Pennsylvania Academy of Family Physicians Foundation & UPMC 43rd Refresher Course in Family Medicine CME Conference March 10-13, 2016 Disclosures: Gout and Pseudogout Wayne Blount MD Speaker has no disclosures and there are no conflicts of interest. The speaker has attested that their presentation will be free of all commercial bias toward a specific company and its products. The speaker indicated that the content of the presentation will not include discussion of unapproved or investigational uses of products or devices.
Gout & PseudoGout (Pain & More of the Same) BY B. WAYNE BLOUNT, MD, MPH JenCare 1 Disclosure The speaker has no conflict of interest, financial agreement, or working affiliation with any group or organization. 2 Learning Objectives 1. Describe the pathogenesis of gout. 2. Implement a plan for the diagnosis and treatment of all 4 stages of gout: including aborting flares, preventing flares, & preventing chronic complications. 3. Review special considerations for select patient populations 4. Distinguish pseudogout from gout in etiology, Dx, & treatment. 3 1
Why worry about gout? Prevalence increasing (3.9%) Most common inflammatory Arthritis: 3.9% of adults May be signal for unrecognized comorbidities (Not to point of searching) Obesity Metabolic syndrome DM HTN CV disease Renal disease 4 Urate, hyperuricemia, & gout Urate: end product of purine metabolism Hyperuricemia: serum urate > urate solubility (> 6.8 mg/dl) Gout: deposition of monosodium urate crystals in tissues 5 Two pathologic mechanisms cause hyperuricemia Overproduction Underexcretion Which one is the predominant cause (in 90% of patients)? Underexcretion 6 2
Gout: a chronic disease of 4 stages Asymptomatic hyperuricemia Acute flares of crystallization Intervals between flares Advanced gout & complications 7 Asymptomatic hyperuricemia Most people with hyperuricemia never develop clinical gout. In those who do, hyperuricemia can last 20 years before an initial attack. Onset before age 35 is often related to an inherited defect or a strict protein diet. 8 2 nd Stage: acute flares 2 nd stage of gout is heralded by the 1 st acute attack 90% of 1 st attacks are monoarticular; any joint is a possibility % are podagra 50 9 3
Acute gouty flares Abrupt onset of severe joint inflammation, often nocturnal Warmth, swelling, erythema, & pain; possibly fever Untreated? Resolves in 3-10 days 10 3 rd Stage: intervals sans flares Asymptomatic If untreated, may advance Intervals may shorten Crystals in asx joints Body urate stores increase 11 4 th Stage: Advanced gout Chronic arthritis X-ray changes Tophi develop Acute flares continue Polyarticular acute flares with upper extremities more involved Avg. time from initial attack to chronic gout is 11.6 yrs. 12 4
Tophi Solid urate deposits In tissues Irregular & destructive 13 Diagnosing gout Hx & PE Synovial fluid analysis Not serum urate Clinical diagnosis? 14 Synovial fluid analysis (polarized light microscopy) The gold standard Crystals intracellular during attacks Needle & rod shapes Strong negative birefringence 15 5
Synovial fluid 16 Differential diagnosis Pseudogout Chondrocalcinosis CPPD Psoriatic arthritis Osteoarthritis Rheumatoid arthritis Septic arthritis Cellulitis 17 Clinical Dx Typical presentation Use colchicine in a typical presentation Familial Mediterranean fever (now also pericarditis) Ultrasonography use is increasing New rule for Dx: next slide 18 6
Rule for clinical Dx Used when joint fluid analysis is not an option Validity of 85% Score of > 8 :+PV =.87 Score < 4; -pv=.95 Kienhorst L. Rheumatology, Sept 16, 2014 Scoring: Male 2 Pts Previous attack 2 Pts Onset < 1 Day ½ Pt Joint redness 1 Pt 1 st MTP involved 2½ Pts HTN or another CV Dz 1½ Pts Urate > 5.88 mg 3½ Pts 19 Treatment goals Rapidly end acute flares Protect against future flares Reduce chance of crystal inflammation Prevent disease progression Lower serum urate to deplete total body urate pool 20 Ending acute flares Control inflammation, pain, & resolve the flare Not a cure Crystals remain in joints Choice of med not as critical as alacrity (within 24 hrs) & duration(?) EBM At least 3 days; usually 5-7 days (or 1-2 days after Sx relief) 21 7
MED considerations NSAIDs: Interaction with warfarin Contraindicated in: Renal disease PUD GI bleeders Any NSAID can work at full doses ASA-induced RAD CHF 22 MED considerations Colchicine: Not as effective late in flare (>72 hrs) Only 1 branded agent on US market now: $$ Now have generic Contraindicated in dialysis pts Cautious use in: renal or liver dysfunction; active infection, age > 70 Numerous Meds increase serum colchicine: Statins, digoxin, macrolides, -azoles, CCBs, grapefruit Loading dose = 1.2 mg; then 0.6 mg 1 hr. later 23 MED considerations Corticosteroids: Worse glycemic control Oral, intraarticular (esp. in monoarticular flare), or parenteral May need to use mod-high doses. New Guidelines suggest 10 mg/day: I disagree Needs to be higher: > 20 mg Useful in patients who have contraindications to NSAIDs & colchicine 24 8
General considerations All anti-gout meds, EXCEPT Uloric, can potentiate warfarin ACEIs may increase risk of allergic reaction to allopurinol Colchicine can have a rare A.E. of myotoxicity; esp. aged 50-70, with CKD, or cardiac transplant 25 Treatment goals Rapidly end acute flares Protect against future flares Prevent disease progression Lower serum urate to deplete total body urate pool 26 Protection vs. future flares Colchicine: 0.6-1.2 mg/day (0.3 if CRI) Low-dose NSAIDs (E.G. 25 mg of indomethacin or 250 mg of naproxen) Both decrease freq. & severity of flares Prevent flares with start of urate-lowering RX Best with 6 mos of concomitant Rx; >3 months w/o flare or > 3 mos after urate < 6.0 & no tophi EBM: B Won t stop destructive aspects of gout 27 9
Use of colchicine Only drug approved by FDA for preventing acute flares Used as 0.6 mg Q day or BID for 6 months EBM: B; (3% flares vs. 40%) A.E.s: Diarrhea, LFTs, HA Start the prophylactic dose 12 hrs. after the 2 nd dose for the acute flare 28 New evidence for preventing flares Cherry intake lowers risk for flares by 35% Cherry extract intake lowers risk for flares by 45% Allopurinol alone reduces risk by 53% Allopurinol & cherries together reduced it by 75%?Anti-inflammatory and/or reduce urate reabsorption in kidneys 29 Treatment goals Rapidly end acute flares Protect against future flares Prevent disease progression Lower serum urate to deplete total body urate pool 30 10
Urate-Lowering Therapy (ULT) Not to be started during an acute attack? New ACR guidelines say can start it right away if still on a flare med. Two good studies support this. Difference of opinion on whom to start ULT Everyone with Gout? Not in patients with only 1 attack & no complications (tophi, CRI, stones, or diuretic use) Shared Decision Definitely all patients with 3 attacks or tophi or urolithiasis or CKD > stage 2 31 Prevent disease progression Lower urate to < 6.0 mg/dl: This depletes total body urate pool & deposited crystals EBM: A Rx is lifelong & continuous MED choices: Uricosuric agent Xanthine oxidase inhibitor Uricase 32 Conservative measures to lower urate Diet: Reduce purines Alcohol: Cut Obese?: Lose Weight Avoid meds that cause inc. urate: thiazides, loops, niacin Stay hydrated Exercise regularly Avoid drinks with high fructose corn syrup Eat more veggies: lower urate 33 11
Above Conservative measures to lower urate The above measures will lower urate by 10-15% Avg. starting level is 9.5 10 Rarely get to < 6.0 with these measures, but they help 34 Uricosuric agents Probenecid: The only FDA approved one Avoid in pts with lithiasis or Ccl < 50 ml/min Losartan & fenofibrate for mild disease Vitamin C supplements Increased secretion of urate into urine (increases stones) Reverses most common physiologic abnormality in gout (90% pts are underexcretors) 1/3 patients discontinue it Increases levels of methotrexate & ketorolac 35 Xanthine oxidase inhibitor Allopurinol, oxypurinol, or febuxostat: Block conversion of hypoxanthine to uric acid Effective in overproducers Also effective in underexcretors Can work in patients with renal insufficiency 36 12
Which agent Past: Based choice on whether pt was an overproducer or underexcretor : Needed a 24-hr. urine for urate excretion: < 700 --- underexcretor (uricosuric) > 700 --- overproducer (allopurinol) NO!!! 37 New evidence Xanthine Oxidase Inhibitors are now the 1 st choice for U.L.T.: Either allopurinol or febuxostat ACR guidelines WHY? 38 Allopurinol Allopurinol may lower all-cause mortality & C.V. events; EBM: C In CKD, allopurinol may slow progression of CKD; EBM: C Adjust dose in CKD Remember AEs; esp. allopourinol hypersensitivity syndrome. (0.1%) If rash, stop med, and come in. (!CKD & diuretics!) Lowering sua is dose-dependent : Achieved goal sua: 26% @ 300 mg/day vs. 78% @ 300 mg BID 39 13
Using allopurinol Treat to Goal Start at 100 mg/day (higher starting dose can increase risk for AHS) 50 mg/day in stage 4 CKD patients Gradually titrate up by 50-100 mg/day every 2 5 weeks Slower titration in CKD Treat to Goal (Lowest dose that gets < 6.0) Lowering urate too quickly can trigger a flare 40 Using allopurinol Treat to Goal Goal is Serum urate < 6 mg/dl Most patients will need > 300 mg/day of allopurinol to achieve this goal 41 New recommendation To reduce allopurinol toxicity, consider HLA- B*5801 screening patients @ high risk: Koreans > Stage 3 CKD & patients of Han Chinese & Thai descent All 42 14
Pseudogout Can cause monoarthritis; clinically indistinguishable from gout. Often precipitated by illness, surgery, trauma, or dehydration. Pseudogout is most common in the knee (50%) and wrist. Reported in any joint (including MTP). CPPD disease may be asymptomatic (deposition of CPP in cartilage). 43 Pseudogout Also called CPPD: Calcium PyroPhosphate Disease Caused by precipitation of calcium pyrophosphate dihydrate crystals in joints Limited to joints 1 st in joint cartilage; move to synovium; then into joint fluid where inflammation ensues Reason CPP deposits is UNK 44 Pseudogout Chondrocalcinosis is CCP crystals in joints sans Sx. (50% of 90 Y.O.s) Occasionally coexists with gout Prognosis: Good Presentation: Same as gout 45 15
Risk Factors Older age Excess Iron Stores History of joint trauma (hemochromatosis) Hyperparathyroidism Amyloidosis Hypomagnesemia Gout Genetics:? which Degenerative arthritis Dehydration Dehydration + surgery + elderly!! 46 Diagnosis Joint fluid analysis (polarized microscopy) Look for positively birefringent rhomboid crystals X-Rays: If see chondocalcinosis in an inflamed joint: maybe. But Chondrocalcinosis can coexist with other causes of inflamed joints 47 Gout vs. CPPD 48 16
Acute Treatment Colchicine: Same dose as gout NSAIDs: none preferred Use full strength Steroids Intra-articular Systemic Aspirate fluid from Joint Limit ROM & wgt bearing 49 Chronic Treatment Same as for DJD Hydration Treat Underlying disease ( Hyperparathy; Hemochromatosis) Nothing to lower CPP Daily colchicine? Daily low- dose NSAID? 50 Practice recommendations Use the correct criteria to diagnose gout or pseudogout Know and use in practice the 4 stages of gout Know the meds that work in each stage Allopurinol is 1 st line for ULT Overlap flare prevention with ULT Watch for & advise of T.E.N.S. Set a goal of < 6.0 for the serum urate level for gout patients 51 17
Thank you! 51 Bibliography Hainer BL et al. Dx, Rx & Prev of Gout. Am Fam Phy.2014;90: 831-6. JFP. June 2012; vol 61, No 6. S11-S16. Zhu Y, et al. Ptrevalence of Gout & Hyperuricemia in the US General Population. Arthritis Rheum. 2011;63:3136-41. Hamburger M, et al. Recommendations for the diagnosis & management of gout & hyperuricemia. Postgrad Med. 2011;123:3-36. Cochrane database. Neogi T, et al. All Alcohol, even wine, raises risk of gout. Am J Med. 2014; Stamp LK. Szfety Profile of Anti-gout Agents. Curr Opin Rheumatol. 2014;26:162-168. 53 Bibliography Burns C et al. Gout Therapeutics: new drugs for an old disease. Lancet. 2011;377:165-77. Burns C et al. Clinical Features & treatment of gout. In Firestein, G (ed), Kelley s Textbook of Rheumatology, 9 th ed. 2012. New York: WB Saunders. Arthritis Care Res. Oct. 2012;64:1447-61 ACR Guidelines for Pharmacologic & Nonpharmacologic Treatment of Gout. AFP. 2013;88:408-12. Hill E, et al. J Clin Rheumatol. 2015;21(3):120-125. 54 18
Bibliography Richette P, Bardin T. Gout. Lancet 2010;375:318-28. So A, Thorens B. Uric Acid transport & disease. J Clin Invest 2010;120:1791-9. Reach G. Treatment adherence in patients with gout. Joint Bone Spine 2011;78:456-9. Baker JF, et al. Update on gout & hyperuricemia. Int J Clin Pract 2010;64:371-7. Sundy JS. Progress in the pharmacotherapy of gout. Curr Opin Rheumatol 2010;22:188-93. Sivera F, et al. Multinational Evidence-Based Recommendations for the Dx & Rx of Gout. Ann Rheum Dis. 2014;73:328-35. 55 Question & Answers B. Wayne Blount, MD, MPH bwbloun@emory.edu benroe.blount@jencaremed.com 56 Febuxostat Xanthine oxidase inhibitor Does lower sua May slow renal disease progression Dose: 40 mg or 80 mg Q day. Start low and increase as tolerated if needed AEs: LFTs Best candidate may be pt intolerant of allopurinol, not controlled with other ULT, or CRI; preferred over uricosurics in patients with lithiasis. Can use in patients with AHS. $$ 57 19
Febuxostat You may have heard it is more effective than allopurinol: Wait! The study was done with doses commonly used. Febuxostat was used at effective doses. Allopurinol was not used at effective doses. Study also funded by maker of febuxostat. Singh J, et al. Arthritis Res Ther. 2015, 17:120 58 Uricase Only 1 in U.S.: Pegloticase Given by I.V. infusion every 2 weeks Steroids & H1 blocker before RX Even with prophylaxis, flares will occur 25% patients have serious AE: inc. anaphylaxis Not in G6PD patients A urate debulking agent I would let my subspecialty consultants use this med for now in limited patients A 3 rd line agent 59 $$$ Future agents RX gaps Can t always get urate < 6 Allergies Drug interactions Allopurinol intolerance Worse renal disease 60 20
Future agents IL-1 inhibitors IL-1: an important mediator of the early inflammatory response to urate crystals Proof of concept established for both treatment and prophylaxis of flares In Development: stay tuned Better uricosurics: selective urate reabsorption inhibitor 61 Gout risk factors Male Postmenopausal female Older Hypertension DM HLD Pharmaceuticals Diuretics ASA Niacin Cyclosporine 62 Gout risk factors Transplant Alcohol intake Highest with beer High BMI (obesity) Diet high in meat & seafood High Fructose corn syrup sweetened drinks (not diet drinks) Dairy products may decrease risk 63 21
Sites of acute flares % of gout patients eventually have podagra: 1st MTP joint 90 64 Other comorbidities to check for when a pt. has gout Lead toxicity ( by Hx) Hx of urolithiasis CKD 65 General considerations Patients with repetitive flares can be instructed to start flare med at home w/o consulting physician. Can use ice. Choose monotherapy based on patient's preference, previous response and assoc. comorbidities. May need combination med Rx in a flare; esp. if < 20% relief in 24 hrs. 66 22
New recommendation from ACR For Gout To get to goal, can use combination of xanthine oxidase inhibitor & uricosuric 67 CASE STUDIES 68 CASE J.F. 80 yo W F c/o acute overnight pain and swelling in R knee PE: 5 1 and 180 lbs. R knee swollen, warm, and erythematous PMH: HTN x 5 yrs Meds: HCTZ (25 QD) & ASA SH: 20 PY smoker; 5 wine drinks/wk 69 23
What are J.F. s risk factors for gout? HTN Smoker HCTZ ASA Wine consumption Obesity Age Postmenopausal 70 How would you Dx gout? Hx and PE compatible Check serum urate level Assess synovial fluid Trial of colchicine Check x-rays 71 IF you Dx gout, which Rx today? (Why?) Motrin Indomethacin Prednisone Allopurinol Probenecid Colchicine 72 24
Modify risk factors Next step for J.F.? Give refills to Rx next flare Start colchicine to prevent flares Check serum urate level Start allopurinol Start probenecid 73 Case M.B. 56 YO W M c/o hand stiffness & growths PE: 6 2 and 205 lbs. Multiple tophi; chronic arthritis PMH: DM x 8 yrs.; gout x 4 yrs., but no flares x 3 yrs., & lost 20 lbs. on Atkins diet Meds: Glyburide; colchicine (0.6 mg TID) Labs: Creat. = 2.0; Urate = 11.4 74 In what stage of gout is M.B.? Doesn t have gout ASX. hyperuricemia Interflare period Advanced gout 75 25
Would you change MD s Rx? No Not gout No No flare x 3 yrs. Yes - Increase colchicine Yes Add allopurinol Yes Add probenecid 76 What other issues would you consider? Renal dysfunction Weight DM Glyburide Diet 77 26