author(s): mark mcquillan, m.d., f.a.c.p., f.h.m., 2011...dm, hyperlipidemia, htn, atherosclerosis,...
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Author(s): Mark McQuillan, M.D., F.A.C.P., F.H.M., 2011 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution – Non-Commercial 3.0 License: http://creativecommons.org/licenses/by-nc/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact [email protected] with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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Henry William Bunbury, Origin of the Gout
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CRYSTAL MEDIATED ARTHRITIDIES
Mark A. McQuillan, MD FACP FHM
Winter, 2011
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Disclosure
Takeda Pharmaceuticals
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ACKNOWLEDGEMENT—Special Thanks to
Dr. Blake Roessler Dr. Seetha Monrad
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What’s new with GOUT?
1—changing epidemiology 2—treating to Sua < 6.0
3—Newer treatments
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Top 10?
Prevalence 2X incr Elderly OA/gout coexist Shorter prophy Persistent crystals UA < 6.0 Newer XO inhib
Chronicity Polycyclic Polyarticular Incr. tophi What initiates
attacks?
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OBJECTIVES The student will achieve: 1. An understanding of the clinical presentation
of crystalline synovitis. 2. Understanding of the importance of
polarizing microscopy in making the diagnosis. 3. Understanding of the diagnostic value of
other clinical data (history , tophi, radiographs, therapeutic response)
4. Understanding of the therapeutic approaches to crystalline synovitis, including pharmacologic information.
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Types of Crystalline Synovitis
Gout (Monosodium urate)
Pseudogout (Calcium Pyrophosphate)
Hydroxyapatite Calcium Oxylate Miscellaneous
Source Undetermined (All images)
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Differential Diagnosis Infectious Inflammatory Degenerative Traumatic Neoplastic
Henry William Bunbury, Origin of the Gout
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Gout - Outline Definition History Epidemiology Diagnosis Clinical Presentation Associated
Conditions Pathophysiology Pathology
Therapy – Acute – Preventive – Chronic – Pharmacology
Prognosis
Source Undetermined
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“Gout” defined: Gout: a metabolic condition characterized by
excessive accumulation of uric acid in the blood stream which may lead to deposition of
uric acid crystals in and around the joints, painful attacks of arthritis, impairment of renal
function, and kidney stones.
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Gout terminology Gout Gouty arthritis Acute gouty arthritis Podagra Monoarticular Monocyclic Chronic gouty arthritis Chronic tophaceous gout Polyarticular Polycyclic Tophus (plural, tophi) Inter-critical gout
(others) Lesch-Nyhan Syndrome Kelley-Seegmiller
Syndrome HGPRT deficiency PRPP synthetase
superactivity Xanthine oxidase Allopurinol Uricosuric
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Gout historic aspects
Famous Gout Sufferers A. Martin Luther (1483-1546). B. Francis Bacon (1561-1626). C. Michelangelo (1475-1564). D. Benjamin Franklin (1706-1790). E. King James I (1566-1625). F. Samuel Johnson (1709-1784). G. William Pitt (1759-1806). H. Charles Darwin (1809-1882). I. Isaac Newton (1643-1727).
J.A. Duplessis, wikimedia commons
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Clinical Aspects/Epidemiology Hyperuricemia w/o sxs (> 80 %) Acute gouty arthritis Chronic gouty arthritis (aka,
tophaceous gout) Associated conditions (obesity,
DM, hyperlipidemia, HTN, atherosclerosis, alcohol, acute illness, pregnancy, post-operative)
Negative association (SLE, RA, amyloid, ?dialysis)
Renal disease – urate nephropathy – acute uric acid nephropathy – calculi
Source Undetermined
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Hyperuricemia (>7.0 mg/dl)
Prevalence rate of 5-10% in adult men >80% of hyperuricemic individuals have
no associated gout Hyperuricemia is associated with
hypertension, cardiovascular, cerebrovascular, renal diseases and metabolic syndrome
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Gout epidemiology
Asymptomatic Hyperuricemia is common All patients with gout have hyperuricemia
chronically Gout is caused by hyperuricemia Acute gouty arthritis patients may have
hyperuricemia (80%) Prevalence of gout ~ 1% of men Estrogen is uricosuric
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Hyperuricemia Causes Under-excretion (90% of
cases) dehydration, starvation,
ketosis (post-op) renal abnormality (RTA) drugs: diuretics low-dose
aspirin toxins, ethanol, lead hypothyroidism
Over-production (10% of cases)
ethanol HGPRT or G6PD
deficiency PRPP synthetase
superactivity myeloproliferative
disorders psoriasis
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Acute Gouty Arthritis Abrupt onset, often at
night Subsides completely
– 3-5 days (with Rx); – 10-14 days (with no Rx)
75% in the first MTP joint Urate crystals in WBCs in
synovial fluid May have hyperuricemia
(80%) Usually monoarticular
and monocyclic
Source Undetermined
Source Undetermined
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(Becker & Roessler, “Hyperuricemia and Gout”, in The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill 1995.)
Purine Catabolic Pathway GMP AMP
2,8-Dihydroxyadenine
Adenine
Adenosine
Adenylosuccinic acid
Guanine Xanthine Hypoxanthine
Guanosine Xanthosine Inosine
XMP
IMP
Uric acid
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How does this fit together? Xanthine oxidase
=XO Conversion of
hypoxanthine to xanthine and xanthine to uric acid
Allopurinol inhibits XO (competitive inhibitor)
XO has Multiple sites of action
Competes with 6MP and azathioprine
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Metabolic basis of hyperuricemia
Only 1:200 cases of gout has identifiable enzymatic defect
HGPRT deficiency
– Complete= – Partial=
PRPP synthetase superactivity
Others?
Numerous mutations characterized
Lesch-Nyhan Syndrome Kelley-Seegmiller
Syndrome
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Lesch-Nyhan Syndrome HGPRT deficiency <1% protein
expression UA Overproduction Mental retardation Microcephaly Compulsive Self-
Mutilation Mutations/Gene Rx
Source Undetermined
Source Undetermined
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Kelley-Seegmiller Syndrome Partial HGPRT
Deficiency Early onset, severe
gout – Arthritis – Renal calculi
Intermediate PET scan appearance in basal ganglia 2,3-FDG utilization
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(Becker & Roessler, “Hyperuricemia and Gout”, in The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill 1995.)
Purine Catabolic Pathway GMP AMP
2,8-Dihydroxyadenine
Adenine
Adenosine
Adenylosuccinic acid
Guanine Xanthine Hypoxanthine
Guanosine Xanthosine Inosine
XMP
IMP
Uric acid
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Acute Gout--Pathophysiology role of crystals role of WBC's unexplained features:
– initiation of attack – self-limited nature of
attacks – joint distribution – role of trauma – Supersaturation is
NOT sufficient explanation
Source Undetermined
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Diagnosis “Clinical” Dx vs. “Pathological” Dx
polarizing microscopy (response to therapy) Radiographs tophi
Source Undetermined (All images)
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Diagnosis of Gout
Synovial fluid aspiration and examination using polarizing microscopy
DIY! Identification of intracellular monosodium
urate crystals Needle-shaped, negative birefringence,
yellow (parallel first order compensator) “parallel-yellow-uric acid” mnemonic
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Radiologic findings in Gouty Arthritis
Large punched-out lesions
Overhanging edges Heterotopic bone
growth Lucencies Quite different from
OA, RA, psoriatic, etc.
Source Undetermined
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Tophi & Tophaceous gout Pure uric acid
deposits Extensor surfaces Other locations Heberden’s nodes Chronic drainage 2-5 yrs to reverse Allopurinol role
Source Undetermined (All images)
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Hyperuricemia and gout
>20% of patients with acute gout may be normo-uricemic
~1-2% of patients with tophaceous gout may be normo-uricemic
Mean serum urate in tophaceous gout ~9 mg/dl
Mean CrCl = 90 +/- 30 ml/min Mean UrCl = 4.5 +/- 1.75 ml/min
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Acute Gouty Arthritis
Historical Prevalence = 0.2% Current Prevalence = 0.4% Annual incidence > 0.02% Annual incidence rate correlates with
mean serum urate levels – <7.0 = 0.1% – 7.0-9.0 = 0.5% – >9.0 = 5%
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Diagnostic Arthrocentesis
Source Undetermined
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Polarizing Microscopy
Source Undetermined
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Polarizing Microscopy
Source Undetermined
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Polarizing Microscopy--examples
Source Undetermined (All images)
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Diff Dx?
Source Undetermined (All images)
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Diff Dx
(you fill in the blanks here…)
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Complications
(you fill in the blanks here also)
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Treatment Historic vs. modern Colchicum autumnale Hippocratic writings Sydenham’s treatise Exquisitely effective Matthei Botanical
Gardens
Hans-Simon Holtzbecker, wikimedia commons
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3 Phases of Gout Treatment Acute Preventive Hyperuricemia control
Source Undetermined
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Treatment--acute Indomethacin 25-50 mg qid, taper over 5 days colchicine 0.6 mg
- one po per hour to max. of 12 in first 24 hours; - then no more than 0.6 mg po TID in the next 7 days
? IV colchicine - dangerous butazolidin IA steroids - other NSAID's IL-1 inhibition such as anakinra
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Preventive indomethacin 25 mg
po daily or BID colchicine 0.6 mg po
daily or BID
Source Undetermined
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Colchicine toxicity IV -- repeated doses
are dangerous -- skin reactions Myelosuppression Muscle disease Neuropathy Aplastic anemia Thrombocytopenia Diarrhea
Hans-Simon Holtzbecker, wikimedia commons
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Long term anti-hyperuricemic Rx
Allopurinol 300 mg po qd (decreases production)
uricosuric – sulfinpyrazone 100 mg (titrate) – probenecid 500 mg qd-bid
– NOTE: Uricosuric therapies require identification of 24 hour urinary uric acid excretion
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Which patients need long term anti-hyperuricemic therapy?
Frequency of attacks Severity Other circumstances
Source Undetermined
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Uricosurics PRO ?safer than
allopurinol? Putative role in
decreasing atherogenesis
Most people are eligible
CON Patient education Renal stones Rashes Tolerability 24 hr urine collection
to establish candidacy
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Uricosuric Treatment
Establish baseline CrCl and UrCl Probenecid: 250 mg bid, increase to
500-1000 mg bid Follow up CrCl and UrCl Change meds to secondary uricosurics
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Primary Uricosurics
Probenecid Sulfinpyrazone Benzbromarone EMD 336340
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Secondary Uricosurics
Fenofibrate Atorvastatin Losartan Ampicillin/β-lactams Valproic acid
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Indications for allopurinol Tophi Renal insuff (CrCI <80) Renal stones (any type) Uric acid over-excretion Contraindications to
uricosurics UA >13 Induction chemotherapy
Source Undetermined
Source Undetermined
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Allopurinol Side Effects
Hypersensitivity syndrome – Begins 2-12 weeks after treatment – Fever, often with maculopapular rash – Hepatitis, interstitial nephritis (ATN/ARF),
myocarditis, rhabdomyolysis, eosinophilia Incidence rate of ~0.4%, mortality 25% Complex pathophysiology
– Idiosyncratic, not related to dose or duration
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Allopurinol Side Effects
Toxic epidermal necrolysis (TEN/ Stevens-Johnson syndrome)
Incidence of ~ 0.5% High serum levels of oxypurinol may
increase risk Azotemia may increase risk
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Allopurinol Safety
Potentiates azathioprine serum levels Potentiates warfarin effects ACE inhibitors increase risk of TEN Arellano & Sacristan, Ann Pharmacother
27:337-43;1993 76/101 patients with hypersensitivity syndrome
were receiving allopurinol for asymptomatic hyperuricemia
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Allopurinol Safety
Roujeau JC et. al, NEJM 333:1600-07;1995.
Case control study in 4 European countries to determine relative risk associated with meds and TEN-Stevens-Johnson syndrome
RR of allopurinol = 52 (16-167) RR of phenytoin = 53 (11-infinity) RR of pen = 7, ceph = 14
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New Therapeutics
Febuxostat; a specific and potent xanthine oxidase inhibitor with hepatic metabolism – US FDA approval 2/13/2009
Rasburicase; (Recombinant Aspergillus) – Approved for tumor lysis syndrome
Potential for anaphylaxis
Uricase-PEG20 (Recombinant Candida) – Approved Oct. 2009 “pegloticase” for IV use
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Important drug interactions Azathioprine Mercaptopurine Cyclosporin
(another important “interaction” is shown: “Boston Tea Party”)
The Boston Tea Party by Sarony and Major
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Aspirin (ASA)
Low dose (100-300 mg) ASA exhibits first-order pharmacokinetics and inhibits tubular secretion of UA
High dose (>1.0 gm) ASA exhibits zero-order pharmacokinetics, is an effective uricosuric, and may be responsible for the historical observation that RA and gout do not co-exist
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Cyclosporin
Major cause of hyperuricemia in organ transplant patients
Tacrolimus similar effects Complex pathophysiology
– Reduced GFR – Reduced urate secretion from proximal tubule – Other effects on tubular function
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Ethanol
High dietary purines (beer) Ethanol -- acetate -- acetyl-CoA
metabolism produces large amounts of AMP in liver
If AMP production exceeds rates of ATP regeneration then excess AMP is metabolized to uric acid
Ethanol inhibits UrCl (organic acids and dehydration)
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Miscellaneous gout issues… What is the role of
oxypurinol? Role of diet Co-existent gout
and... – OA – CPPD – Septic arthritis
Source Undetermined
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Co-existing conditions
Gout can occur with infectious arthritis, CPPD, psoriatic arthritis or rheumatoid arthritis
Joint aspiration with cultures and crystal examination is optimal approach to diagnosis and management
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Hyperuricemia and Gout
Hyperuricemia is not a disease (?) – Feig et al. NEJM October 23, 2008
Gout is diagnosed by examination of
synovial fluid
Allopurinol is not the only treatment
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PSEUDOGOUT Clinical Syndromes
associated with CPPD – Radiographic Dx
(“Chondrocalcinosis”) – Familial Clusters – Endocrinopathies – Intra-operative diagnosis
(cause or effect?) – Pseudogout attacks – Polarizing Microscopy
Source Undetermined
Source Undetermined
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Chondrocalcinosis Locations Knee Shoulder Wrist Symphisis Pubis
Source Undetermined (All images)
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Diagnosis of Pseudogout
Synovial fluid aspiration and examination using polarizing microscopy
DIY! Identification of intracellular CPPD crystals Rhomboid shaped, positive birefringence,
blue (parallel first order compensator)
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CPPD some more clinical facts
“DISH” diffuse idiopathic skeletal hyperostosis is common
CPPD is a common radiographic finding in the elderly
Radiographs and symptoms do not always correlate
Treatment is simpler than gouty arthritis therapies
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Pseudogout Treatment
Response to Indomethacin Response to Colchicine Monophasic treatment only Intra-articular steroids Epiphenomenon/ cause or effect?/ is
treatment worthwhile?
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CPPD Treatment Symptomatic NSAIDS Colchicine Intra-articular steroids Metabolic risk factors
– Thyroid disease – Hyperparathyroidism – Hemachromatosis – DM
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Miscellaneous Crystals
Source Undetermined (All images)
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Source Undetermined
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Thank you! Questions?
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Slide 3: Henry William Bunbury, Origin of the Gout Slide 10: Source Undetermined Slide 11: Henry William Bunbury, Origin of the Gout Slide 12: Source Undetermined Slide 15: J.A. Duplessis, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Franklin-Benjamin-LOC.jpg Slide 16: Source Undetermined Slide 20: Sources Undetermined Slide 24: Sources Undetermined Slide 27: Source Undetermined Slide 28: Sources Undetermined Slide 30: Source Undetermined Slide 31: Sources Undetermined Slide 34: Source Undetermined Slide 35: Source Undetermined Slide 36: Source Undetermined Slide 37: Sources Undetermined Slide 38: Sources Undetermined Slide 41: Hans-Simon Holtzbecker, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Gc23_colchicum_autumnale.jpg Slide 42: Source Undetermined Slide 44: Source Undetermined Slide 45: Hans-Simon Holtzbecker, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Gc23_colchicum_autumnale.jpg Slide 47: Source Undetermined Slide 52: Sources Undetermined Slide 58: The Boston Tea Party by Sarony and Major Slide 62: Source Undetermined Slide 65: Sources Undetermined Slide 66: Sources Undetermined Slide 71: Sources Undetermined Slide 72: Source Undetermined
Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy