10 0 1 Year2 Years199 patients with early RA were randomly assigned to combination therapy with methotrexate 7.5 mg/week, sulfasalazine 1 g/day, hydroxychloroquine 300 mg/day, and prednisolone 5 mg/day (with flexible dosage adjustment to achieve remission), or single DMARD therapy with sulfasalazine 2 g/day with or without prednisolone. If necessary because of adverse events or lack of efficacy, sulfasalazine was replaced by methotrexate and subsequently azathioprine Mottonen T et al. Lancet. 1999;353:1568-1573. 40. Principles of Therapy EARLY initiation of therapyTreat to target Combine medications to achieve remission 41. What to treat with 42. RA: Current Pharmacologic Options Agents that are effective in controlling the signs and symptoms of RA, but have no effect on disease progression NSAIDs reduce inflammation and pain COX-2 inhibitors are similar to NSAIDs, but with improved GI safety and tolerability and higher cardiac side effects Analgesics- these medicines do not affect inflammation, but work on pain pathways to decrease subjective feeling of pain. DMARDs impact the signs, symptoms, and disease progression of RA, as well as improve the quality of life and functionality of the patient Corticosteroids have anti-inflammatory and immunoregulatory activity, but nominal disease-modifying capability Irvine S, et al. Ann Rheum Dis. 1999;58:510513; Madhok R, Capell HA. Lancet 1999;353:257258; ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328346; Goldbach-Mansky R, Lipsky PE. Annu Rev Med. 2003;54:197216. 43. T C e lls A c tiv a te M u ltip le C e llu la r P ro c e s s e s th a t L e a d s to In fla m m a tio n a n d D e s tru c tio nA d a p te d fro m C ho y a nd P a na y i. N E n g l J M e d 2 0 0 1 ; 3 4 4 (1 2 ): 9 0 7 1 6 ; D M A R D = d ise a se -m o d ify ing a ntirhe um a tiic d rug 44. RA: Disease Modifying therapies Traditional DMARDsBiological DMARDSFor exampleFor example Methotrexate Leflunomide (Arava) Sulfasalazine (SSZ, Azulfidine) Hydroxychloroquine (HCQ, Plaquenil) Azathioprine, cyc losporine TNF antagonists Etanercept (Enbrel) Adalimumab (Humira) Infliximab (Remicade) Certolisumab pegol (Cimzia) Golimumab (Simponi) Abatacept (Orencia) Rituximab (Rituxan) Tocilizumab (Actemra) Tofacitinib (Xeljanz) 45. Methotrexate Most effective single DMARD (used as baseline therapy in most patients.) Typical dose is 15 mg/week. Good benefit-to-risk ratio. Screen Hepatitis serologies before use, ETOH counseling, LFT, CBC, creatinine prior to use and every 2-3 months. Side effects include liver damage, oral and mucosal ulcers and rarely lung toxicity. Rarely may cause bone marrow suppression. Must be taken with folic acid supplementation. 1mg every day except on day of MTX. Avoid use with TMP/SMX: bone marrow suppression. 46. TNF antagonists 5 currently approved agents: Etanercept, adalimumab, infliximab, certolizumab pegol, golimumab. Subcutaneous (etanercept, adalimumab, certolizumab pegol, golimumab) and intravenous administration (infliximab and golimumab.) Administration in combination with MTX is superior to monotherapy. Time to onset: rapid (weeks) Adverse events: Infection, TB, multiple sclerosis/demyelination, lupus-like syndrome. Malignancy: higher rates as compared with normal population but not higher than the background of lymphoma and solid tumors in RA population. Increased risk of non melanotic skin cancers. Monitoring: TB screening including PPD prior to therapy. Periodic CBC, LFTs. Infection. 47. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of diseasemodifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritisArthritis Care & Research Volume 64, Issue 5, pages 625-639, 2 APR 2012 DOI: 10.1002/acr.21641 http://onlinelibrary.wiley.com/doi/10.1002/acr.21641/full#fig1 48. British Journal of Nursing (2013) volume: 22 issue: 6 308, 310, 318 49. British Journal of Nursing (2013) volume: 22 issue: 6 308, 310, 318 50. Special situations: Urgent issues Fever and infections Septic arthritis Dyspnea and cough in a patient on MTX Pre-op issues in long standing RA 51. Infections in RA Infections in RA increased (up to 6 to 9 fold) Immune dysfunction of RA. Corticosteroids, even low dose. Immunomodulatory drugs, in particular biologic therapies. Assessing RA patient with fever, suspected infection Prompt and thorough evaluation of symptoms Prompt initiation of antibiotics (especially for patients on biologics) Avoid use of trimethoprim/sulfamethoxazole (Bactrim, Septra) in patients on MTX Usual bacterial culprits, skin and soft tissue infections, as well as rare infections Opportunistic organisms (especially with biologics) Mycobacterial (atypical or disseminated presentation) Fungal (eg. Histoplasma, Coccidioides, Cryptococcus, Aspergillus, Candi da) Viral (e.g. Zoster) 52. Conclusions Early introduction of effective treatment with minimal delay in introduction of combination therapy, including prednisolone or TNF blockers. Result-driven (for instance DAS