4. Flare: Classic Description
The victim goes to bed and sleeps in good health. About two o’clock in
the morning he is awakened by a severe pain in the great toe; more
rarely in the heel, ankle, or instep. The pain is like that of a dislocation,
and yet the parts feel as if cold water were poured over them . . . Now it
is a violent stretching and tearing of the ligaments – now it is a gnawing
pain, and now a pressure of tightening. So exquisite and lively
meanwhile is the feeling of the part affected, that it cannot bear the
weight of the bedclothes nor the jar of a person walking in the room. The
night is spent in torture.
Sydenham, 1683
Sydenham, T: The Works of Thomas Sydenham, London, New Sydenham Soc. 1850 (translation)
8. Common Sites of Acute Flares
Midfoot
Gout can occur
in bursae, tendons,
and joints
Olecranon Bursa
Elbow
Wrist
Knee
Ankle
Subtalar
1st MTP
(eventually affected in ~90%
of individuals with gout)
Fingers
9. Classic Gout vs Atypical Gout
Chronic form can be
misdiagnosed as rheumatoid
arthritis or osteoarthritis: acute
flare-ups can be misdiagnosed as
cellulitis or infection
Can be misdiagnosed as cellulitis
or infection
Chronic but can have acute flare-
ups
Acute
Tophi common at presentationTophi rare at presentation
Any joint, upper or lower extremityUsually in lower extremity
Symmetric or asymmetricAsymmetric
PolyarthritisMonarthritis
Diagnosed in as many women as
men
Predominantly men
Observed in elderly patientsCan present at any age, including
patients older than 60 years
Atypical GoutClassic Gout
13. Choi, H. K. et. al. Ann Intern Med 2005;143:499-516
Uric Acid Homeostasis
14. Protein Consumption and Relative Risk
of Gout
Variable Relative Risk 95% CI
Total Protein 1.07 .84-1.36
Animal Protein .98 .74-1.23
Vegetable Protein .73 .56-.96
Dairy Protein .52 .40-.69
Non-Dairy Animal
rotein
1.18 .90-1.53
47,150 male participants (the Health Professionals Follow-up
Study [HPFS], 730 incident gout cases) with no history of gout at
baseline
Choi, HK et al NEJM 2004
15. Alcoholic Intake and Relative Risk of
Incident Gout
Variable RR 95%CI
Total Alcohol Intake (per
10 g daily)
1.17 1.11-1.22
Beer
(per 12 oz daily)
1.49 1.32-1.70
Liquor (per
shot daily)
1.15 1.04-1.28
Wine (per
4 oz glass daily)
1.04 .88-1.22
Choi, HK et al Lancet 2004
47,150 male participants (the Health Professionals
Follow-up Study [HPFS], 730 incident gout cases) with no
history of gout at baseline
18. Definitive diagnosis is established by joint aspiration and identification of
negatively birefringent intracellular crystals by polarized microscopy.
22. Correctable Factors
Contributing to Hyperuricemia
• Obesity
• Hyperlipdemia
• ETOH
• Diuretic Therapy
• High Fructose Corn Syrup
• Poorly controlled hypertension
• High purine consumption
• Decreased urine flow (<1 ml per minute)
23. Xanthine Oxidase Inhibitors
Allopurinol
•Start low eg: 50-100 mg qd
•Increase by 50-100mg every 2-3 weeks according to symptoms and
measured SUA
•“Average” dose 300 mg daily
– lower dose if renal/hepatic insufficiency but can push to target
– higher dose in non-responders.
•Treat to Target
• Usually UA < 6mg/dL , but 5mg/dL if Tophi
Febuxistat
•40-80 mg daily
•Theoretically safer in pts with renal insufficiency, but increased overall
mortality
For patients with gout and CVD, febuxostat and allopurinol had a similar overall
cardiovascular safety profile, but febuxostat was associated with greater risks for all-cause
and cardiovascular mortality. Despite febuxostat's known advantage over allopurinol in
lowering uric acid levels, its cost and mortality disadvantages suggest that it be reserved for
patients who have allergic reactions to, or do not benefit from allopurinol. N Engl J
Gore, J Med 2018 Mar 12;
24. New Agents
• Lesinurad (Zurampic)
• Blocks URAT1 and OAT4 transporters in kidney, blocking uric acid
reabsorption
• Used in conjunction with Xanthine Oxidase Inhibitors
• 200mg dosing in pts who have not reached target levels of UA on XOI’s
• Pegloticase (Krystexxa)
• Pegylated Uricase
• IV every 2weeks
• 30% risk of infusion reactions
• Cannot be used in pts w/ G6PD deficiencies
26. Control of Hyperuricemia
• Differing opinions regarding initiation esp. around 1st
attack.
• Clear evidence if:
• erosions + on X-ray / chronic tophaceous gout
• >2 gout attacks per year.
• May decrease risk of CVD and CRI
27. LASSO Trial
Max Dose
Allopurinol
% of Pts Duration of Rx
(days)
Treatment
Emergent Events
< 300 mg 14.4% 155.5 15.2%
300 mg 65.4% 152 9.5%
>300 mg 20% 159.7 11.4%
6 month safety trial
1732/1735 pts received >1 dose Allopurinol
Treatment Emergent Events: Rash < 1.5 %
No cases of Allopurinol Hypersensitivity Sydrome
Becker M et al Seminars in A&R 2017 45; 2: 174-183
28. Allopurinol Hypersensitivity Syndrome
• < 0.1% pts w/ mortality rate approx. 27%
• Risk Factors
• Genetics
• HLA B 5801
• Renal Function
• Diuretic Use
• Recent start of Allopurinol
• Starting dose of Allopurinol
• Recommendations:
• HLA testing in high risk individuals; ie. Han Chinese, Koreans, Thai, AA(?)
• Starting dose <1.5mg/mL/min eGFR
• Not > 100mg for normal
• 50 mg fo rpts w/ eGFR < 60 mL/min
Stamp L et al Joint, Bone & Spine 2016;1:19-24
31. CPPD Disease Under-recognized
• CPPD disease: Prevalence 4-7%, based on radiographic criteria
(chondrocalcinosis)
• Unusual in patients under 60-years-old
• Considered an arthritis of aging
• CPPD disease is underdiagnosed
• 29-43% TKRs have CPP crystals (not previously diagnosed with CPPD disease)
• CPPD disease includes a broad range of clinical presentations
• Acute presentation = “pseudogout”
• Chronic CPP crystal inflammatory arthritis
34. CPP Deposition
(Pseudogout)
• Gout• Pseudogout
Weakly positively birefringent
Rhomboid-shaped crystals
(Blue when parallel to polarizer)
Calcium pyrophosphate
dihydrate
Gout
(Monosodium urate)
Strongly negatively
birefringent
Needle-shaped crystals
(Yellow when parallel to
Gout
35. Chronic CPP arthritis:
AKA “Chronic pseudogout”
• Chronic large joint effusions (knees, shoulders) lasting weeks-months
• Polyarticular arthritis involving knee, wrist, elbow, shoulder (glenohumeral
joint), MCPs of hand
• Difficult-to-treat osteoarthritis suggests underlying CPPD disease
• If chronic joint effusion, consider diagnostic arthrocentesis
• Chroninc CPP arthritis may mimic rheumatoid arthritis
• Chronic CPP arthritis can present with symmetric synovitis of the MCP joints
of the hands
• Seronegative inflammatory arthritis (RF, CCP negative)
• CPPD disease may cause erosive disease in severe cases, though erosions are
much less common in CPPD disease than in RA
• Older age of onset than rheumatoid arthritis
36. Xray Findings: Hand MCP Joint Arthritis
• Osteoarthritis (joint space narrowing) does not typically involve the
metacarpal phalangeal (MCP) joint of the hand
• Suggests other arthritis such as CPPD disease or rheumatoid arthritis
• “Hook-like” osteophytes
37. CPPD Disease:
Associated Conditions
• Hereditary hemochromatosis
• Hyperparathyroidism (OR 3.03%) (primary or secondary)
• Hypomagnesemia
• Magnesium is a cofactor for pyrophosphatases
• Magnesium increases solubility of CPP crystals
• Gitelman syndrome (autosomal recessive)
• Hypophosphatasia (rare congenital disease)
• Chronic kidney disease, Stage V
• Particularly acute CPP arthritis
38. Risk Factors for Acute CPP Arthritis
(Pseudogout)
• Age (strongest known risk factor)
• Prior joint trauma, h/o meniscectomy, OA
• Post-operative period
• Post-parathyroidectomy (may be related to hypomagnesemia)
• Post-hip fracture repair
• Loop diuretic use
• Not seen with thiazides
• May be related to hypomagnesemia
39. Factors Not Associated
with CPP Deposition Disease
• Calcium supplementation does not increase risk of CPPD disease
• No dietary factors (unlike gout)
• Rheumatoid arthritis
• Thyroid disease
• Diabetes
40. Screening for Associated Conditions
• Consider screening if:
• CPPD disease with polyarticular involvement
• Younger than 60-years-old
Check:
• Iron studies
• Iron, transferrin, % Saturation, ferritin
• Serum calcium
• Parathyroid hormone
• Magnesium
• Alkaline phosphatase
• Family history of similar symptoms
• Treatment of the associated disease does not necessarily improve CPPD
disease
41. Calcium Pyrophosphate Deposition
(CPPD) Disease: Treatment Overview
• Acute calcium pyrophosphate (CPP) arthritis (“pseudogout”)
• Chronic CPP arthritis
• All treatments are off-label
• Small RCTs, retrospective studies, or expert opinion
o Methotrexate
o Colchicine
o HCQ
o Low dose Prednisone
o NSAID’s
o Chronic Anakinra
• Asymptomatic chrondrocalcinosis does not require treatment
No treatments reduce CPP crystal load
No disease modifying drugs for CPPD disease
42. Chronic CPP Arthritis: Treatment
• Oral NSAID with gastroprotection
• Colchicine 0.6 mg daily or BID
• Caution with liver or renal insufficiency
• Glucocorticocoids, low dose
• Prednisone 5 mg daily
• Hydroxychloroquine (plaquenil) 200-400 mg daily
• Methotrexate (5-20 mg once per week) with daily folic acid
supplementation
• Caution with liver or renal insufficiency
• Interleukin-1β inhibitors: anakinra (Kineret) daily injection
• May be used with CKD
• Combine low doses of several different therapies
• Treatment often dictated by comorbidities
Zhang W, Doherty M, Pascual
Prevalence data uses chondrocalcinosis / radiographic findings which are inaccurate in diagnosis of CPPD disease. Likely underestimates true prevalence.
Typically we see chondrocalcinosis on xrays
Pseudogout, Calcium pyrophosphate dihydrate crystals: Positively weakly birefringent rhomboid shaped crystals
By convention, negative / positive birefringence is defined by the orientation to the polarizing lens. Positive bireferingence is defined by crystals are blue when parallel to polarizer.
Patient &gt;70 years old, with significant shoulder GH OA suggests crystal arthritis.
PIC Hand xray MCP OA, hook like osteophytes
Abhishek A, Doherty M. Epidemiology of calcium pyrophosphate crystal arthritis and basic calcium phosphate crystal arthropathy. Rheum Dis Clin N Am. 2014; 177-191.
Nephrolithiasis?
Gitelman’s: AR disorder, loss of function mutation of the thiazide sensitive sodium chloride symporter of DCT= hypokalemic metabolic alkalosis, hypocalciuria, hypoMag
Hypophosphatasia: tissue non-specific alkaline phosphatase (TNSALP), Osteomalacia stress fractures
Rheumatoid arthritis: 11% have CPP crystals
Abhishek A. Calcium pyrophosphate deposition disease: a review of epidemiologic findings. Curr Opin Rheum. 2016; 28 (2):133-139.
EULAR recommendations 2011
Treatment of CPPD disease is independent of any associated conditions
Trial-and-error approach for treatment of chronic CPPD disease
HCQ, MTX may take weeks-months to see prophylaxis effect