Crystal-Induced Arthritis

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. Two main types of crystals cause joint disease: 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 Disease

Gout

Gout is a type of inflammatory arthritis caused by the deposition of monosodium urate crystals in synovial fluid and other tissues. The three clinical phases of gout are:

• acute gouty arthritis

• intercritical period: asymptomatic period between attacks of gout

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

(Source: Gout. N Engl J Med 2022.)

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

• intake of alcohol or other sources of dietary purines

• 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 strongly negatively birefringent monosodium urate (MSU) crystals under polarizing microscopy. A “crystal-proven” diagnosis of gout should be pursued whenever possible; however, not all clinical scenarios allow for this. In some joints, it may be technically challenging to perform an arthrocentesis for crystal analysis. Imaging can be used to help establish a diagnosis in such cases:

• Radiographs often demonstrate characteristic juxta-articular erosions (erosions of the bone distal or proximal to the joint line itself) which may have overhanging edges or rat-bite appearance.

• Ultrasound of affected areas may demonstrate the double-contour sign indicative of MSU deposition along the articular cartilage.

• Dual-energy CT, an advanced CT imaging modality designed for the detection of polarizing material, may identify regions of MSU deposition in and around joints.

Identification of MSU crystals using imaging, synovial fluid analysis, or both should be done whenever possible. However, a clinical diagnosis can also occasionally be made, particularly early in the disease process. A typical example is recurrent episodes of podagra (acute, severe synovitis of the first metatarsophalangeal joint [MTP]) in the setting of hyperuricemia with asymptomatic intercritical periods. This clinical scenario likely represents gout, even if synovial fluid analysis is not available and imaging shows no erosions or other clear features of MSU deposition.

In patients with at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa, the ACR-EULAR Gout Classification Criteria Calculator can be used to classify the patient as having gout for research purposes.

(Source: Gout. N Engl J Med 2022.)

(Source: Tophaceous Gout. N Engl J Med 2012.)

Management

Lifestyle modifications and comorbidity management:

• Diet: Although patients with gout are often counseled to avoid purine-rich foods, studies have shown that diet has a limited role in the management of gout. Diets such as the DASH and Mediterranean diets should be encouraged due to the beneficial effects in the metabolic syndrome, of which gout is an important component. Patients who are overweight or obese should also be counseled on the potential benefit of weight loss in gout management. Excessive alcohol and high-fructose corn syrup should be avoided, as these increase uric acid and may have negative effects on a patient’s health. However, although lifestyle modifications are important to consider in patients with gout, they alone typically only lead to modest reductions in serum uric acid and risk of flares, and most patients ultimately require pharmacologic therapy to lower urate levels.

• Medication management: Clinicians should review patients’ list of medications and, when able, remove or modify any that may raise serum uric acid, particularly antihypertensives. When otherwise clinically appropriate, the preferred antihypertensives in patients with gout are calcium-channel blockers and losartan. In contrast with other angiotensin II-receptor blockers (ARBs) or angiotensin-converting-enzyme (ACE) inhibitors, losartan has a uricosuric effect that is beneficial in patients with gout. Thiazide diuretics have an especially pronounced effect of raising serum uric acid, and these should be avoided in patients with gout if other comorbidities allow.

Acute gout attacks: Therapeutic options for the management of acute gouty arthritis are listed below. Practice patterns vary widely with respect to dosing and duration of treatment. In most cases, treatment duration of 1-2 weeks is required, as shorter durations frequently result in rebound flares after completion of treatment.

• Nonsteroidal anti-inflammatory drugs (NSAIDs): Any NSAID can be used, although the full anti-inflammatory dose on a scheduled rather than as-needed basis is required (e.g., naproxen 500 mg twice daily, ibuprofen 600-800 mg three times daily).

• Colchicine is most effective if started within the first 24-36 hours of an attack (standard dose, 1.2 mg, followed by 0.6 mg one hour later, and then 0.6 mg twice daily). Dose reductions are needed in patients with renal insufficiency. Colchicine should be avoided for the treatment of acute flares (as opposed to prophylaxis of flares) in patients with severe renal insufficiency (i.e., glomerular filtration rate [GFR] <20-30).

• Oral or intravenous glucocorticoids (starting dose of 30-60 mg): The dose will depend on the severity of the flare.

• Intra-articular glucocorticoids are the preferred treatment in patients with mono- or oligoarticular flares of medium-to-large joints amenable to intra-articular injection.

• Anti-inflammatory agents that target interleukin-1 (e.g., anakinra and canakinumab) are investigational therapies to consider in patients with resistant disease.

• Urate lowering therapy (ULT) consists of medications targeted at lowering serum uric acid, which allows for a substantial reduction in flare frequency, prevention of radiographic damage, and improvement of tophaceous burden, when present. The 2020 American College of Rheumatology (ACR) guideline on the treatment of gout describes clinical situations in which ULT is either strongly or conditionally recommended:

  • strongly recommended:

    • presence of tophi

    • radiologic damage (e.g., erosions on x-rays)

    • frequent flares (defined as at least two per year)

  • conditionally recommended:

    • chronic kidney disease (CKD) stage 3 or higher

    • prior urolithiasis

    • serum urate ≥9 mg/dl

    • more than one flare but infrequent flares (less than two per year)

  Patients presenting with their first flare without the comorbidities listed above and those with asymptomatic hyperuricemia and no history of gout need not be treated with ULT. Patients with gout who do not receive ULT should be counseled on lifestyle modifications as described above.

  In patients who warrant ULT, this therapy can be started in conjunction with treatment for acute gout flare or can be delayed and started after an acute episode resolves. Regardless of the agent used, the dose should be gradually titrated to achieve a goal serum uric acid level of <6 mg/dL in combination with gout prophylaxis. 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 for further details on treating gout to target.

  • Allopurinol is the first line ULT agent and should be started at a low dose (≤100 mg daily or 50 mg daily in patients with CKD) and up-titrated every 2 to 6 weeks to reach a goal uric acid level of <6 mg/dL.

    • Allopurinol is safe in patients with all stages of CKD, but these patients require lower starting doses with slower titration schedules.

    • 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-B*5801 allele (most commonly found in Black people and people of Thai, Korean, and Han Chinese descent) are susceptible, and allopurinol use is contraindicated in patients with this genetic variant. Screening for this allele is recommended for individuals in these higher-risk populations.

    • Unless there is an adverse reaction, allopurinol should NOT be stopped or the dose reduced, as this can provoke further flares. This applies to patients admitted for other conditions; if the patient is tolerating their usual outpatient dose of allopurinol, it can be continued at the same dose even in the setting of renal insufficiency.

  • Febuxostat is an alternative ULT generally reserved for patients with an allergy or intolerance to allopurinol. The FDA required a warning with this drug’s prescribing information owing to an observed increase in cardiovascular events in clinical trials. However, the increased risk as compared to allopurinol has not been replicated in more-recentstudies.

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

  • Pegloticase is approved in the United States but rarely used. It may be administered in patients with high tophaceous burden for whom rapid reduction of tophi is desired as an intravenous infusion every 2 weeks. Use of methotrexate may prevent infusion reactions.

  • Prophylaxis: In the early weeks to months after initiating ULT, the fluctuation in serum urate may predispose patients to developing gout flares. For this reason, all patients who are being initiated on ULT should receive gout flare prophylaxis preferably with low-dose colchicine. Low-dose NSAIDs or glucocorticoids are options for patients unable to use colchicine. 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.

(Source: Gout. N Engl J Med 2022.)

Calcium Pyrophosphate Deposition Disease

Calcium pyrophosphate deposition disease (CPPD) or pseudogout is a crystal-induced joint disease caused by the deposition of calcium pyrophosphate crystals into connective tissues. CPPD manifests as a spectrum of conditions including the following four general categories:

• asymptomatic chondrocalcinosis (incidentally found on radiographs)

• accelerated osteoarthritis (managed using the same approach as osteoarthritis not associated with CPPD)

• episodes of acute inflammatory arthritis that mimic gout (often termed “pseudogout”)

• symmetric, chronic polyarthritis (pseudo-rheumatoid arthritis)

CPPD most often affects older patients who have multiple comorbidities. The knee is the most commonly affected joint, followed by the wrist. Other frequently involved joints include the second and third metacarpophalangeal (MCP) joints, elbows, shoulders, and cervical spine.

Risk factors: Although most cases of CPPD are idiopathic, risk factors include:

• hypercalcemia

• hypomagnesemia

• hypophosphatemia

• hyperparathyroidism

• hypothyroidism

• hypophosphatasia

• hemochromatosis

• trauma

Screening: Younger patients with CPPD should be screened for secondary causes. Screening for the conditions outlined above can be considered 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: Arthrocentesis and synovial fluid analysis showing polymorphic rhomboid and rod-shaped crystals that exhibit weak positive birefringence are usually required for diagnosis.

(Source: Calcium Pyrophosphate Deposition Disease. N Engl J Med 2016.)

Treatment: 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. Addressing risk factors for CPPD may lower the risk of future flares. However, no drugs have been shown to have a disease-modifying effect on CPPD itself. Colchicine, NSAIDs, or glucocorticoids are sometimes prescribed to prevent flares. Refractory disease may require treatment with hydroxychloroquine or methotrexate, although 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.