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Update in Rheumatoid Arthritis

Update in Rheumatoid Arthritis. Gregory Gardner, M.D. Gilliland-Henderson Professor of Medicine Division of Rheumatology University of Washington. Outline of Discussion. Pathophysiology Clinical Features Treatment Update Perioperative Management. Rheumatoid Arthritis. Pathophysiology.

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Update in Rheumatoid Arthritis

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  1. Update in Rheumatoid Arthritis Gregory Gardner, M.D. Gilliland-Henderson Professor of Medicine Division of Rheumatology University of Washington

  2. Outline of Discussion • Pathophysiology • Clinical Features • Treatment Update • Perioperative Management

  3. Rheumatoid Arthritis Pathophysiology

  4. Rheumatoid arthritis demographics • Autoimmune disease • Affects 1-2% of US population • 1st degree relative has double the risk • Women:Men 3:1 • Occurs in two peaks:-Women during child bearing years-Men and women after age 60

  5. Treating RA: think Bolero N Engl J Med. 1990;322:1277–1289 J Rheumatol. 1996;239(suppl 44)2-4 Early 1990 RA immunologically staged by Harris (modified) • Stage 0 -1 - Benign autoimmunity to early RA; antigen processed/presented to T-cells; autoantibody production • Stage 2 - T cells proliferate & induce B cell proliferation. New blood vessels develop as a scaffold for proliferating synovitis. Acute inflammation in synovial fluid • Stage 3 - Marked synovial proliferation and inflammation develop with production of of cytokines • Stage 4 - Synovitis polarized into aggressively invasive front of macrophages and synovial cells that begins irreversible destruction of cartilage, ligaments and bone • Stage 5 - Progressive loss of articular cartilage & bone; tendon/ligamenous attenuation and loss; joint deformity

  6. Genetic issues in RA • Genetic factors account for 50-60% of RA riskand environmental factor account for 40-50% • Shared epitope (SE) on 3rd hypervariable region on the HLA DR beta 1 chain, amino acid sequences 67-74, associated with susceptibility and severity of RA • The presence of anti-citrullinated peptide antibodies (ACPA ie anti-CCP) is the strongest predictor of developing rheumatoid arthritis; ACPA are also prognostic • Citrulline results from deimination of arginine; peptides with citrulline are immunogenic • In high risk populations, a long period of benign autoimmunity can proceed the onset of active RA • Anti-CCP antibodies my be present before RA develops

  7. Structure/functionof HLA molecule Fig 1 Fig 2 Figure 1 is representation of structure of the HLA class II molecule present on and antigen presenting cells. Figure 2 shows the position of the shared epitope on the HLA DR molecule. Figure 3 illustrates the function of the class II molecule Fig 3 ACR and Hochberg 2008

  8. Benign autoimmunity: Specific auto-antibodies may precede the symptoms of rheumatoid arthritisNielen et al. Arthritis Rheum 2004;50:380 • Study of 79 RA pts who had donated blood several times prior to onset of RA • 67% RF + 6 yrs after Dx; no data for CCP • 2100 control sera: 1.1% + for RF; 0.6% + for CCP

  9. Environmental issues in RA • Are genetic mechanism responsible for the development of the benign autoimmune state and the inability to control the immune activation once initiated? • Are environmental factors responsible for initiating citrullination of peptides that genetic factors then react to? • Current environmental risk factors that appear to play a role in RA include by leading to citrullination of proteins • Smoking • Periodontal disease

  10. Is rheumatoid arthritis caused by an environmental agent from the New World? ? Rothschild BM, et al: Semin Arthritis Rheum 1992;22:181

  11. Antiquity of rheumatoid arthritis • Paucity of reports of RA in medical literature prior to the 1800’s; first clear case reported in 1676 by Sydenham • Rothschild et al examined 35,000 European skeletal remains without finding an example of RA-like Dz • Gout, osteoarthritis, ankylosing spondylitis etc. common • RA found in Pre-Colombian skeletons in N America • Especially in Tennessee, Ohio, Alabama, and Kentucky • Prevalence: 7% female, 3% males Rothschild BM, et al: Semin Arthritis Rheum 1992;22:181

  12. RA in European art: Siebrandus Sixtius, Dutch Priest 1631J Dequeker Ann Rheum Dis. 1992 April; 51(4): 561–562

  13. European contact with North American RA Numerous NW Tribes with RA Yakama Makah Tlingit Etc. French Dutch English Spanish French

  14. Can we treat earlier?Klareskog et al. Nature Clinical Practice Rheumatology 2006;2:425

  15. Rheumatoid Arthritis Clinical Features

  16. 2010 ACREULAR/RA Criteria 6/10 points Needed for classification Small joints: MCPs PIPs Wrists 2-5 MTPs High RF/ACPA > 3x ULN

  17. DDx of Inflammatory Polyarthritis • Rheumatoid arthritis • SLE - systemic features, + ANA/ENA • Psoriatic arthritis - rash, dactylitis • Viral arthritis ie parvovirus - more pain than swelling, rash, season • Polyarticular gout • Other CTD - other systemic features ie Raynaud’s, myositis, etc…

  18. Joint Distribution • Cervical spine • Shoulders • Elbows • Wrists • Hands • PIPs • MCPs • SPARES DIPs • Hips • Knees • Ankles • Tibiotalar • Subtalar • Feet • MTPs

  19. Earliest RA

  20. RA Hands Late

  21. RA Feet

  22. Rheumatoid Arthritis:Extra-Articular Disease Pulmonary Nodules Scleritis in RA Rheumatoid Vasculitis

  23. Nodules RA nodule or gouty tophus?

  24. Other complication of RA • Felty’s syndrome • Leukopenia, splenomegaly, RA • Infections, leg ulcers • C1-C2 subluxation • Neck pain, myelopathy • C spine flexion/extension views, MRI • Septic arthritis • Large joints, fewer systemic symptoms • Staph > Strep > gram negatives • Morbidity/mortality high • Tendon ruptures • Especially ring/little finger extensor tendons

  25. Rheumatoid Factor • Rheumatolgic DiseaseRA, SLE, Sjogren’s, MCTD, PM/DM, Cryoglobulinemia • Infectious DiseaseSBE, TB, Syphilis, Hep C • OtherAging, IPF, Cirrhosis, Sarcoidosis, Waldenstrom’s IgM Rheumatoid Factor IgG Fc Region Points to remember! -High level; worse prognosis -May take months to appear -20-30% of RA Pts never develop -Not specific for RA

  26. Anti-CCP (ACPA) • Antibodies to Cyclic Citrullinated Peptide (CCP) have a sensitivity of 78% and specificity of 96% for RA • 40% of “seronegative RA” are anti-CCP + • Level of CCP is directly correlated with the development of erosions • Negative , low-moderate (35-200) or high CCP (>200) • OR of radiographic progression vs CCP negative RA pts after10 yrs • Negative 1.0 • Low-moderate 3.2 • High 15.2 • Other ACPA being investigated for utility in diagnosis and prognosis Schellekens. Arthritis Rheum 2000;43:155

  27. Imaging in RA • 5th MTP may show earliest changes in RA • RA X-ray findings: • Osteopenia • Marginal erosions • Jnt space narrowing • Ultrasound • MRI

  28. Progressive X-ray changes in RA Joint Erosions in RA: From Bad to Worse

  29. Prediction Model for Erosive vs Nonerosive RA Early in Disease Course 524 consecutive patients with early arthritis; total score corresponds to predictive value for erosive vs nonerosive arthritis given the presence of persistent RA. Visser H et al. Arthritis Rheum. 2002;46:357-365; Visser H. Best Pract Res Clin Rheumatol. 2005;19:55-72.

  30. Rheumatoid Arthritis Treatment Issues

  31. Therapy for Rheumatoid Arthritis circa 1989 • Medications • Gold • Penicillamine • Hydroxychloroquine • Sulfasalazine • New drug, methotrexate • Treatment philosophy • Pyramid with sequential DMARD monotherapy • “Rheumatoid arthritis is a disabling but otherwise benign disease”

  32. Rheumatoid Arthritis Circa 1989 • Frequent complications • Rheumatoid vasculitis • C1-C2 subluxation • Felty’s syndrome • Extensor tendon rupture • Septic arthritis • Pathophysiology of RA • Macrophage mediated disease

  33. Outcome of RA over 20 years in 112 consecutive patients by functional class and mortality Scott DL et al. Lancet 1987;1108-1111 “The concept of remission-inducing drugs is fallacious. Early treatment may be advantageous, but the prognosis of RA in not good”

  34. Business as usual was not working • > 90% of RA patients have erosions after 2 yrsFuchs HA, et al: J Rheumatol 1989;16:585-591 • 5 - 10% of RA patients become disabled each yrKushner I: J Rheumatol 1989;16:1-4 • Only 18% of RA patients achieve a period of remission during the course of their disease.Wolfe F, Hawley DJ:J Rheumatol 1988;12:245-252 • Median life expectancy decreased 4 yrs for men and 10 yrs for women with RAMitchell DM, et al: Arthritis Rheum 1986;29:706-713

  35. “What we need in RA is a drug for which one does not need a statistician to see the beneficial effects” Irving Kushner, M.D. J Rheumatol 1989;16:1-4

  36. “Time and comparative observations will be needed to show the optimum combination of drugs and whether step down bridge concept will achieve the sought for and presently unobtainable goal of early and sustained control of inflammation, improved quality of life and prevention of bone and joint damage.” J Rheumatol. 1989;16:565-7

  37. Changes in Treatment Approaches to RA Biologics Combination therapy Early intervention Pyramid inversion Treatment pyramid Single-drug Rx 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000

  38. RA treatment themes 2011 • Early recognition, early institution of therapy especially with those with poor prognostic markers • Presence of erosions • High titer anti-CCP/RF • Treat to DAS (disease activity score) or some other measure of disease activity (SDAI, CDAI etc) • Methotrexate mainstay in most pts; dose to 15-20 mg/week • Consider early institution of biologic therapy • Strategies for using biologics under study ieinitial therapy with subsequent withdrawlvs add (discussed below)

  39. Non-Biologic DMARDs for RA • Methotrexate • 7.5-25 mg/week po or sc • ETOH restriction, avoid pregnancy, folic acid • Leflunomide • 10-20 mg poqd • Avoid pregnancy, liver toxicity • Sulfasalazine • 500 mg 2 po bid • Sulfa allergies, agranulocytosis, azospermia • Hydroxychloroquine • 200-400 mg poqd (6.5mg/kg) • Rash, retinal toxicity

  40. Biologic Therapies 2011 • Anti-TNF agents • Etanercept • Adalimumab • Infliximab • Certozilumab • Golimumab • Anti-B cell agent • Rituximab • Anti-T cell agent • Abatacept • Anti-IL-6 receptor antagonist • Tocilizumab • Coming attractions • Jak-2 inhibitors • Anti-IL-17 therapy

  41. Monitoring DMARDS • Hydroxychloroquine • Baseline eye exam, repeat at 5 yrs then every yr • Sulfasalazine • Baseline CBC LFTs; repeat q month time 3 then every 3 mo • Methotrexate • Baseline CBC, creatinine, LFTs, CXR, Hep B &C; CBC LFTs q mo x 6 mo then every 1-3 mos thereafter • Leflunomide • Baseline CBC, creatinine, LFTs, Hep B&C; CBC LFTs monthly for 6 mos then 1-3 mos thereafter • TNF inhibitors • Baseline CBC LFTs, Hep B (ok for Hep C!), PPD; CBC q mo x 3 then q 6 mos; consider monitoring for PPD (Quantaferon) conversion

  42. Intensive treatmentgroup (n = 55) 6 Routine case group (n = 55) 5 4 3 Disease Activity Score 2 1 0 0 3 6 9 12 15 18 Months Treating to clinical goal results in better outcomes (TICORA) Grigor C, et al. Lancet. 2004;364:263-269 Mean DAS Scores Over Time Total Sharp Score Progression Routine Rx 8.5 Intensive Rx 4.5 P < 0.0001, intensive vs routine after month 3.

  43. COMETEmery. Lancet 2009;372:375-382 MTX vs MTX plus etanercept in early RA; Rx 52 wks 542 pts with early RA (<2 yrs) and MTX naïve MTX alone vs MTX+ETN with remission being primary endpoint SAE is 12% combo vs 13% MTX alone

  44. PREMIER study: radiographic changes of combination TNF+Mtx better than Mtx alone (RA pts with < 3 yrs of disease and MTX naïve)Breedveld FC, et al. Arthritis Rheum. 2006;54:26-37 Sharp Units

  45. †p<0.05 vs. etanercept ‡p<0.05 vs. etanercept TEMPO Study: Mean Change in Total Sharp Score From Baseline at 2 Years1 3.3 1.1† Mean Change From Baseline -0.6† Baseline 1 Year 2 Years Inhibition *Total Sharp Score is based on combined scores of joint erosions in the hands on a scale of 0 to 5, feet on a scale of 0 to 10 (0=no damage), and joint space narrowing in hands and feet on a scale of 0 to 4 (0=no narrowing). Klareskog L, et al. Lancet. 2004;363:675-681.

  46. Healing of Erosions 1998 42 y/o woman with 10 yrHx of RA. On etanercept since Note filling of erosions On 3rd an to a lesser extent 4th MTP heads 2005

  47. Can we stop therapy in RA?BeST remission/radiographic data at 4 yearsKooij et al. Ann Rheum Dis published online 28 Jul 2008 • Pt with < 2 yrs of RA treated to DAS 44 score of <2.4 (remission <1.6) • As patients went into remission, medications withdrawn • Drug free remission more likely to be males, sero-negative, shorter symptom duration before starting therapy

  48. RA Mortality and Current TherapyMichaud K, Wolfe F. Arthritis Rheum 2005;52(suppl)S145 19,580 Pts, 63,811 pt years of observation, Deaths: 33% CV, 22% malignancy, 19% lung

  49. DL Scott on Early Aggressive TherapyScott DL. British Medical Bulletin 2007 81-82(1):97-114 “At present, it seems sensible to focus on trying to rapidly identify patients with the most severe early RA, particularly patients who are sero-positive for rheumatoid factor and have early erosive damage, and give them intensive treatment. There is some evidence, albeit incomplete, that combination therapy using TNF-inhibitors is most effective.”

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