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Rheumatology Update: Pearls for Primary Care

Rheumatology Update: Pearls for Primary Care. Greg Gardner, MD, FACP Gilliland-Henderson Professor of Medicine Division of Rheumatology University of Washington. Rheumatology Pearl #1. There are only 3 patterns to joint pain: Inflammatory Mechanical (non-inflammatory) Fibromyalgia.

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Rheumatology Update: Pearls for Primary Care

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  1. Rheumatology Update:Pearls for Primary Care Greg Gardner, MD, FACP Gilliland-Henderson Professor of Medicine Division of Rheumatology University of Washington

  2. Rheumatology Pearl #1 • There are only 3 patterns to joint pain: • Inflammatory • Mechanical (non-inflammatory) • Fibromyalgia

  3. Inflammatory • AM stiffness > 30 min (often several hrs) • Improvement with activity • Swelling common • Rheumatoid arthritis, polymyalgia rheumatica • Mechanical • 10-15 minutes of AM stiffness • Pain worse with use • Osteoarthritis, tendonitis • Fibromyalgia • AM stiffness significant • Poor sleep quality • Afternoon pain and fatigue • Exercise intolerance i.e. feeling “wiped out” • Other somatic illnesses common ie headaches

  4. Patient History • A 45 y/o woman with a 5 year history of rheumatoid arthritis reports 2 hrs of AM stiffness, pain with activity especially in the left knee, and if she overdoes it she can have diffuse joint pain for a day or two after. Reports poor quality sleep. • Meds: Methotrexate 15 mg po/wk, etanercept 50 mg sc/wk • Exam: No swelling of the small joints of the hands or feet. Small effusion in the left knee. She has multiple tender points of fibromyalgia. • Testing: X-ray diffuse loss of cartilage in the left knee; CBC normal, CRP normal • WHICH PATTERNS?

  5. Rheumatology Pearl #2Occam Razor vs Hickman’s Dictum • William of Ockam • Entianon suntmultiplicandapraeterneccessitatem • Entities should not be multiplied beyond necessity i.e. the simplest explanation is usually correct • John Hickam, MD • The patient can have as many diseases as they D_ _ _ well please

  6. Pearl 3: Do I Really Want to Check an ANA? • 44 y/o woman complains of 10 years of aches and pains and fatigue. Her local care provider checked an ANA and found it was 1:80 and told her she had lupus and referred her to you. She complains of several hours of morning stiffness and any continuous level of activity causes increased diffuse pain. She quit her job as an electronics assembler due to her symptoms. • Examination is positive for diffuse tender points otherwise negative. There is no rash, joint swelling, weakness (Pt gives way with strength testing) • She wants to know what you are going to do about her lupus?

  7. ANA Pearls: The Pearl of Checking an ANA • The sensitivity and specificity of the ANA test along with the rarity of CTDs like SLE mean that most positive ANAs are really false positives! • Current gold standard, according to the ACR, is to do ANA screen by IFA and give a pattern and titer and follow with a panel of extractable nuclear antigens • Many labs will now only do multiplex method and skip IFA; ANA is positive if ANY of the autoantibodies are detected • Multiplex method alone is less sensitive than ANA by IFA and also less specific so higher false positive and negative rates

  8. Patterns of ANA by Indirect Immunofluorescence (IFA) Five basic ANA patterns representing antibodies to specific groups of nuclear antigens by IFA: • Homogeneous (SLE) • Speckled (non-specific) • Peripheral (SLE) • Centromere (CREST) • Nucleolar(SLE/Scleroderma) Homogeneous FANA Pattern

  9. Screening for Antinuclear Antibodies by Indirect Immunoflorescence Technique (IFA) Step 1: Patient serum containing ANAs placed on slide containing HEp-2 cells. ANAs attach to cell nucleus Ab Y Nucleus Anti-human IgG Slide Y Y Step 2: Fluorescein Tag The preparation is washed and fluorescent labelled anti-immunoglobulinis added. Preparation glows when viewed under fluorescence microscope

  10. Extractable Nuclear Antigens (ENA) Dectected by Various Methods Antigen Abbreviation Saline extractable nuclear antigens are targets of ANAs that help characterize specific illnesses Sjogren’s syndrome A (aka Ro)SSA (SLE/SS) Sjogren’s syndrome B (aka La)SSB (SS/SLE) Double stranded DNA DsDNA (SLE) Smith antigen Sm (SLE) Ribonuclear protein RNP (SLE/MCTD) Scleroderma 70 SCL 70 Chromatin (SLE) Centromere AB (CREST)

  11. Multiplexed Method for Detecting Autoantibodies • Autoantigen is fused to colored micropheres • Pt serum is then incubated with microspheres; if autoantibodies are present these will attach to the autoantigen/sphere complex • Antihuman IgG/fluorochrome tag then added • Microsphere then placed in flow cytometry column that uses two lasers, one to detect color of sphere and one to identify the presence of the antibody/fluorochrome complex • Results reported as a number not titer 4. 2. 1. Spheres/Antigen + Pt’s serum DsDNA 3. Fluorochrome tagged antihuman IgG SSA RNP

  12. Important Points for Primary Care • Always order a reflexive panel • ANA particularly useful for Dx of 4 CTDs • SLE • Scleroderma (Diffuse/CREST) • Sjogren’s syndrome • Mixed connective tissue disease • Negative ANA and negative SSA essentially rules out SLE (sensitivity of doing both is 99% for Dx of SLE) • Rare Pt with mild SLE or Sjogren’s will be SSA only + • A low titer ANA ie 1:40 or 1:80 is generally clinically irrelevant as is an isolated low level result by multiplex assay • 20-30% Nl blood donors have ANA at 1:40; 12% > 1:80

  13. Important Points for Primary Care • ANA 1:160 or greater accompanied by other disease characterizing antibodies means disease is present or will be present • SLE Pts can have SLE antibodies present prior to the onset of clinical manifestations (mean 3.3 yrs range up to 9 yrs) • Specific ENA help characterize disease • Pts with high titer ANA plus other autoantibodies should be referred to rheumatology (other clues to CTD?) • Other autoimmune diseases can be associated with a positive ANA i.e. autoimmune thyroid diseases, PBC, autoimmune hepatitis, RA

  14. Other ANA Pearls • Anti-DsDNA & anti-Sm (Smith) are generally specific for SLE • Anti-DsDNA goes up and down with disease activity • Referral to a community rheumatologist with + ANA and no Dx – up to 50% will have a CTD Dx(approx 20% SLE), and 10% may have autoimmune thyroid disease • Pts with isolated + ANA and no disease: 5.6% will come to a Dx of CTD in 5 yrs(data reassuring) • Remember that the ANA has to make sense • Check an ANA when clinical symptoms and signs point to possible CTD Myckatyn J Rheum 2003;30:736

  15. Patient 1ANA 1:640 speckledSSA >100SSB 30DSDNA negSmnegRNP negRF 150 Patient 2ANA 1:320 homogeneousSSA >100SSB negDSDNA 632SmnegRNP 66RF neg ANA Profiles SLE Sjogrens

  16. Patient 3 ANA 1:320 speckledSSA neg SSB neg DSDNA negSmnegRNP > 100 RF 35 Patient 4 ANA 1:320 Nucleolar SSA neg SSB negDSDNA neg SmnegRNP neg SCL 70 >100 ANA Profiles Diffuse Scleroderma Mixed Connective Tissue Disease

  17. ANA Profiles Patient 5ANA 1:160 speckledSSA negSSB negDSDNA negSmnegRNP negRF neg Patient 6ANA 1:40 speckledSSA negSSB negDSDNA negSmnegRNP negRF neg Clinically insignificant ANA ANA in isolation

  18. References for ANA • Waits JB. Rational use of laboratory testing in the initial evaluation of soft tissue and joint complaints Prim Care Clin Office Pract2010;37:673–689 • Arbuckle MR et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. NEJM 2003;349:1526-1533 • Shel WC, Jason M. The diagnostic associations of patients with antinuclear antibodies referred to a community rheumatologist. J Rheumatol 1989;16:782-785 • American College of Rheumatology Position Paper on ANA testing www.rheumatology.org

  19. Pearl 3# Cold Hands or Raynaud’s Phenomenon? • A 55 y/o woman complains of 6 months of her hands being very uncomfortable in the cold. Notes that her fingers of both hands turn white when in cold. No report of skin changes in her fingers, joint swelling, difficulty swallowing, DOE,nor family history of Raynaud’s • Her general examination is normal • How would you evaluate thispatient?

  20. Step 1: Is it Raynaud’s Phenomenon? • Maurice Raynaud first described the manifestation that bears his name in 1862 • Vasospasm involving the digits, ears, nose with cold exposure OR emotional distress • Populations based survey: 12% report RP • Three phases: • Pallor related to initial vasoconstriction • Cyanosis due to severe flow restriction • Erythema due to rebound vasodilitation • Cold emersion test available when uncertain

  21. Step 2: Is it Primary or Secondary Raynaud’s • Primary Raynaud’s Criteria • Vasospastic attacks precipitated by cold or emotion • Symmetric attacks involving both hands • Absence of tissue necrosis or gangrene • No examination findings of secondary Raynaud’s • Normal nail-fold capillary exam • Normal ESR • Negative serologic findings in particular ANA • Median age of onset 14 yrs old; 27% onset after 40 yrs old • 2 yrs of PRP w/o manifestations of CTD; unlikely to be SRP

  22. Secondary Raynaud’s Phenomenon • Features that suggest secondary Raynaud’s: • RP after age > 30 yrs • Severe episodes that lead to ischemia • Nail fold capillary abnormalities • Positive ANA/disease-related antibodies • Clinical features of the below diseases • Diseases to consider: • Scleroderma specturm disease • Mixed connective tissue disease • Systemic lupus erythematosus • Dermatomyositis • Polymyositis

  23. Features of Secondary Raynaud’s • ANA features suggesting CTD • High titer ANA • Nucleolar pattern • Centromere pattern • High titer RNP • Elevated DsDNA

  24. NailfoldCapillaroscopy Normal Dilatation Dilatation Dropout Bizarre Loops Can also use ophthalmoscope

  25. Step 3: Evaluation for Secondary Raynaud’s • Careful history and exam • Nail fold exam (has the highest positive predictive value) • Laboratory studies • CBC, ESR • TSH • ANA reflexive panel • Consider SPEP, cryoglobulins, CPK • Medications & RP • Interferon, estrogen nicotine, tobacco, narcotics, cyclosporine, cocaine, ergotamines, clonidine, B blockers sympathomimetics • Environment & RP • Previous frostbite, repetitive vibration exposure, hypothenar hammer syndrome

  26. Step 4: Treatment of Raynaud’s Phenomenon • Mild PRP only may require exposure intervention • Central warmth • Windblock gloves • Good handwarmers • Crazy thermabands • Avoidance behavior • Nicotine • Caffeine • Meds that worsen • Biofeedback? • Medications • Ca channel blockers • Not verapamil • Losartan • Prazosin • Topical NTG • SSRIs • LD ASA with Ca blockers • 2 g/day of α-linoleic acid

  27. Take home primary care pearls • Primary Raynaud’s is common • Secondary disease is rare but common enough that with recent onset Raynaud’s, CTD should be considered • Unilateral Raynaud’s requires vascular evaluation • Treatment should begin with physical measures and avoidance of medications that can make disease worse • Referral for: • Evaluation suggests secondary Raynaud’s • Severe disease not responsive to usual therapy • Acute digit threatening ischemia

  28. Raynaud’s References • Wigley F. Raynaud’s Phenomenon. N Engl J Med2002;347:1001-1008 • LeRoyEC, Medsger TA Jr. Raynaud’s phenomenon: a proposal for classification. ClinExpRheumatol 1992;10:485-8. • M. García-Carrasco et al. Treatment of Raynaud’s Phenomenon. Autoimmunity Reviews 2008;8:62–68

  29. Pearl 5: Hyperuricemia: More than Just Gout • A 55 y/o male with a history of hypertension, type 2 DM, and CRI develops an acute left 1st MTP pain. Pain is so severe that he is unable to walk on it and even the bed sheets are painful. In the ED noted to have a red painful left 1st MTP and resists you trying to move the joint. • Laboratory tests show a normal CBC, creatinine is 1.9 mg/dl, uric acid is “normal” at 7.5 mg/dl, CRP is elevated at 20 mg/L • DDx?

  30. Treasure Chest of Gout Pearls • Most common form of inflammatory arthritis in men over 40; > 5 million affected; rare in women pre-menopause • A serum uric acid above 6.8 mg/dl is abnormal even if your lab says 8.5 mg/dl is normal! • Uric acid level may go down to normal during attack • Certain groups i.e. Pacific Islanders have genetic predisposition to gout • Very rarely other diseases produce podraga • Small joints of the hands and feet are RARELY septic unless directly invaded • Do I really need to aspirate that 1st MTP?? Acute Urate Gout IntervalHyperuricemia Tophaceous Gout

  31. Step 1: Treat the Acute Attack • NSAIDs • Potent short acting agent ieindomethocin • Oral Steroids • Need 30-40 mg with 5-10 day taper to affect inflammation • IM/IA steroids • Colchicine • Start within 24 hrs; 1.2 mg followed 1hr by 0.6 mg – done • Anakinra • IL-1 inhibitor works like miracle for complex hospitalized patients who can’t take standard medications • 100 mg SQ daily x 1-3

  32. What causes the tiny crystals to cause so much pain? Answer: the innate immune system • Uric acid supersaturates, crystallizes and is recognized by inflammatory cells via Toll-like receptors • Inflammatory mediators, in particular IL-1, produced and lead to rubor, calor, dolor

  33. Step 2: Modify Risk Factors • Avoid certain medications • Avoid beer/ale • Encourage slow wt loss • Discuss a low purine diet and one low in fructose • Medications to avoid • Diuretics • Niacin • Calcinurin inhibitors • LD ASA • Laxatives in excess • “Medications” that help • Vitamin C • Losartan • Statins • Dairy products

  34. Step 3: Decisions Regarding Hypouricemic Therapy • Reasons to consider hypouricemic therapy • > 2 attacks/year, tophi, kidney stones, chronic persistent gout • CKD, CAD?? • Hypouricemic agents • Allopurinol - 100-800 mg/d; rash, hypersensitivity syndrome; reduce dose of azathioprine to 1/4 • Febuxistat - 40-80 mg/d; liver toxicity, azathioprine issue • Probenecid - 250-1000 mg BID; use with meals and hydration; decrease elimination of meds ie PCN • Lowering uric acid INCREASES risk of gouty attack • Use colchicine prophylaxis where possible 0.6-1.2 mg/day • If unable to use provide Pt with as need use predisone,

  35. 2012 ACR Guidelines for the Treatment of Gout • Educate patient on diet, lifestyle, and treatment objectives • Xanthine oxidase inhibitors are first line therapy • Treat to target ie < 6 mg/dl (< 5 if tophi present) • Starting dose of allopurinol should e no greater that 100 mg/day and less than 100 mg/day in Pts with CKD; slow upward titration that could exceed 300 mg/day even in CKD • Screen for HLA B5801allele in Koreans with CKD and all Pts of Thai and Han Chinese descent BEFORE starting allopurinol due to risk of severe hypersensitivity • Can combine uricosuric agent with XOI • (Pegloticase (pegolateduricase) can be used in severe gout)

  36. 1984 Hande guidelines for renal dosing of allopurinol based on concern for drughypersensitivity not renal toxicity • Severe hypersensitivity reactions are not dose dependent; may not correlate with oxypurinol levels.Puig. J. Rheumatol 16:842-844, 1989 • No increase in allopurinol SE in pts receiving higher than Hande recommended doses.Vazquez-Mellado. Ann Rheum Dis 60:981-983, 2001 • Following Hande guidelines led to suboptimal control of hyperuricemia & did not prevent hypersensitivityDalbeth. J Rheumatol 2006;33: 1646-1650 • Gardner’s guideline: Go low go slow and treat to SUA level

  37. Gouty Tophi

  38. Bad Tophaceous Gout

  39. Tophi + Allopurinol + Patience = Success

  40. Summary of Some of the Recent Information on Uric Acid and Inflammation Xanthine Oxidase is a superoxide producing enzyme; allopurinol inhibits XO and thus has antioxidant properties by preventing generation of free radicals Filiopoulos et al Renal Failure 2012

  41. Hyperuricemia and CKD/CAD • Emerging literature on the role of hyperuricemia and progression in CKD • Control of hyperuricemia can improve BP • Control of hyperuricemia slows/halts progression of CKD • Uric acid level is an independent risk factor for all cause mortality in men and women with a known history of CAD as well as an independent risk factor for CHF • Hyperuricemia affect may be more pronounced in African Americans

  42. Outcome of BP/Creatinine at 12 mo using allopurinol to normalize hyperuricemia in Pts with CKDSiu et al. Am J Kidney Dis 2006;47:51-59 • 54 pts randomized and followed for 12 months. • Initial UA in Rx group 9.75 & trial end 5.88; control group 9.92 vs 10.08 • 84% Rx group stable renal function vs 53% control group

  43. Hyperuricemia and Mortality 2013 • 1054 Pts with known CAD followed > 3 yrs and all cause mortality evaluated by quartiles of UA • 79% male • Mean age 65 yrs • Unadjusted and adjusted mortality evaluated Lin et al. J Cardiology 2013

  44. Take Home Points • More reasons for gouty Pts to lower uric acid level than just gout • Role of xanthine oxidase inhibitors and CKD/CAD to be further elucidated • Not quite ready to lower UA primarily to address CKD/CVD but certainly do for pts with gout • Old thinking about simply treating gouty attacks until tophi appear then instituting hypouricemic therapy is out of date and not in Pts best interest

  45. References for Hyperuricemia and Gout • Terkeltaub R. Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol 2010;6:30-38 • Filiopoulos V, et al. New insights into Uric acid effects on the progression and prognosis of chronic kidney disease. Renal Failure 2012;34:510-520. • Bhole V Krishnan E. Gout and the heart. Rheum Dis Clin NA 2014;40:125-143.

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