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Update in Rheumatology 2010

Update in Rheumatology 2010. Brian F Mandell md phd facr facp Professor and Chairman of Medicine Department of Rheumatic and Immunologic Diseases Center for Vasculitis Care and research Cleveland Clinic. Update in Rheumatology. Rheumatoid arthritis Diagnostic guidelines CCP

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Update in Rheumatology 2010

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  1. Update in Rheumatology 2010 Brian F Mandell mdphdfacrfacp Professor and Chairman of Medicine Department of Rheumatic and Immunologic Diseases Center for Vasculitis Care and research Cleveland Clinic

  2. Update in Rheumatology • Rheumatoid arthritis • Diagnostic guidelines • CCP • Role and complications of new agents • Perioperative meds • Cardiovascular risks • Fibromyalgia (new diagnostic guidelines, Really…REALLY?) • Gout (something is new??) • Trial data supports physical chemistry concepts (and empiric practice) • Urate linked to hypertension, CKD, CVD, Gatorade and Freunds Adjuvant • Osteoporosis – maybe everyone with bones does NOT need drugs after all… the concept of the FRAX • But those taking steroids probably do • Quick peek at changing paradigms-SLE, APLS, Vasculitis

  3. Ringless in Cleveland 26yo F c/o acute onset of fatigue, with pain and swelling of bilat wrists, MCPs (2,3,5), PIPs (2,3,4,5), and knees 12 days previously. She needed to remove her rings. 10 months post partum, daughter in day care, not breast feeding ROS: negative PE: Markedly tender synovitis with effusions as above; no oral or skin lesions. Rest of exam is normal. LABS: ESR 38, CBC, AST, ALT, Creat, UA normal. RF + @ 24.

  4. Ringless in Cleveland 26yo F c/o acute onset of fatigue, with pain, tenderness and swelling of bilat wrists, MCPs , PIPs, and knees 12 days previously. ESR 38, CBC, AST, ALT, Creat, UA normal. RF +. You decide to: • Start weekly methotrexate 15mg weekly with daily folic acid • Xray the hands/wrists • Obtain viral hepatitis and parvovirus antibodies • Check a TSH

  5. Parvovirus in Adults • PARVOVIRUS • RASH ABSENT OR ATYPICAL IN ADULTS • 80% ARTHRALGIA / 60% ARTHRITIS • TRANSIENT RHEUMATOID FACTOR • APLASTIC CRISES • SEROLOGIC EVIDENCE of PAST INFECTION COMMON Hep C is a mimic of seropositive RA!!

  6. Rheumatoid Factor and Anti-CCP in RASummary • “Anti–CCP” fairly specific marker for RA • Anti-CCP and RF do not vary with disease activity • Anti–CCP and RF – unclear direct role in pathogenesis • Anti-CCP and RF are markers of worse outcome (ccp = cyclic citrullinated peptide)

  7. How does Anti CCP compare to RF? • Anti CCP may be a more sensitive test in EARLY RA than rheumatoid factor • In hepatitis C polyarthritis: • RF usually positive • Anti CCP is negative • In psoriatic arthritis • Anti CCP may be pos; RF negative • Both predict worse prognosis in RA • Radiographic erosions • Linked to certain HLA DR loci (shared epitopes)

  8. RA Markers of worse prognosis • CCP or RF positivity • Genetic determination • Cigarette smoking • Early knee involvement • Early erosions because prognosis is hard to predict, current trend: Treat early and treat aggressively. Goal is to prevent damage from occurring.

  9. 2010 Rheumatoid Arthritis Classification CriteriaARTHRITIS & RHEUMATISMVol. 62, No. 9, September 2010, pp 2569–2581 “This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with developing persistent and/or erosive disease, rather than defining the disease by its late-stage features.”

  10. The 2010 ACR / EULAR classification criteria for rheumatoid arthritis Target population (Who should be tested?): Patients who 1) have at least1 joint with definite clinical synovitis (swelling) 2) with the synovitis not better explained by another disease Add A–D; a score of 6/10 is needed to classify patient as having definite RA A.Joint involvement 1 large joint. 0 2-10 large joints 1 1-3 small joints (with or without involvement of large joints) 2 4-10 small joints (with or without involvement of large joints) 3 3-10 joints (at least 1 small joint) 5 B. Serology (at least 1 test result is needed for classification) Negative RF and negative ACPA 0 Low-positive RF or low-positive ACPA 2 High-positive RF or high-positive ACPA 3 C. Acute-phase reactants (1 test result is needed for classification) Normal CRP and normal ESR 0 Abnormal CRP or abnormal ESR 1 D. Duration of symptoms 6 weeks 0 >6 weeks 1

  11. Rheumatoid Arthritis Treatment Strategies • Things we agree on: • Early diagnosis is good • Early institution of DMARD therapy is good • Tight control improves outcomes • Unanswered questions: • Optimal treatment strategy in early disease • ? Monotherapy with step up • ? Initial combination therapy • ? Early institution of biologics • How much steroid initially

  12. Evaluation of Two Strategies (initial methotrexatemonotherapyvs its combination with adalimumab) In Management of Early Active Rheumatoid Arthritis: Data from the GUEPARD Trial Martin Soubrier Rheumatology 2009 Volume 48, Number 11: 1429-1434

  13. ACR Responses at Weeks 12 and 52 N=65 Soubrier, M. et al. Rheumatology 2009 48:1429-1434

  14. Recommendations from GUEPARD • Initial therapy with TNF inhibitor is not justified • If there is persistent disease activity on MTX mono therapy at 12 weeks, TNF inhibitors should be added • Regardless of the strategy, tight control is effective

  15. What do internists need to know about the use of anti-TNF agents?Summary • Very effective in early and late active disease • RA, psoriasis, psoriatic arthritis, spondylitis, JIA • Decrease symptoms and disease progression in RA • Increasingly used in other conditions – uveitis, sarcoid • all agents not the same efficacy • Very expensive (paperwork…. assistance programs) • Unique side effects • TB reactivation (check a PPD pre – treatment) • Fungal infections • Demyelination (rare) • MAY worsen severeCHF (infliximab) • MAY increase rate of skin, soft tissue, perioperative infections. • ? Increased melanoma

  16. Rheum Therapies in the PerioperativePeriod • NSAIDs – withhold due to bleeding risk, ARF • MTX- can continue, no incr infections • Leflunomide –? increased infection, but long T1/2 • Sulfasalazine – continue • Anti-TNF – hold few T1/2, increased infection • Abatacept/ Rituximab - ? • IL1 orIL6 antagonists-hold, NO DATA • Steroid – common sense “coverage” NO PROLONGED TAPERING

  17. Rheum Therapies in the PerioperativePeriod • Colchicine – gout prophylaxis • try to continue, diarrhea concern • Allopurinol- continue

  18. Cardiovascular Disease in RA • Excess cardiovascular risk and mortality in RA • Not explained by traditional CV risk factors • Avina-Zubieta A&R 2008, Wolfe A&R 2008 • Inflammatory immune mechanisms in atherosclerosis play a role in the pathogenesis of CV disease • Provan, Arth Res Ther, 2008 • Elevated inflammatory markers are associated with CV disease • Rho A&R 2009 • Risk may be as high (or higher!)than in Diabetes • HDL may NOT be “protective”

  19. Cardiovascular Event Free Probability Non-diabetic controls Type II DM [HR=2] Rheumatoid Arthritis [HR=2.2] Years Peters et al Arthritis and Rheumatism 2009

  20. Approaches to Reducing CV Risks(none proven) • Aggressive control of the RA • Liberal use of low dose ASA • Control LDL as in a diabetic

  21. A 42 yowf with RA for 2 years, previously well controlled on MTX, nabumetone, and 2.5 mg prednisone daily presents 3 months following the birth of a healthy boy. MTX was held during pregnancy, restarted 6 wks ago. Now increasing fatigue, swelling and “pain all over”. She describes increased AM stiffness of her back, neck, hands, hips, chest with trouble sleeping, and difficulties with painful “flares” following any physical exertion. ESR is 32, RF is high titre. Exam: multiple tender, non-swollen joints; mild ulnar deviation with prolif non-tender bilat 2,3 MCPs, normal grip strength; bilateral trochanteric bursitis / gluteal tenderness / costochondral tenderness.

  22. WHAT TO DO? A. INCREASE PREDNISONE TO 10 mg q A M B. INCREASE MTX 20 mg WEEKLY C. ADD A TRICYCLIC AND EXERCISE D. ADD AN ANTI-TNF AGENT

  23. FIBROMYALGIA • CHRONIC PAIN SYNDROME • DIFFUSE - “I HURT ALL OVER” • NOT REGIONAL • MAY WAX AND WANE • WEATHER • STRESS • INCREASES POST EXERTION • “FIBRO FOG” • TENDER POINTS THE MACK TRUCK SYNDROME

  24. FibromyalgiaNeed for aformalized, practical redefinition • Problems with prior definitions • Over-reliance on ”tender points” • Variability of examination • Under-reliance on conceptual image

  25. FibromyalgiaPractical redefinition Criteria: 1.Widespread pain index (WPI) >7 and Symptom severity score (SS) >5 or WPI 3-6 and SS >9 2. Symptoms present > 3 months 3. No other disorder to explain pain WPI – listing of 19 different anatomic sites (1 point per site) SS - (scored in severity in past week) Fatigue (0-3) Waking unrefreshed (0-3) Cognitive symptoms (0-3) Wolfe et al. Arth Rheum 62:600-10, 2010

  26. A 48yo foreman presents for his annual physical. You have treated him for hypertension and tophacious gout for several years. He feels good. Last attack of gout was mild, and > 6 months ago. It resolved promptly with few doses of naproxen. Prior to current therapy, he had several severe attacks/yr causing him to miss work. Current meds: enalapril 20 mg, colchicine 0.6 daily, and allopurinol 300 mg qd. BP 126/70. He has a few olecranonnontender movable nodules, a cool tender left 1st MTP joint with overlying nodule. He has no gallop or edema. The examination is otherwise normal. Lab: normal CBC, AST, glucose and creatinine. urate is 7.2 (normal < 7.8 mg/dl).

  27. A 48yo foreman presents for his annual physical. You have been treating him for his hypertension and tophacious gout for several years. He is feeling good, last attack of gout was mild, and > 6 months ago. It resolved promptly with few doses of naproxen. Prior to current therapy, he had several severe attacks/yr causing him to miss work. Current meds: enalapril 20 mg, colchicine 0.6 daily, and allopurinol 300 mg qd. BP well controlled at 126/70. He has a few olecranonnontender movable nodules, a tender left 1st MTP joint with overlying nodule. He has no gallop or edema. The examination is otherwise normal. Lab: normal CBC, AST, lytes, glucose and creatinine. The serum urate level is 7.2 (normal <7.8 mg/dl). You suggest: A. Stop colchicine; continue allopurinol 300; naproxen as needed. B. Stop colchicine and stop allopurinol, use naproxen as needed. C. Stop colchicine and increase the allopurinol to 400mg daily; use naproxen as needed. D. Continue colchicine and increase the allopurinol to 400 mg daily; use naproxen as needed.

  28. Defining Hyperuricemia 40 Males Females 35 30 Urate crystallizes at a level of ~6.7 mg/dL ( biological hyperuricemia ) Serum urate levels in 1515 men and 1670 women aged ≥30 in Taiwan 1991-1992 25 20 Distribution, % Patients may fit the biological definition for hyperuricemia but be in the “normal “ range 15 10 5 0 11 12 13 1 2 4 5 6 7 8 9 10 0 3 Serum urate, mg/dL Lin et al. J Rheumatol. 2000;27:1045-1050.

  29. DEFINING HYPERURICEMIA LABORATORY “NORMAL” LEVEL of URATE ~8.0mg/dl IS NOT BIOLOGICALLY “NORMAL” URATE SATURATES BIOLOGICAL FLUIDS AT A LEVEL > 6.7

  30. EFFECT OF ALLOPURINOL ON PLASMA [URATE] • 49 PATIENTS WITH GOUT GIVEN 300 mg ALLOPURINOL. • MEAN REDUCTION 8.6 5.85 BUT: 47% of Pts HadINADEQUATERESPONSE to 300mg ! IFDOSE ADJUSTED TO ACHIEVE TARGET [URATE] LEVEL: < 6 mg / dl Perez-Ruiz et al Ann Rheum Dis 57:545-49,1998

  31. Real World Allopurinol Dosing

  32. Management of Goutpractice review data • Retrospective claims based review of 5942 patients with Dx of gout ‘99 – ‘04 • Managed care group SE USA • 1.6% prevalence with gout • 40% HTN • 25% CAD • 18% DM • 13% CKD • Allopurinol use: • 65% Rx was for 300mg dose • ~ 3% received doses > 300mg • 83% had NO recorded serum urate testing within 180 days of Rx Sarawate et al Mayo Clin Proc 81:925-34, 2006

  33. There ARE Improved Outcomes in Gout with SUA Reductions ≤ 6mg/dl • Deplete synovial crystals (Li-Yu J et al. J Rheumatol 28:577-580,2001) • Reduced frequency of attacks(Li-Yu J et al. J Rheumatol 28:577-580,2001; Shoji A et al. Arthritis Rheum 51: 321-325, 2004; Becker MA et al. N Engl J Med 353: 2540-2461, 2005) • Reduced tophus size( Perez-Ruiz F et al. J Clin Rheumatol 5: 49-55, 1999; Becker MA et al N Engl J Med 353: 2540-2461, 2005) • Improved renal function with reduction of NSAID use(Perez-Ruiz F et al. Nephron 856: 287-291, 2000) • Slows progression of existing renal disease( Siu Y-P et al. Am J Kidney Dis 47:51-59, 2006) Perez-Ruiz F and Liote F. Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arth Rheum 57: 1324-1328, 2007

  34. sUA <6.0 mg/dL sUA 6.0 mg/dL Gout Flares After Hypouricemic TherapyInfluenced by Post-Treatment Urate Level Early flares with acute hypouricemia (when prophylaxis stopped) 50% Longer term: fewer flares with hypouricemia 40% 30% Subjects Requiring Treatment 20% *p< 0.05 10% 1 to 8 0% 8 to 16 16 to 24 24 to 32 32 to 40 40 to 48 48 to 52 Weeks of Treatment (allopurinol of febuxostat) prophylaxis Becker et al NEJM353:2450-61,2005

  35. WHEN INITIATING HYPOURICEMIC Rx Colchicine reduces gout flares 40 PATIENTS WITH GOUT; STARTED ON ALLOPURINOL, GIVEN COLCHICINE or PLACEBO (20 in each group) 39 WITH 3 MONTH, 22 WITH 6 MO F/UP Borstad et al Arth Rheum 46:S140, 2002; J Rheumatol 31:2429-32, 2004.

  36. Flare rate (8 weeks) correlates with drop in serum urate Gradual drop, fewer flares (?) 200-300

  37. Duration of Therapy • Prophylactic therapy • Aim for at least 6 months after initiation of hypouricemic therapy (or after last flare) • 6 months after tophi resolution ? • Little information re NSAID prophylaxis • Low dose steroids may not work • Hypouricemic therapy is generally for life

  38. Uric acid URAT1 Transporter The Hyperuricemia - Metabolic Syndrome Link With a Twist ( in the RAT ) ALLOPURINOL or BENZBROMARONE Fructose (vs. dextrose to rats) Increased TG Increased BP Increased weight Urate synthesis In liver HYPERURICEMIA Endothelial NO + Increased Insulin Insulin resistance Nakagawa et al Am J Physiol Renal Physiol 290:F625-31, 2006

  39. Allopurinol blocks fructose associated increase in BP Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response S E Perez-Pozo, J Schold, T Nakagawa, L G Sánchez-Lozada, R J Johnson and J López Lillo. International Journal of Obesity advance online publication 22 December 2009 Increase mm P <0.04 2 week study, n=74 200g fructose daily +/- allopurinol 300 mg

  40. A 70-year-old man with active giant cell arteritis begins treatment with prednisone and low dose aspirin. His only manifestation of giant cell arteritis is severe temporal headache. Bx + GCA. Erythrocyte sedimentation rate is 80 mm/h. Results of bone mineral density testing using dual-energy x-ray absorptiometry are normal. In addition to initiation of calcium and vitamin D therapy, which of the following is the most appropriate next step in this patient’s management? • Nasal Calcitonin • An oral bisphosphonate • Teriparatide • No additional therapy, repeat DXA 1 year

  41. 70 yo With GCA Even with a “normal” bone density, the age and the high dose corticosteroids needed to treat the GCA significantly increases the fracture risk. The addition of bisphosphonate therapy should be strongly considered.

  42. Bone health in patients receiving corticosteroids • Bone loss greatest in the first 6-12 months of steroid use – up to 20% • Not everyone loses bone density • Variable dose response • Trabecular > cortical bone loss • BMD underestimates fracture risk • Fractures occur in up to 1/3 steroid Rx patients • Postmenopausal women at greatest risk for fracture • Doses of prednisone > 5mg cause bone loss Excess resorption, Oclasts Osteoblast death Reduced Ca absorption Hypercalciuria PTH Muscle weakness

  43. Fracture risk by spine BMD is higher in post menopause corticosteroid users vs non-users 56 postmenopausal patients in placebo arm of BP/steroid OP trials compared to 1899 post-menopausal (placebo) women from other trials. Fracture incidence at 1 year at specific BMDs. Fracture Incidence (%) Steroid treated post-menopause N=56 Post menopause, No steroid Lumbar Spine T-Score Van Staa TP et al Arth Rheum 48:3224-29, 2003

  44. Clinical Pearlettes • Decisions re institution of anti-resorptive therapy should be based on overall therapeutic goal of reduced risk of fracture. • Individualized assessment of fracture risk • It is more than the T Score Question # 9

  45. The FRAX http://www.shef.ac.uk/FRAX/tool Question # 9

  46. And……a few evolved and evolving paradigms • Lupus Nephritis • More MMF (cellcept), less cyclophosphamide • Antiphospholipid Syndrome • INR of target 2-3 for thrombosis • ANCA associated vasculitis • Induction then consolidation therapy • Shorter course cyclophosphamide • Longer MTX / azathioprine • PCP prophylaxis, almost always • More rituximab • Spondylitis - initial Anti-TNF therapy

  47. The End

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