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Rheumatology - Crystal-Induced Arthritis - Fast Facts | NEJM Resident 360

Crystal-induced arthritis is characterized by an acute arthritis of one or several joints; typical features include pain, swelling, erythema, heat, and restricted function. Fever and elevated markers of inflammation in peripheral blood are common findings, so infection is the main alternative in the differential diagnosis.

Ideally, every case of suspected crystal-induced arthritis is confirmed by arthrocentesis and synovial fluid analysis, with visualization of the relevant crystal and the absence of bacterial growth on culture media, although joint aspiration is not possible or positive in every case. There are two main types of crystal: monosodium urate (gout) and calcium pyrophosphate (pseudogout).

A third crystal type, basic calcium phosphate, is associated with osteoarthritis, calcific periarthritis, and, more rarely, severe joint destruction. It is not discussed further in this section.

In this section, we review the following conditions:

• Gout

• Calcium Pyrophosphate Deposition (CPPD) Disease or Pseudogout

Gout

Gout is a type of inflammatory arthritis that is caused by the deposition of monosodium urate crystals in synovial fluid and other tissues.

Three Clinical Phases of Gout

• acute gouty arthritis

• intercritical period: patients are entirely asymptomatic during this phase

• chronic gout: if hyperuricemia is not treated, chronic tophaceous gout may develop, characterized by polyarticular attacks, symptoms between attacks, and crystal deposition (tophi) in soft tissues or joints

Risk Factors

• medications: thiazide and loop diuretics, cyclosporine, and low-dose aspirin (<1 gram daily)

• insulin resistance, metabolic syndrome, and obesity

• chronic renal insufficiency

• hypertension

• congestive heart failure

• organ transplantation

• disorders of high cell turnover (e.g., hematologic malignancy)

• high intake of dietary purines (particularly meat and seafood), ethanol (particularly beer and spirits), soft drinks, and other sources of high-fructose corn syrup

Triggers of Gout Flares

• recent diuretic use

• alcohol intake

• hospitalization (particularly if dehydrated or admitted with sepsis)

• surgery

• urate-lowering therapy in the early period after its initiation (especially if treatment is not accompanied by therapy for flare prophylaxis, such as with colchicine)

Diagnosis

The gold standard for diagnosis of gout is aspiration of synovial fluid or tophi aspiration with identification of negatively birefringent monosodium urate crystals under polarizing microscopy.

Tophaceous Gout

Gouty tophi of the right index finger (panel A), osteolysis of the distal phalanx (panel B), and urate crystals on polarized light microscopy (panel C).
(Source: Tophaceous Gout. N Engl J Med 2012.)

Management

Acute gout attacks: The following table describes pharmacologic management options for acute gout attacks:

(Source: Gout. N Engl J Med 2011.) 

In circumstances where oral glucocorticoids are unsuitable (such as vomiting), intra-articular or intramuscular administration of glucocorticoids can be used as an alternative. In patients with resistant disease, investigational therapies to consider include anti-inflammatory agents that target interleukin-1, such as anakinra and canakinumab, though they increase the risk of infection.

Chronic gout: Patients with tophi, frequent attacks (≥2 per year), polyarticular attacks, chronic kidney disease stage 2 or worse, or previous urolithiasis should be considered for urate-lowering therapy. This therapy can be started in conjunction with treatment for acute gout or can be delayed and started after an acute episode resolves.

• Allopurinol is the first-line agent and should be started at a low dose (≤100 mg daily) and up-titrated every 3 to 5 weeks to reach a goal uric acid level of <6 mg/dL. Underdosing of allopurinol is common.

  • Treating to a uric acid target of <6 mg/dL (or lower) will promote regression of tophi, reduce frequency of flares, and improve imaging-detected synovitis. See this review article for further details on treating gout to target.

  • Allopurinol is rarely associated with a life-threatening hypersensitivity reaction. This reaction is most likely to occur within the first 3 months of treatment, in those with renal insufficiency, and in genetically susceptible individuals. Patients with the HLA-B5801* allele (most commonly found in African Americans and people of Thai, Korean, and Han Chinese descent) are a susceptible group, and allopurinol use is contraindicated for patients with this genetic variant. Screening for this allele is recommended for individuals in these higher risk populations.

  • All patients started on allopurinol should receive gout prophylaxis with low-dose colchicine, low-dose nonsteroidal anti-inflammatory drugs (NSAIDs), or glucocorticoids. The choice of therapy is individualized to the patient and their concomitant medications and comorbidities.

  • Gout prophylaxis (using colchicine, NSAIDs, or glucocorticoids) should continue for at least 3 to 6 months after achieving the goal uric acid level if there are no additional flares.

  • Unless there is an adverse reaction, allopurinol should NOT be stopped, because stopping can provoke further flares. This applies to patients admitted for other conditions; if the patient is hemodynamically stable and tolerating their usual outpatient dose of allopurinol, it can be continued even in the setting of renal insufficiency.

• Febuxostat is an alternative urate-lowering therapy and is generally reserved for when there is an allergy or intolerance to allopurinol. Concerns have been raised regarding an observed increase in cardiovascular events in clinical trials with febuxostat, and the FDA required a warning with this drug’s prescribing information.

• Probenecid promotes the excretion of uric acid in the urine. It is less potent than allopurinol or febuxostat, raises the risk of nephrolithiasis, and may be ineffective in the setting of renal dysfunction.

• Pegloticase is approved in the U.S. but rarely used. It is administered as an intravenous infusion every 2 weeks and often causes infusion reactions.

Calcium Pyrophosphate Deposition (CPPD) Disease or Pseudogout

CPPD is a crystal-induced joint disease caused by the deposition of calcium pyrophosphate crystals into connective tissues. It manifests as a spectrum of conditions including asymptomatic chondrocalcinosis (which is incidentally found on radiographs), episodes of arthritis that mimic gout (pseudogout), rheumatoid arthritis (pseudo–rheumatoid arthritis), and accelerated osteoarthritis.

CPPD most often affects older patients who often have multiple comorbidities. The knee is the most commonly affected joint, followed by the wrist.

Risk Factors

Most cases are idiopathic, but risk factors include:

• hypercalcemia

• hypomagnesemia

• hypophosphatasia

• hemochromatosis

• trauma

Secondary causes should be suspected in younger patients with CPPD. Screening for the conditions outlined above is recommended at least once in all patients with CPPD.

Imaging

Radiographs often demonstrate chondrocalcinosis. However, the absence of this radiographic finding does not rule out disease, and its presence is common in asymptomatic older individuals; therefore, chondrocalcinosis does not itself require treatment. Chondrocalcinosis typically develops in the cartilage of the knee joint, the triangular fibrocartilaginous complex of the wrist, the pubic symphysis, or any combination of these. 

Diagnosis

Diagnosis usually requires arthrocentesis and synovial fluid analysis showing polymorphic rhomboid and rod-shaped crystals that exhibit weak positive birefringence.

Calcium Pyrophosphate Deposition

Rhomboid, birefringent calcium pyrophosphate (CPP) crystals are seen under polarizing light microscopy in this sample of synovial fluid that was obtained from a patient with acute CPP crystal arthritis of the wrist (panel A). The hands of an elderly patient with CPPD disease show swelling in the left wrist and the third proximal interphalangeal joint of the left hand (panel B).
(Source: Calcium Pyrophosphate Deposition Disease. N Engl J Med 2016.)****

Treatment of Acute CPPD

Treatment of acute CCPD is similar to that of gout and can include:

• NSAIDs

• colchicine

• systemic or intra-articular glucocorticoids

Prevention

Prevention of CPPD is challenging. If there are risk factors for CPPD, these should be addressed. However, no drugs prevent further CPPD. Colchicine, NSAIDs, or glucocorticoids are sometimes prescribed to prevent flares. Refractory disease may require treatment with hydroxychloroquine or methotrexate, though there is little evidence of benefit for these drugs and their use is generally not recommended. Interleukin-1 inhibitors, such as anakinra, are considered investigational for the treatment of CPPD.

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