COPYRIGHT. Update in Internal Medicine December 4, 2016

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1 Update in Internal Medicine December 4, 2016 Fadi Badlissi, MD, MSc Director of the Musculoskeletal Medicine Unit The Orthopedic Department & Rheumatology Division Beth Israel Deaconess Medical Center Assistant Professor of Medicine Harvard Medical School

2 Disclosure No conflicts

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4 50% Increase in Prevalence 3.0 million had self-reported gout in 2007 up from 2.1 million in 1995» Lawrence RC, et al. Arthritis Rheum 2008 Estimate in US adults 3.9% 8.3 million» Zhu U, et al. Arthritis Rheum ,920-4,946 adult rheumatologists in the US» Deal CL, et al. Arthritis Rheum 2007» American College of Rheumatology, Workforce and Training Committee 2010

5 American College of Rheumatology, Workforce & Training Committee 2010

6 Internists Can Help Tremendously Recognizing gout They can treat and prevent at least 80% of gout Optimal use of uric acid lowering agents when indicated In combination with suppressive agents initially

7 What is Gout? Gout is hyperuricemia and extracellular urate saturation leading to monosodium urate crystal deposition Acute inflammatory arthritis Chronic arthropathy Tophaceous deposits of urate crystals Uric acid nephrolithiasis Chronic nephropathy

8 Q1 40 yo male presented for the first time with acute painful swollen big toe On exam erythema, swelling and excruciate tenderness Courtesy of Jonathan S. Hausmann, MD

9 Q1 What will you do? Choose the most appropriate answer A. Aspirate the first MTP joint B. Inject the first MTP joint with corticosteroids C. Prescribe antibiotics D. Treat with non steroidal anti-inflammatory drugs (NSAIDs)

10 A1 What will you do? A. Aspirate the first MTP joint B. Inject the first MTP joint with corticosteroids C. Prescribe antibiotics D. Treat with non steroidal anti-inflammatory drugs (NSAIDs)

11 Clinical Presentation 5 th century BC Hippocrates podagra, Gutta drop Podagra [pəˈdægrə], gout of the foot or big toe [via Latin from Greek, from pous/pod foot + agra a trap] 1 st MTP > mid foot > ankle Monoarticular > oligoarticular > polyarticular

12 Diagnosis Clinically suspected based on history and exam Diagnosis is confirmed by arthrocentesis showing monosodium urate crystals Adapted from the ACR Teaching Slide Collection

13 Alternatively, diagnosis may be based upon fulfillment of six or more of the following criteria from the American College of Rheumatology (ACR) Diagnosis Adapted from the ACR Teaching Slide Collection

14 The American College of Rheumatology Criteria for Gout 1. More than one attack of acute arthritis 2. Maximum inflammation developed within 1 day 3. Monoarthritis attack, redness observed over joints 4. First metatarsophalangeal joint painful or swollen 5. Unilateral first metatarsophalangeal joint attack 6. Unilateral tarsal joint attack 7. Tophus (confirmed or suspected) 8. Hyperuricemia 9. Asymmetric swelling within a joint on x-ray film 10.Subcortical cyst without erosions on x-ray film 11.Joint culture negative for organism during attack» Wallace SL, et al. Arthritis Rheum 1977

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16 2015 Gout Classification Criteria An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative Neogi T, et al. Arthritis Rheum 2015

17 When To Aspirate? To rule out infection New presentation of inflammatory arthritis, other than podagra Atypical presentation Diagnose and treat with one procedure

18 Laboratory Data Synovial fluid MSU crystals WBC > Neutrophils dominant Uric acid level NOT reliable during a gout attack

19 Imaging & Diagnosis

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21 Ultrasound is More Sensitive in Detecting Erosions than X-ray and Able to Identify Tophi Snow like appearance tophus Double contour sign, MSU crystals deposits Erosion Ottaviani S, et al. Joint Bone Spine

22 Which NSAIDs would you choose to treat that patient? Do you have to use Indomethacin?

23 NSAIDs Probably Have Equal Efficacy There is no evidence that indomethacin is superior to other NSAIDs for acute gout Two noninferiority studies showed indomethacin was as efficacious as etoricoxib and was associated with more adverse effects» Schumacher HR Jr, et al. BMJ 2002» Rubin BR, et al. Arthritis Rheum 2004

24 Q2 75 yo female hospitalized for sepsis complicated with acute on chronic renal failure (Cr 4.5). She developed an acute onset swelling in her left knee. You were consulted to discuss diagnostic approach and treatment On exam temp 100.5, large L knee effusion with warmth, tenderness, painful range of motion

25 Q2 What will you do to establish the diagnosis and for treatment? Choose one answer A. Aspirate B. Aspirate and inject with corticosteroids once infection is ruled out C. Oral corticosteroids D. Low dose colchicine E. NSAIDs

26 A2 What will you do? A. Aspirate B. Aspirate and inject with corticosteroids once infection is ruled out The Synovial fluid showed WBC, 95% PMN, +MSU crystals, G stain/cx were negative C. Oral corticosteroids D. Low dose colchicine E. NSAIDs

27 Treatment, Acute Gout NSAIDs Colchicine Low dose 1.8 mg vs. high dose 4.8 mg, 38%, 33% and 16% (placebo) achieved > 50% pain reduction within 24 h Diarrhea 23%, 77% and 16 %» Terkeltaub R, et al. Arthritis Rheum 2010 Corticosteroids Parenteral, oral Intraarticular Pain Control IL-1 blockade

28 canakinumab rilonacept anakinra

29 Anti IL-1 Therapy, Canakinumab Canakinumab, a fully human antiinterleukin-1β monoclonal antibody Effective somewhat in the treatment of acute gout and preventing gout flares while initiating treatment with allopurinol compared to colchicine»so A, et al. Arthritis Rheum 2010»Schlesinger N, et al. Ann Rheum Dis 2011 Canakinumab was rejected (June 2011) by the FDA out of concerns regarding elevation in uric acid levels, triglycerides and creatinine

30 Anti IL-1 Therapy, Rilonacept Rilonacept, a soluble IL-1β receptor-fc fusion protein Effective in reducing gout flares during initiation of urate-lowering therapy compared to placebo» Schumacher HR Jr, et al. Arthritis Care Res 2012 The FDA requested additional clinical data on Rilonacept (May 2012)

31 Q3 56 yo male with history of podagra once every couple of years, he was told in the past that he has gout. He usually takes Indocin for few days when he has an attack At times he has milder joint pain and swelling for which he starts taking Indocin right away On exam

32 Q3 What will you do? Choose the most appropriate answer A. NSAIDs B. Allopurinol 300 mg C. Allopurinol 100 mg with colchicine 0.6 mg or NSAIDs daily D. Colchicine 0.6 mg daily E. Febuxostat

33 Q4 The patient comes back complaining that he has been having more gout flare ups since he started the allopurinol and he stopped it for the past week. What should you do? Choose the most appropriate answer A. Restart allopurinol at a lower dose B. Restart allopurinol and add colchicine C. Increase the dose of allopurinol D. Switch to febuxostat

34 A4 The patient comes back complaining that he has been having more gout flare ups since he started the allopurinol and he stopped it for the past week. What should you do? A. Restart allopurinol at a lower dose B. Restart allopurinol and add colchicine C. Increase the dose of allopurinol D. Switch to febuxostat

35 A3 What will you do? A. NSAIDs B. Allopurinol 300 mg C. Allopurinol 100 mg with colchicine 0.6 mg or NSAIDs daily D. Colchicine 0.6 mg daily E. Febuxostat

36 Suppressive Therapy with Uric Acid Lowering Rx NSAIDs versus colchicine Corticosteroids For how long? 3-6 months after: Not having clinical attacks Reaching a stable dose of allopurinol with uric acid < 6 mg/dl Possibly longer in patients with tophi

37 Indications for Uric Acid Lowering Agents Recurrent attacks 2 per year (A) Tophaceous gout (A) Urate Nephrolithiasis (C)? Gout with CRI (C)» Khanna D, et al. Arthritis Care Res 2012 (American College of Rheumatology guidelines) Debilitating attack, polyarticular gout or patient preference Evidence of joint damage

38 Target Uric Acid < 6 mg/dl ( µmol/l) Uric acid is a weak acid It presents in the plasma as urate The solubility of urate is temperature dependent The saturation threshold is 6.8 mg/dl at 37C» Fiddis RW, et al. Ann Rheum Dis 1983

39 Relationship Between Uric Acid Level and Incidence of Gout Campion EW, et al. Am J Med 1987 Campion EW, et al. Am J Med 1987

40 Allopurinol versus Febuxostat Allopurinol is cheaper and effective Ability to titrate allopurinol up to 800 mg daily A longer safety record with allopurinol

41 Is Febuxostat more Effective than Allopurinol? Febuxostat is a non-purine selective xanthine oxidase inhibitor Two phase III clinical trials showed that febuxostat was more effective than allopurinol 300 mg in reducing the uric acid (sua) level to below 6 mg/dl (40-60% vs 20%) Open extension up to 40 months, 80% of subjects on febuxostat compared to 46% on allopurinol maintained a sua level <6 mg/dl Be cautious in interpreting the results, as they compared febuxostat to a maximum of 300 mg of allopurinol» Becker MA, et al. N Engl J Med 2005» Schumacher HR Jr, et al. Arthritis Rheum 2008» Becker MA, et al. J Rheumatol 2009

42 Allopurinol 100 mg as a Starting Dose A case controlled study suggested increased risk of hypersensitivity to allopurinol when used in a dose higher than 1.5 mg per ml of GFR» Stamp LJ, et al. Arthritis Rheum 2012 A retrospective study of a Tai population estimated the annual incidence of hypersensitivity reaction in at 4.68/1000 with a mortality of 0.39/1000 Risk factors, initial dose > 100 mg, asymptomatic hyperuricemia with renal insufficiency (odds ratio [OR], 1.61; 95% CI, ; P <.001), or with cardiovascular diseases (OR, 1.52; 95% CI, ; P <.001)» Yang CY, et al. JAMA Intern Med 2015

43 Target Uric Acid < 6 mg/dl 360 Urate saturation µmol/l No recurrent gout attacks Monitor liver function tests, complete blood counts and creatinine Start two weeks after the resolution of the attack

44 Q5 75 yo male with clinical diagnosis of gout and chronic renal insufficiency (Cr 2-2.5) on stable dose of allopurinol 300 mg daily. He was hospitalized due to the flu in February The hospital pharmacy recommended adjusting the allopurinol dose to 200 mg due to his renal insufficiency

45 Q5 What will you do? Choose the most appropriate answer A. Decrease the allopurinol to 200 mg B. Decrease the allopurinol to 200 mg and add colchicine C. Ignore the pharmacy recommendations and keep him on 300 mg D. Switch to febuxostat

46 Q5 continued And his allopurinol was adjusted to 200 mg The following month he presented with bilateral wrists and hands pain and swelling, aspiration 12,000 WBC, PMN 95%, no crystals, he was taken to the OR for bilateral wrist debridement and R/O septic arthritis There is no need to adjust the allopurinol dose for renal insufficiency as long as it is tolerated and you are monitoring for adverse reactions

47 A5 What will you do? A. Decrease the allopurinol to 200 mg B. Decrease the allopurinol to 200 mg and add colchicine C. Ignore the pharmacy recommendations and keep him on 300 mg D. Switch him to febuxostat

48 When to Use a Uricosuric agents: Probenicid Normal renal function Could be combined with allopurinol or febuxostat to reach Uric acid < 6 mg/dl Always check 24 hour uric acid level if > 700 mg avoid probenicid due to the risk of nephrolithiasis Benzbromarone might be effective in moderate renal insufficiency, was withdrawn from the US market due to liver toxicity

49 Urate transport mechanisms in human proximal tubule.urat1oat1oat3mrp4u. Choi H K et al. Ann Intern Med 2005;143: by American College of Physicians

50 Lesinurad, CLEAR 1 & 2 Two phase III trials compared combination of 200 or 400 mg of lesinurad with allopurinol vs. allopurinol alone mg in 1200 subjects UA < 6 was achieved at month six in 28-23%, 54-55% and 59-67% in ALL+PBO, ALL+LESU 200, and ALL+LESU 400 respectively Increased of 1.5x in Cr of 1-3%, 6%, 15% in ALL+PBO, ALL+LESU 200, and ALL+LESU 400 respectively» Saag, KG, et al. Ann Rheum Dis 2015» Bardin, T, et al. Ann Rheum Dis 2015

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52 N. Dalbeth et al. Ann Rheum Dis 2015;74: by BMJ Publishing Group Ltd and European League Against Rheumatism

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54 SUMMARY Livers of Dalmatian dogs excreting large amounts of uric acid are rich in uricase. No correlation was found between the amount of uricase present in the liver and the destruction of uric acid in vivo. Actively respiring liver slices were observed to have less uricolytic activity than ground liver suspensions. No uricase was found in kidney, muscle, or spleen of the dogs examined.

55 Pegloticase Intravenous pegloticase (PGL), a pegylated recombinant mammalian uricase Effective in reducing uric acid and clearing tophi In patients who could not tolerate the other uric acid lowering agents Prescribed by rheumatologists High rate of infusion reactions and gout flares» Sundy JS, et al. JAMA 2011

56 Quick & Pragmatic Guide for Uric Acid Lowering Agents Start two weeks after the resolution of the attack Always with suppressive Rx Titrate slowly for target uric acid <6 mg dl Never stop or decrease unless it is a must Check 24 hour urine uric acid before initiating uricosuric agents (700 mg) If significant CRI skip uricosurics

57 Drugs in the Pipes Diaz-Torne C, et al. Curr Opin Rheumatol 2015

58 New Drugs Topiroxostat, xanthine oxidase inhibitor (XOR), available in Japan BCX4208 (Ulodesine), purine nucleotide pohsphorylase inhibitor (PNP), used in combination with allopurinol, phase II

59 New Uric Acid Renal Transporter (URAT1) Inhibitors With Dual Effects BMX-102 (Arhalofenate), URAT1, OAT4 & OAT10, phase II KUX-1151, URAT1 & XOR, phase II RLBN1001, URAT1, XOR, Glu9b, phase I

60 Poiley J, et al. Arthritis Rheum 2016

61 Poiley J, et al. Arthritis Rheum 2016

62 61% in the allopurinol without colchicine arm, & 35% in the arhalofenate 800 mg arm experienced a flare

63 Poiley J, et al. Arthritis Rheum 2016

64 Gout Therapy: Lost in Translation? Podagra [pəˈdægrə] pous/pod foot + agra a trap]

65 When to Refer to a Rheumatologist The diagnosis is not clear initially If you question the diagnosis later on, or you suspect another form of inflammatory arthritis Inability to control the disease Frequent flare ups Persistent Uric acid > 6 mg/dl Patient can not tolerate many medications

66 Untreated Gout Associated with Renal Insufficiency A study of 2116 men in a veterans population with gout and hyperuricemia for a mean follow up of 6.5 years Higher rates of renal insufficiency in subjects with high serum uric acid level (sua > 7 mg/dl) at year 1, 2, and 3, compared to those with low sua (4% versus 2%, 6% versus 3%, and 9% versus 5%, respectively; p<0.0001) Uncontrolled sua was associated with a risk of renal disease (adjusted HR 1.43, 95% CI )» Krishnan E, et al. J Rheumatol 2013

67 Hyperuricemia and Increased Cardiovascular Mortality Uric acid > 7.0 mg/dl was associated with cardiovascular mortality in over 70 without cardiovascular disease, diuretic use or severe renal insufficiency (GFR < 30) Pooled adjusted HR 1.38 ( ) from the Iowa-EPESE (n=1,028) and NHANES III (n = 1,316) cohorts» Dutta A, et al. J Am Geriatr Soc 2013

68 Allopurinol and Decreased Mortality Allopurinol might be associated with a modest decrease in the risk of death in subjects with hyperuricemia, HR 0.89 (95% CI ). When the analysis was restricted to those with the diagnosis of gout the HR was 0.81 (95% CI ) An incident cohort study using the Health Improvement Network (a UK general population database) compared 5927 patients starting allopurinol and 5927 matched comparators, mean follow-up time was 2.9 years» Dubreuil M, et al. Ann Rheum Dis 2014

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70 An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma» Kool M, et al. Immunity 2011.

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73 Gout Therapy: Lost in Translation? Podagra [pəˈdægrə] pous/pod foot + agra a trap]

74 People wish their enemies dead, but I do not; I say give them the gout, give them the stone! Attributed to Lady Mary Wortley Montagu ( ) The Wordsworth Dictionary of Quotations By Charles Jervas, after 1716 Wikipedia

75 Q6 65 yo male with established diagnosis of gout comes for an urgent visit for acute onset pain and swelling in his right knee. You saw him for an annual follow up a month earlier and his uric acid level was 4.5 mg/dl, he has not had any gout attacks for about four years. He has been adherent to his treatment and diet On exam he had a warm and large effusion in the right knee, with diffuse tenderness and painful limited range of motion

76 Q6 What do you think is the most plausible explanation to his symptoms? A. Internal derangement such as meniscal tear B. Pseudogout C. Septic arthritis D. Gout

77 Chondrocalcinosis Weakly positively birefringent CPPD crystal

78 A6 What do you think is the most plausible explanation to his symptoms? A. Internal derangement such as meniscal tear B. Pseudogout C. Septic arthritis D. Gout

79 Calcium Pyrophosphate Deposition Diseases (CPPD) McCarty % chronic polyarthritis» McCarty DJ. Bull Rheum Dis 1975 A great mimic for many arthropathies Pseudogout can look exactly like gout >50 year-old, risk doubles every decade Knee then wrists are the most common sites Diagnosis by crystals which could be more difficult to find than monosodium urate crystals Radiographically, chondrocalcinosis

80 CPPD, Chondrocalcinosis (CC) CC: cartilage calcification, identified by imaging or histological examination. This is not always due to CPPD and may occur as an isolated finding in an apparently otherwise normal joint or coexist with structural changes resembling osteoarthritis (OA)» EULAR guidelines on CPPD, Ann Rheum Dis 2011

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82 CPPD Clinical Presentations Asymptomatic CPPD, isolated CC, or osteoarthritis (OA) with CC OA with CPPD: CPPD in a joint that also shows changes of OA, on imaging or histological examination Acute calcium pyrophosphate (CPP) crystal arthritis: acute onset synovitis with CPPD (replacing the term pseudogout ) Chronic CPP crystal inflammatory arthritis: chronic inflammatory arthritis associated with CPPD mimicking rheumatoid arthritis

83 CPPD, Diagnosis Crystals are confirmatory Radiographs supportive but not diagnostic, the lack of radiographic finding does not exclude the disease Ultrasound could be helpful in making the diagnosis and differentiating it to a certain degree from gout

84 Ultrasound in CPPD versus Gout Normal hyaline cartilage of the femoral condyle disease Gout, double contour sign Hyperechoic spots, CPPD Filippucci E, et al. Osteoarthritis Cartilage 2009

85 Risk factors Previous joint injury, post menisectomy Hereditary/familial predisposition to CPPD Specific diseases Hemochromatosis Primary hyperparathyroidism (OR=3.03, 95% CI: ) Hypophosphatasia Hypomagnesaemia (OR=13.5, 95% CI: ), Gitelman s disease

86 CPPD, treatment OA with CPPD, treat as OA Acute: NSAIDs Corticosteroids Colchicine Chronic prevention: colchicine, NSAIDs Chronic CPPD: Colchicine NSAIDs Low dose corticosteroids Hydroxychloroquine, MTX Treat secondary causes

87 Online CME & Physician Resources escriptions.asp?course_id=221&group_name =Medicine

88 Guidelines, Gout Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group SGAWG. Rheumatol. 2007;46: Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part I: diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65: Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65: Khanna D, Fitzgerald JD, Khanna PP, et al American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64: Khanna D, Khanna PP, Fitzgerald JD, et al American College of Rheumatology guidelines for management of gout. Part 2: Therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64:

89 Guidelines, CPPD Disease European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. W Zhang, M Doherty, T Bardin, V Barskova, P-A Guerne, T L Jansen, B F Leeb, F Perez- Ruiz, J Pimentao, L Punzi, P Richette, F Sivera, T Uhlig, I Watt, E Pascual. Ann Rheum Dis 2011;70: European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part II: Management. W Zhang, M Doherty, E Pascual, V Barskova, P-A Guerne, T L Jansen, B F Leeb, F Perez- Ruiz, J Pimentao, L Punzi, P Richette, F Sivera, T Uhlig, I Watt, T Bardin. Ann Rheum Dis 2011;70:

90 Patients Resources on Gout MedlinePlus, the U.S. National Library of Medicine and National Institutes of Health ml Patient.co.uk National Institute of Arthritis and Musculoskeletal and skin diseases