Background and General Information

• Gout is caused by the precipitation and deposition of monosodium urate crystals in synovial fluid and tissue
• Gout is most commonly caused by elevated uric acid levels which can be caused by decreased renal excretion or increased production; Hyperuricemia is necessary but not sufficient to cause gout - it is 3-5 times as common in gout
• Gout is characterized by the chronic deposition of monosodium urate into the synovium; flares are when the increased deposition or mobilization of these crystals leads to inflammation in the joint space
• If left untreated, flares can last days to weeks, but they will always resolve on their own
• If gout is not treated relatively early in its course, gout flares tend to become increasingly frequent and severe and are often polyarticular.

Pathophysiology

• The “solubility” threshold for monosodium urate is >6.8 mg/dL at which time circulating uric acid can turn into crystals
• Almost all serum urate is filtered at the glomerulus, but approximately 90% is reabsorbed in the proximal tubule; in most patients with gout, hereditary underexcretion of uric acid is the primary cause of hyperuricemia, but CKD also increases the risk (secondary underexcretion)
• A sudden increase OR decrease in uric acid levels can lead to a flare. A decrease can lead to mobilization of deposits in the joints and provoke a flare. This is the reason a flare can happen when starting and up-titrating allopurinol and you should have anti-inflammatory ppx for 3-6 months when you start (colchicine 0.6mg 1-2 times daily or low dose NSAID)
• Flares are triggered when macrophages in the synovium ingest the crystals, leading to activation of the NLRP3 inflammasome and generation of interleukin (IL)-1B which propagates inflammatory pathways.
• Gout flares often begin or are worse at night, waking the patient - flares start at night due to lower body temps, a higher likelihood of dehydration, and possibly due to lower cortisol levels
• Uric acid is the end-product of purine metabolism and is excreted by Kidneys
• Tophi are aggregations of urate crystals and giant cells that are formed after repeated attacks and can cause deformities and arthritis of joints
• Premenopausal women are generally protected from hyperuricemia by estrogenic effects - first flares almost always after menopause

Etiology and Risk Factors

• Food that can quickly raise uric acid and precipitate a flare include organ meat (liver), beer, and other high-purine foods - possibly seafood, red meat, high-fructose
• Alcohol metabolites compete with uric acid to be excreted by the kidneys
• Diuretics (both loops and thiazides) can raise uric acid levels; losartan, calcium-channel blockers, fenofibrate, and sodium-glucose transport protein 2 (SGLT2) inhibitors promote uricosuria and lower serum urate concentrations
• Aspirin can raise uric acid via stimulation of  URAT1 which reabsorbs uric acid in the kidney, but the ACR recommends against stopping it in patients with an indication for being on it
• CPPD (pseudo-gout) has deposits in cartilage, and it's very common in patients >80, but often asymptomatic; it’s treated with intra-articular steroids as the first line, followed by typical gout treatment
• CPPD is more likely to be associated with hyperparathyroidism, hypothyroidism, and hypomagnesemia, hemochromatosis, and more commonly involves the knees, wrists, and metacarpophalangeal joints instead of the MTP joint (will more likely show articular chondrocalcinosis on Xray)

Clinical Presentation and Diagnosis

• Gout can be diagnosed clinically without evidence of monosodium urate crystals in joints
• Podagra (painful big toe or metatarsophalangeal joint - MTP) is the first symptom in 50% of patients in early gout flares
• Tophi are masses of uric acid and fibrous tissue - can appear on extensor surfaces of the elbows, distal Achilles tendon, fingers (usually the proximal and distal interphalangeal joints)
• Uric acid of >6-8 favors gout, but can be low/normal during flare since all of the uric acid is depositing in the joints or inflammation may lower serum levels; A serum urate level 2 weeks after gout flare resolution more accurately measures baseline level
• WBCs in the synovial fluid are usually 10-50k in gout, and much higher than that would be concerning for a septic joint
• LR for septic joint - recent surgery is 6.9, prosthesis with overlying skin infection is 15.0, WBC > 100 is 28, WBC >50 is 7.7, WBC >25 is 2.9
• Negatively birefringent needle-shaped crystals on arthrocentesis have a sensitivity of 63-78% and specificity of 93-100% for gout; Pseudogout will show positive birefringent rhomboid-shaped crystals
• The presence of crystals does not rule out an infection!
• Xrays are usually negative in gout but can help rule out fractures and possibly septic joint
• Ultrasound may show a “double contour” sign at cartilage surfaces - specific for urate deposition
• Sleep apnea is highly associated with gout - similar risk populations
• In cellulitis will often see erythema on an area not directly around the joint

Treatment

• Treatment for a flare can be empiric if high suspicion, otherwise keep DDx broad and get synovial fluid
• Patients should have a “pill-in-pocket” approach to early anti-inflammatory treatment
• Allopurinol is a xanthine oxidase inhibitor - xanthine and hypoxanthine are more water soluble and easier to excrete
• We usually do not start allopurinol during acute flares, but it does not need to be held if the patient is already taking it
• When starting allopurinol, can lead to a flare so patients should be treated with NSAID or steroid 1 week before starting - the goal is to get UA <6 and should continue indefinitely
• Patients with the HLA-B*5801 allele have an increased risk of hypersensitivity to allopurinol - should screen Asian patients and black patients of African ancestry; it can cause SJS/TLS, and DRESS
• Naproxen is essentially just longer-acting ibuprofen
• Colchicine binds and stabilizes tubulin subunits which inhibits phagocytosis of urate crystals and neutrophil activation and degranulation; the most common symptom associated with colchicine therapy is diarrhea and it can make myopathy worse if taken with a statin
• Intra-articular injections of steroid like triamcinolone are good since they act locally where inflammation is and avoid systemic effects of PO steroid
• IL-1 inhibitors like Anakinra are more commonly given for flares, especially in patients with significant contraindications for steroids and NSAIDs such as acutely ill cardiac patients or those with brittle diabetes
• Pegloticase (pig uricase) can also be given as an infusion every 2 weeks; works because humans don’t make uricase; risks are allergic reactions
• Diet alone can likely only lower uric acid by 1 mg/dL (noting the studies looking into the effect of diet are of poor quality) - will usually need therapy to lower

• Gout Review (NEJM, 2022)
• STOP Gout Trial (NEJM, 2022) - allopurinol non-inferior to febuxostat for preventing flares and for reaching target urate concentrations at 48 weeks
• CARES Trial (NEJM, 2018) suggested an increased risk of mortality in febuxostat, but a follow-up FAST Trial (Lancet, 2020) showed no difference compared to allopurinol - FDA still has a black box warning‍
• Calcium Pyrophosphate Deposition Disease (CPPD) Review (NEJM, 2016)

• Clinical Problem Solvers: CPS Gout Illness Script
• MD Calc: ACR/EULAR Gout Classification - helps rule in or out gout determining if need to get synovial fluid; if 7+ points, consistent with gout, otherwise should get arthrocentesis to assess for crystals
• MD Calc: ‍‍Acute Gout Diagnosis Rule - score less than 4 is less likely to be gout and other causes should be considered