1. Rheumatoid Arthritis By Dr. Nate Josephson

2. Case Presentation 32 year old WF presents to PCP with a 3 month history of progressive pain and stiffness of several joints, notably the wrists, hands, feet, and ankles. She feels worse in the morning and takes several hours to loosen up. On your exam you think there may be some mild swelling in her MCP joints and wrists, but you are not absolutely sure. You are concerned that she may early rheumatoid arthritis.

3. Questions 1.How do you confirm the diagnosis of rheumatoid arthritis? 2.If she does have rheumatoid arthritis, is it okay to see how she does for a while on NSAIDS +/- corticosteroids? 3.Is it important to refer to rheumatology early?

4. Rheumatoid Arthritis A symmetric, peripheral polyarthritis of unknown etiology that, untreated or if unresponsive to therapy, typically, leads to deformity and destruction of joints through the erosion of cartilage and bone.

5. Epidemiology of RA Prevalence ranges from 0.5 to 1.0%, affecting more than 2 million Americans Age of onset typically between 20 and 45 years but over 25% cases start over 60 years old Female to male ratio is nearly 3:1 Annual incidence: 36 cases per 100,000 women

6. Initial Clinical Presentation - Classic Insidious onset of symmetric polyarthritis, particularly MCPs, MTPs, PIPs, wrists Morning stiffness lasting more than one hour Constitutional symptoms such as fatigue common

7. Initial Clinical Presentations – Less Common Acute polyarthritis with prominent myalgias and constitutional symptoms Palindromic rheumatism – one or several joints acutely involved for hours to few days with symptom free intervals lasting days to months Persistent monoarthritis as herald of disease

8. Key Physical Findings Symmetrical soft tissue swelling / tenderness in peripheral joints >20 joints in severe disease Most common are MCP and MTP joints MCP and MTP squeeze test

12. Confirmation of Synovitis Synovitis needs to be confirmed by reliable examiner since it is essential requirement for diagnosis If synovitis is equivocal on exam *May need to follow patient *Occasionally imaging techniques such as MRI helpful as MRI helpful

13. Clinically Useful Biologic Markers Rheumatoid factor Anti-CCP antibody ESR / CRP

14. Rheumatoid Factor(s) Found in 75-80% of RA patients Positivity lower at onset but peaks by 6-12 months High levels associated with more aggressive disease Nonspecific – can occur in chronic infections (such as HCV) and other autoimmune disease

15. Anti-Cyclic Citrullinated Peptide (CCP) Antibodies Found in 50-75% of RA patients May precede clinical symptoms Confers increased risk of progressive disease More specific than RF

17. Testing for both RF and anti-CCP antibodies SensitivitySpecificity RF 73% 82% Anti-CCP 56% 90% Both positive 48% 96% Remember: higher the specificity, higher the positive predictive value (more likely to have disease)

18. Acute Phase Reactants – ESR/CRP Not specific, but fairly sensitive Elevation of both: stronger indication of radiographic progression Correlate with disease activity and used in various metrics to follow disease activity

19. Imaging Plain film radiography: unlikely to reveal erosive disease in very early disease but may serve as baseline MRI: much more sensitive for erosive disease How often is MRI needed for diagnosis and as a guide to therapy – remains controversial given cost

21. Rheumatoid Arthritis - Diagnosis Based on a constellation of compatible features and exclusion of other causes of chronic (>6 weeks) inflammatory arthritis

22. Other Causes of Chronic Inflammatory Arthritis SLE and other connective tissue diseases Psoriatic arthritis Reactive arthritis and undifferentiated spondyloarthropathy Polyarticular gout / pseudogout Inflammatory (erosive) interphalangeal OA Polymyalgia rheumatica/RS3PE syndrome in elderly

26. Natural History & Prognosis of RA (Prior to DMARDS) At 20 years 70% of RA patients severely disabled Although disease activity (inflammation) varies, structural damage is cumulative and irreversible Up to 90% of patients < 2 years disease show radiographic damage Poor outcomes, including life expectancy, associated with early adverse prognostic factors – functional limitation, extraarticular disease, positive RF or anti-CCP, bony erosions

31. Aims of Therapy 1.Relief of signs and symptoms. 2.Improvement in patient reported outcomes 3.Inhibition of structural damage These 3 interrelated aims best achieved by rapid and sustained suppression of disease to remission or low disease activity with DMARDs.

32. Disease Modifying Antirheumatic Drugs (DMARDS) Traditional DMARDS HydroxychlroquineSulfasalazineDoxycyclineMethotrexateLeflunomide Biologic agents – targeting the immune system

34. Biologic Agents for RA TargetDrug TNFetanercept infliximab adalimumabgolimumabcertolizumab B cellsrituximab T cellabatacept 1L-6 receptortocilizumab

40. What Emerges from Randomized Clinical Therapeutic Trials in Early RA Clearly the earlier the therapy the better the outcome The tighter the control the better the outcome Combinations employing biologic agents are more effective in controlling symptoms and radiographic progression than traditional DMARDs

41. Measures of Disease Activity A metric utilizing several parameters to assess activity Used to initially stage disease Can evaluate response to therapy – adequate (tight) or not Can be used to define remisson

45. Assessment of Disease Activity in Early RA Semi Quantitative MildModerateSevere # joints 20 ExtraarticularNoNoCommon ErosionsNo+/-++ RF/CCP++/-+++ ESR/CRP+/-+++ Quantitative DAS 282.4-3.63.7-5.5> 5.5

46. Treatment of Mild Disease in Early RA NSAIDS and traditional DMARDs may suffice – *hydroxychloroquine(HCQ) *sulfasalazine(SSA) *methotrexate(MTX) *leflunomide(LEF) *doxycycline Combination of traditional DMARDS sometimes used Corticosteroids – not at all or sparingly

47. Treatment of Moderate/Severe Early RA Goal: Remission of low disease activity A. MTX (or LEF) monotherapy for 8-12 week trial B. Inadequate responders to A: MTX + anti-TNF C. Inadequate responders to B: TNF switching or MTX + other traditional DMARDs or MTX + newer biologic agent tocilizumab (Actemra) rituximab (Rituxin) abatacept (Orencia) NSAIDS and Corticosteroids adjunctive

48. Role of Corticosteroids in Early RA If patient systemically ill or experiencing rapid decline in function, prednisone 10 mgm/daily Once patient responds sufficiently, dose should be tapered to 5 mgm/day or less Intraarticular route very effective and may bypass systemic use Also consider protection for osteoporosis if prednisone used at >5 mgm/day for greater than 3 months

50. Safety Issues - NSAIDS Toxicity increases with dose escalation regardless of agent Gastroprotection in patients with risk factors for gastropathy – age > 65, past history of ulcer

51. Safety Issues - Methotrexate Hepatotoxicity Pulmonary toxicity Bone marrow suppression Teratogenecity Although not nephrotoxic lower doses with reduced renal function

52. Potential Safety Issues with TNF Inhibitors Target Related (general immunomodulatory / TNF Specific) Infectious / serious infections Opportunistic infections (eg, TB) Malignancies (lymphoma, skin, etc) Demyelinating conditions Hematologic abnormalities Congestive heart failure Autoantibodies (>40% het ANA+, 10% anti-DNA; ACL also seen: however, few other autoantibodies, and lupus-like syndromes rare) Hepatotoxicity Skin reactions / psoriasis Agent related Administration reaction Immunogenicity

53. Tuberculosis & TNF Antagonists Latent TB (LTBI): +PPD/-Sxs/-CXR All TNF inhibitor Rx patients should be evaluated for LTBI with a tuberculin skin test prior to initiation Obtain CXR? Not routinely advocated in USA. Do: *If PPD positive *If signs/Sxs present *Recent known TB contact If latent TB (no signs/Sxs): initiate INH prior to or with TNF inhibitor therapy If active TB infection, treat 4 drugs, delay initiation of TNF inhibitor therapy

54. Prevention While on TNFi General precautions *General infection control *Manage comorbidities (alcohol and smoking cessation, DM control, minimize steroid dose) control, minimize steroid dose) 2006 ACIP Guidelines on Immunizations *Influenza vaccine every year *Pneumococcal vaccine *Meningococcal, Hepatitis B where exposure is likely *Avoid live-attenuated vaccines (oral polio*, MMR, varicella, shingles) shingles)

55. Conclusions Early diagnosis important, which leads to – Early treatment, aggressive if necessary, which leads to – Better outcomes Communication important between PCP and rheumatologist