Study guide
6.4 Urate-Lowering Therapy & Calcium Pyrophosphate Deposition Disease
ABIM Internal Medicine Exam
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1.1 Ischemic Heart Disease & Acute Coronary Syndromes 1.2 Antithrombotic Therapy, Secondary Prevention & Mechanical Complications of MI 1.3 Atrial Fibrillation, Atrial Flutter & Stroke Prevention 1.4 Supraventricular Tachycardias, Ventricular Arrhythmias & Bradycardias 1.5 Heart Failure: Classification, Staging & Guideline-Directed Medical Therapy 1.6 Device Therapy, HFpEF & the Cardiomyopathies 1.7 Valvular Heart Disease & Endocarditis Prophylaxis 1.8 Pericardial Disease & Acute Aortic Syndromes 1.9 Hypertension: Classification, Diagnosis & Secondary Causes 1.10 Hypertensive Crises & Dyslipidemia 1.11 Adult Congenital Heart Disease & Coarctation of the Aorta 1.12 Syncope: Reflex, Orthostatic & Cardiac Causes 1.13 Cardiac Physical Examination, Murmurs & Antithrombotic Selection
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6.1 Rheumatoid Arthritis: Diagnosis & Systemic Manifestations 6.2 Antirheumatic Pharmacotherapy & the Spondyloarthropathies 6.3 Gout: Pathophysiology & Acute Management 6.4 Urate-Lowering Therapy & Calcium Pyrophosphate Deposition Disease 6.5 Osteoarthritis 6.6 Systemic Lupus Erythematosus 6.7 Systemic Sclerosis, Sjogren Syndrome & Inflammatory Myopathies 6.8 The Vasculitides 6.9 Regional Musculoskeletal Syndromes, Back Pain & Sports Injuries 6.10 Other Primary Rheumatic Disorders & Mixed Connective Tissue Disease 6.11 Osteonecrosis & Metabolic Bone Disease
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9.1 Acute Kidney Injury: Staging, Etiology & Urine Microscopy 9.2 Glomerular Disorders & Nephrotic Syndrome 9.3 Nephritic Syndromes, RPGN & Indications for Renal Replacement Therapy 9.4 Chronic Kidney Disease: Staging & Progression Retardation 9.5 Complications of Chronic Kidney Disease: Anemia, CKD-MBD & Acidosis 9.6 Hyponatremia, Hypernatremia & Water Balance 9.7 Potassium Disorders & Systematic Acid-Base Analysis 9.8 Renal Tubular Acidosis & Nephrolithiasis 9.9 Prostate Disorders, Urinary Incontinence & Other Urologic Conditions 9.10 Cystic Kidney Disease, Obstructive Uropathy, Tubulointerstitial Disease & Hematuria
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13.1 Contraception, Preconception Care & Teratogenicity 13.2 Hypertensive Disorders of Pregnancy & Gestational Diabetes 13.3 Thyroid Disease & Venous Thromboembolism in Pregnancy 13.4 Menopause & Menopausal Hormone Therapy 13.5 Abnormal Uterine Bleeding, Endometrial Disease & Gynecologic Cancer Screening 13.6 Breast Disorders & Diseases of the Vulva and Vagina 13.7 Menstrual Disorders, Fibroids, Endometriosis & Early Pregnancy Complications
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20 Chapter 19: Ophthalmology (1% of Exam)
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21 Chapter 20: Otolaryngology & Dental Medicine (1% of Exam)
20.1 Dizziness, Vertigo & Epistaxis 20.2 Ear Disorders, Hearing Loss & Upper Respiratory Infections 20.3 Oral Cavity, Salivary Gland, Laryngeal & Taste and Smell Disorders
6.4 Urate-Lowering Therapy & Calcium Pyrophosphate Deposition Disease
Key Takeaways Explain This Topic AI
Urate-lowering therapy is titrated to a serum urate below 6 mg/dL, or below 5 mg/dL when tophi are present.
HLA-B*5801 testing before allopurinol is recommended in populations at elevated risk of severe cutaneous adverse reaction, including those of Han Chinese, Thai and Korean ancestry.
Anti-inflammatory prophylaxis should accompany the first three to six months of urate-lowering therapy because initiation provokes flares.
Calcium pyrophosphate crystals are rhomboid and positively birefringent, the opposite of monosodium urate.
Calcium pyrophosphate deposition in a patient under 60 warrants evaluation for hemochromatosis, hyperparathyroidism, hypomagnesemia and hypophosphatasia.
Last updated: August 2026
- Long-Term Urate-Lowering Therapy (ULT)
- Indications for Initiating ULT (2020 ACR Guidelines)
Strong Indications (Class I):
>=1 subcutaneous tophi on physical exam or imaging.
Radiographic damage attributable to gout (e.g., periarticular rat-bite erosions).
Frequent gout flares (>=2 flares per year) .
Conditional Indications (Class II):
Prior flare with CKD Stage >=3 , serum uric acid >9.0 mg/dL , or history of urolithiasis (nephrolithiasis) .
Target Serum Urate Level:
Standard Target: <6.0 mg/dL (360 µmol/L) in all patients.
Severe Tophaceous Target: <5.0 mg/dL (300 µmol/L) in patients with extensive subcutaneous tophi or chronic tophaceous arthropathy to accelerate crystal dissolution.
Anti-Inflammatory Flare Prophylaxis: When initiating or titrating ULT, mobilization of urate stores frequently precipitates acute secondary flares. Concomitant anti-inflammatory prophylaxis is mandatory:
Colchicine 0.6 mg PO daily or BID (0.3 mg daily in CKD), OR low-dose NSAID (Naproxen 250 mg BID with PPI), OR low-dose Prednisone (<=10 mg daily).
Duration: Continue prophylaxis for 3 to 6 months (continue for 6 months if tophi are present or if target urate has not yet been achieved).
Critical Management Pearl: Do NOT discontinue pre-existing ULT during an acute gout flare! Discontinuation causes sudden serum urate fluctuations, prolonging and exacerbating the acute attack.
Urate-Lowering Pharmacotherapy Options
Allopurinol (First-Line Anchor Drug):
Mechanism: Purine-analog competitive inhibitor of xanthine oxidase , preventing hypoxanthine and xanthine conversion to uric acid.
Dosing Strategy: Start low, titrate slow! Initial starting dose is 100 mg PO daily (start at 50 mg PO daily in CKD stage >=3 ). Titrate upward by 100 mg every 2 to 4 weeks (can titrate beyond 300 mg up to 800 mg daily if needed) until the serum urate target (<6.0 mg/dL) is achieved.
HLA-B*5801 Allele Screening (MANDATORY High-Yield Rule): Testing for the HLA-B*5801 allele is mandatory prior to initiating allopurinol in individuals of Southeast Asian descent (Han Chinese, Taiwanese, Thai), Korean descent with stage >=3 CKD, and African American descent . Carriage of HLA-B*5801 confers a massive risk of Allopurinol Hypersensitivity Syndrome / Severe Cutaneous Adverse Reactions (SCAR) , including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS), and Toxic Epidermal Necrolysis (TEN) with ~25% mortality.
Febuxostat (Uloric):
Mechanism: Potent, non-purine selective inhibitor of xanthine oxidase. Metabolized by the liver (safe in moderate renal disease without dose adjustments).
Dose: 40 mg daily, titrate to 80 mg daily if needed.
FDA Black Box Warning (CARES Trial): Increased risk of cardiovascular death compared to allopurinol. Reserve Febuxostat for patients who cannot tolerate allopurinol, who have failed maximal allopurinol titration, or who test positive for HLA-B*5801.
Probenecid (Uricosuric Agent):
Mechanism: Inhibits renal tubular urate reabsorption via the URAT1 transporter in the proximal convoluted tubule, increasing urinary uric acid excretion.
Prerequisites: Requires normal renal function (ineffective if eGFR <30 mL/min/1.73m2) and contraindicated in patients with a history of nephrolithiasis or uric acid overproduction (24-hour urine uric acid >800 mg) due to high risk of acute uric acid crystal nephropathy. Maintain vigorous hydration.
Pegloticase (Krystexxa):
Mechanism: Recombinant pegylated mammalian uricase (urate oxidase) enzyme that metabolizes uric acid into allantoin , an inert, highly water-soluble metabolite readily excreted by the kidneys.
Dosing: 8 mg IV infusion every 2 weeks.
Indication: Severe, refractory, chronic tophaceous gout with persistent joint damage failing maximal oral ULT.
Safety & Monitoring: Screen for G6PD deficiency prior to administration (contraindicated due to risk of life-threatening methemoglobinemia and hemolysis). Development of anti-pegloticase antibodies leads to loss of efficacy and high risk of anaphylaxis. Pre-infusion serum uric acid >6.0 mg/dL signals antibody formation; Pegloticase must be immediately discontinued.
- 1. Calcium Pyrophosphate Dihydrate (CPPD) Crystal Deposition Disease (Pseudogout)
- Pathophysiology & Chondrocalcinosis
CPPD results from the precipitation of Calcium Pyrophosphate (CPP) crystals within articular hyaline cartilage, fibrocartilage, synovium, and joint capsules. Inorganic pyrophosphate (PPi) generation is mediated by the ANKH transporter and ectonucleotide pyrophosphatase (ENPP1).
Chondrocalcinosis: Calcification of cartilage visible on plain radiographs as punctate or linear radio-opacities within the joint space. Classic sites: knee menisci , triangular fibrocartilage complex (TFCC) of the wrist , symphysis pubis , and acetabular/glenoid labrum.
Synovial Fluid Polarized Light Microscopy
Microscopy Findings: Rhomboid-shaped or rectangular, weakly positively birefringent crystals :
When the crystal's long axis is parallel to the red compensator filter, the crystal appears blue .
When the crystal's long axis is perpendicular to the compensator, the crystal appears yellow .
Synovial fluid is inflammatory (WBC 2,000–50,000/µL with neutrophil predominance).
Clinical Phenotypes of CPPD
Acute CPP Crystal Arthritis (Pseudogout): Acute, severe, inflammatory monoarthritis or oligoarthritis. The knee is the most common joint (>50% of cases) , followed by the wrist, MCP joints, shoulder, ankle, and hip. Often triggered by acute medical illness, surgery (e.g., parathyroidectomy, joint arthroplasty), or joint trauma.
Chronic CPP Inflammatory Arthritis (Pseudo-Rheumatoid Arthritis): Symmetric inflammatory polyarthritis involving wrists and MCPs with morning stiffness and elevated ESR/CRP (~10% of cases).
Osteoarthritis with CPPD (Pseudo-Osteoarthritis): Progressive degenerative changes in non-typical OA joints (e.g., glenohumeral joints, radiocarpal joints, MCP joints) with superimposed inflammatory episodes.
Crowned Dens Syndrome: CPP crystal deposition in the transverse and alar ligaments around the odontoid process (C1-C2), causing severe neck pain, fever, rigidity, and markedly elevated ESR/CRP mimicking meningitis or temporal arteritis in older adults.
Screening for Secondary Causes of CPPD
While idiopathic CPPD is primarily a disease of aging (>60 years), any patient presenting with CPPD under the age of 55 warrants mandatory screening for underlying secondary endocrine and metabolic disorders :
Hereditary Hemochromatosis: Screen with serum ferritin and transferrin saturation (iron overload stimulates cartilage crystal nucleation; characteristic involvement of the 2nd and 3rd MCP joints with hook-like osteophytes).
Primary Hyperparathyroidism: Screen with serum calcium, phosphorus, and intact Parathyroid Hormone (PTH) (hypercalcemia promotes pyrophosphate crystal formation).
Hypomagnesemia: Screen with serum magnesium (magnesium is an essential cofactor for alkaline phosphatase, which breaks down pyrophosphate; low Mg prevents CPP dissolution).
Hypophosphatasia: Screen with serum alkaline phosphatase (ALP) (low ALP leads to substrate accumulation of pyrophosphate).
Treatment of Acute CPPD Flare
First-line: Intra-articular glucocorticoid injection (triamcinolone 20–40 mg) once infection is excluded, especially for large accessible joints like the knee.
Oral Regimens: Short-course oral NSAIDs or low-dose oral Colchicine (0.6 mg daily to BID). Oral Prednisone taper for polyarticular flares or severe contraindications.
Note: There is no currently available disease-modifying therapy capable of dissolving CPP crystals from cartilage.