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Treatment of calcium pyrophosphate crystal deposition (CPPD) disease

Treatment of calcium pyrophosphate crystal deposition (CPPD) disease
Literature review current through: Jan 2024.
This topic last updated: Jan 12, 2024.

INTRODUCTION — Precipitation of crystals of calcium pyrophosphate (CPP) in connective tissues may be asymptomatic or may be associated with several clinical syndromes. These disorders, including acute inflammatory, chronic inflammatory, and degenerative arthropathies, as well as radiographic calcification, comprise the spectrum of calcium pyrophosphate crystal deposition (CPPD) disease [1-3].

Treatment of CPPD disease is discussed here. The pathogenesis, etiology, clinical manifestations, and diagnosis of this disorder are discussed separately. (See "Pathogenesis and etiology of calcium pyrophosphate crystal deposition (CPPD) disease" and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

TERMINOLOGY — This topic review uses the nomenclature for calcium pyrophosphate crystal deposition (CPPD) disease outlined by the European Alliance of Associations for Rheumatology (EULAR) consensus panel [4-6]. Differences between this nomenclature and older classifications (eg, pseudogout, chondrocalcinosis, pyrophosphate arthropathy) are described in detail elsewhere. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Terminology'.)

GENERAL APPROACH — The approach to treatment of calcium pyrophosphate crystal deposition (CPPD) disease depends on the subtype, which is based on clinical manifestations and acuity. Asymptomatic patients who have evidence of cartilage calcification (also called chondrocalcinosis) on imaging do not need any specific treatment.

Acute symptoms – Patients with intermittent episodes of inflammatory arthritis are categorized as having acute calcium pyrophosphate (CPP) crystal arthritis. Treatment of acute episodes consists of supportive measures as well as intraarticular or systemic antiinflammatory therapy. The choice of antiinflammatory therapy is based upon factors such as the patient’s clinical presentation (eg, number of joints) as well as the potential adverse effects of each agent. Prophylaxis against acute flares may be indicated for patients with frequent episodes (≥3 episodes/year). (See 'Acute CPP crystal arthritis (pseudogout)' below and 'Prophylaxis for acute CPP crystal arthritis' below.)

Chronic symptoms – Patients with persistent symptoms of inflammatory arthritis are categorized as having chronic CPP crystal inflammatory arthritis and may benefit from more prolonged antiinflammatory therapy. Patients with preexisting osteoarthritis (OA) or severe joint degeneration who have evidence of CPPD are generally treated for these conditions without specific therapy targeted against CPPD. (See 'Chronic CPP crystal inflammatory arthritis' below and 'Osteoarthritis with CPPD' below and 'Severe joint degeneration' below.)

Patients who have a disease associated with CPPD (table 1) should receive specific therapy directed at the underlying disorder; however, such interventions usually do not reverse CPPD disease. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Post-diagnostic evaluation for associated diseases' and 'Treatment of associated diseases' below.)

Treatments for CPPD disease and gout (acute monosodium urate crystal deposition disease) share many similarities. However, while urate-lowering therapy is used to prevent or reverse deposition of monosodium urate in patients with gout, there are no known therapies that prevent or reverse deposition of CPP in patients with CPPD disease.

In general, treatment approaches for various forms of CPPD disease are modeled after the treatment of conditions with similar manifestations (eg, gout for acute CPP crystal arthritis, rheumatoid arthritis [RA] for chronic CPP crystal arthritis). However, the evidence directly examining and supporting specific treatments in CPPD disease is quite limited. The European Alliance of Associations for Rheumatology (EULAR) panel has issued guidance around treatment strategies, which generally concurs with our approach outlined below [5-7]. (See 'Society guideline links' below.)

ACUTE CPP CRYSTAL ARTHRITIS (PSEUDOGOUT) — The treatment of an attack of acute calcium pyrophosphate (CPP) crystal arthritis (previously known as pseudogout) consists of supportive measures for symptomatic relief as well as antiinflammatory therapy for most patients, as discussed below.

Supportive measures for all patients — All patients with acute CPP crystal arthritis should receive supportive measures for symptomatic relief. These include the following:

Application of ice or cool packs (for no more than 20 minutes at a time) to the affected joints.

Rest of the affected area for 48 to 72 hours. This involves restriction of weightbearing activity and possibly immobilization with splinting, depending on the specific joint affected.

Use of analgesic medications (such as acetaminophen or opioids) or nonsteroidal antiinflammatory drugs (NSAIDs) at analgesic rather than antiinflammatory doses for pain relief. These medications should not substitute for systemic antiinflammatory therapy when indicated. Patients with involvement of smaller and more peripheral joints (eg, knuckles, wrists) may benefit from the addition of topical diclofenac.

The use of these strategies is based largely upon our clinical experience and that of other experts. Since attacks of acute CPP crystal arthritis are usually self-limited, supportive measures may be sufficient to treat the acute flare in patients with contraindications to all of the available antiinflammatory therapies [6].

Initial antiinflammatory therapy

Selection of agent — We use antiinflammatory therapy for most patients with acute CPP crystal arthritis. While supportive measures may provide some relief, they are often insufficient. The aim of antiinflammatory therapy is to prevent the pain and disability associated with acute CPP crystal arthritis, and treatments are generally well tolerated and widely available. Options include glucocorticoids (intraarticular or systemic), colchicine, NSAIDs, and interleukin 1 (IL-1) antagonists.

Therapy should be started as close to the onset of symptoms as possible to prevent the flare from worsening. The choice of antiinflammatory therapy depends upon the number of joints affected, whether local glucocorticoid injection is feasible, whether patients can take oral medications, and whether there are contraindications to the major types of oral antiinflammatory therapy. It also depends on whether there is concern for a concurrent septic joint (eg, signs and symptoms of systemic inflammation, rash, or associated foci of infection) (algorithm 1).

For patients for whom there is concern for a concomitant septic joint, we avoid immunosuppressive agents that could worsen infection, such as glucocorticoids and anti-IL-1 therapy, as well as NSAIDs, given the increased risk of bleeding should the patient require surgical intervention. We treat with colchicine rather than with other antiinflammatory therapies. Patients should be evaluated and treated as appropriate for septic joint, as detailed elsewhere. (See 'Colchicine' below and "Septic arthritis in adults".)

In patients with low suspicion of a septic joint, we use the following approach:

For patients with one or two affected joints that are amenable to arthrocentesis, we suggest thorough joint aspiration and treatment with intraarticular glucocorticoids rather than systemic antiinflammatory therapy. If an experienced provider is not available to perform this procedure, we treat with systemic antiinflammatory therapy. (See 'Intraarticular glucocorticoids' below.)

Joint fluid aspiration and glucocorticoid injection usually provide relief in pain and swelling within 8 to 24 hours; this therapy also avoids complications associated with systemic therapy.

For patients with more than three affected joints or one or two affected joints that are not amenable to arthrocentesis (eg, knuckles), we suggest systemic antiinflammatory therapy rather than intraarticular glucocorticoids.

-If the patient can take oral medications, we treat with either oral glucocorticoids, NSAIDs, or colchicine. There is no strong evidence to suggest clinical benefit of one of these agents over another for acute CPP crystal arthritis. Selection of therapy should therefore be based on the patient’s history of treatment response in prior flares and an evaluation of the risks of therapy, including medication adverse effects and contraindications for an individual patient based on comorbidities and other medications (table 2). Notably, acute CPP crystal arthritis is most common in older adults, who are more likely to have comorbid conditions and polypharmacy that can complicate treatment choice. (See 'Systemic glucocorticoids' below and 'NSAIDs' below and 'Colchicine' below.)

-If the patient cannot take oral medications, we treat with intravenous (IV) glucocorticoids in the inpatient setting or intramuscular (IM) glucocorticoid injection in the outpatient setting. (See 'Systemic glucocorticoids' below.)

-If the patient is unable to receive glucocorticoids, NSAIDs, or colchicine, we treat with an IL-1 inhibitor such as anakinra or canakinumab. (See 'Anti-interleukin 1 therapy' below.)

There is little high-quality evidence to guide the optimal antiinflammatory therapy for acute CPP crystal arthritis. Our approach, which is largely consistent with the recommendations of the European Alliance of Associations for Rheumatology (EULAR) expert consensus group [6], is primarily based upon the clinical experience of the authors and editors of this topic as well as data supporting the use of systemic antiinflammatory therapies in patients with gout, given the similarities between the mechanisms of acute CPP crystal and acute monosodium urate crystal-induced inflammation. A more detailed discussion of the studies comparing antiinflammatory treatment regimens in gout is presented elsewhere. (See "Treatment of gout flares".)

Data directly comparing antiinflammatory therapies for acute CPP crystal arthritis are limited. In an open-label, multicenter trial in over 100 hospitalized patients aged 65 years and older with an acute flare of calcium pyrophosphate crystal deposition (CPPD) arthritis within 36 hours of symptom onset, patients randomly assigned to colchicine (1.5 mg on day 1 and 1 mg on day 2) or prednisone (30 mg daily) for two days had similar improvements in self-reported pain at 24 hours [8]. Adverse effect profiles differed among the treatment groups, with more patients on colchicine reporting diarrhea and more patients on prednisone experiencing hypertension and hyperglycemia [9].

Limited data on certain IL-1 inhibitors suggest that these agents may improve clinical symptoms of acute CPP crystal arthritis, and thus we reserve their use for patients who cannot take or do not respond to other therapies. While data from large clinical trials are not available, a systematic review noted that 80 percent of patients receiving anakinra for acute CPP crystal arthritis experienced clinical improvement [10]. A small double-blind trial in which patients with acute CPP crystal arthritis were randomly assigned to three days of anakinra or oral prednisone showed lower pain scores among patients receiving anakinra, but this did not reach statistical significance, possibly due to the study being underpowered [11].

Glucocorticoids

Intraarticular glucocorticoids — Intraarticular glucocorticoids are generally used for patients who have acute CPP crystal arthritis affecting one or two joints that are amenable to arthrocentesis and glucocorticoid injection. (See 'Selection of agent' above.)

Intraarticular glucocorticoid injection should be performed only when the likelihood of a septic joint, which can be mistaken for acute crystal-induced synovitis, has been deemed unlikely. Characteristics that make an infection less likely include the absence of systemic signs and symptoms, such as fever, or a suspected focus of infection. Absence of infection is further supported by a lack of microorganisms on Gram stain of synovial fluid and sterile synovial fluid and blood cultures. In patients with suspected infection, glucocorticoid injection should be deferred until synovial fluid culture is negative, and interventions other than glucocorticoid injection should be employed. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Diagnosis' and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Differential diagnosis'.)

For injections into large joints, including the knees and shoulders, we use triamcinolone acetonide (1 mL, 40 mg) mixed with 1 or 2 mL of 1% lidocaine. When smaller joints are involved, smaller doses of the respective glucocorticoid preparations can be utilized. (See "Joint aspiration or injection in adults: Technique and indications" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?", section on 'Choice of glucocorticoid preparation' and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?", section on 'Should the glucocorticoid be mixed with a local anesthetic?'.)

Joint fluid aspiration and glucocorticoid injection usually provide relief in pain and swelling within 8 to 24 hours. Patients who experience worsening symptoms shortly after aspiration and injection, do not improve within 48 to 72 hours, or develop additional inflamed joints may require escalation to systemic antiinflammatory therapy. (See 'Initial antiinflammatory therapy' above.)

Systemic glucocorticoids — Systemic glucocorticoids are an option for antiinflammatory therapy in patients with acute CPP crystal arthritis affecting three or more joints, or one to two joints that are not amenable to arthrocentesis, when there is low concern for septic arthritis. The route of glucocorticoids depends on the patient's ability to take oral medications and whether care is in the inpatient or outpatient setting. (See 'Selection of agent' above.)

Oral glucocorticoids – We use oral glucocorticoids unless patients are unable to take oral medications, regardless of the clinical setting.

Dosing and duration – When using oral glucocorticoids for acute CPP crystal arthritis, we use prednisone (or other equivalent oral glucocorticoid) in doses of 30 to 50 mg once daily or in two divided doses until flare resolution begins. We then taper the dose of glucocorticoids, usually over 5 to 10 days. A response to oral glucocorticoid therapy is usually seen within two to three days, particularly if the flare is limited to one or two joints, but may take longer in the case of a greater number of inflamed sites.

Contraindications – Glucocorticoids should be avoided inpatients with concomitant infection, heart failure, poorly controlled hypertension, brittle diabetes mellitus, and/or glucocorticoid intolerance.

Adverse effects – Systemic glucocorticoids can cause adverse effects even when used for short periods of time, including gastritis, insomnia, weight gain, fluid retention, hypertension, and hyperglycemia. Adverse effects of glucocorticoids are described in detail elsewhere. (See "Major adverse effects of systemic glucocorticoids".)

Intravenous or intramuscular glucocorticoids – For patients who are unable to take oral medications and who are not appropriate candidates for intraarticular injection, we use IV glucocorticoids in the inpatient setting or IM glucocorticoids in the outpatient setting.

For IV glucocorticoids, the dose is equivalent to that suggested above for oral glucocorticoids (eg, methylprednisolone 24 to 40 mg once daily or in two divided doses), with a gradual taper over 5 to 10 days once symptoms start to improve. In patients who are later able to take oral medications after initiating therapy, we switch to an oral route.

For IM glucocorticoids, we use a one-time dose of 60 mg of triamcinolone acetonide [12].

Contraindications and adverse effects for IV and IM glucocorticoids are the same as those listed above under oral glucocorticoids.

NSAIDs — NSAIDs are an option for systemic antiinflammatory therapy in patients with acute CPP crystal arthritis affecting three or more joints, or one to two joints that are not amenable to arthrocentesis, when there is low concern for septic arthritis. (See 'Selection of agent' above.)

Dosing, type, and duration – When using NSAIDs for acute CPP crystal arthritis, we use antiinflammatory doses of a nonselective NSAID (eg, naproxen 500 mg twice daily). Any NSAID can be used for acute CPP crystal arthritis, although we avoid high-dose indomethacin because of its common adverse effects, particularly in the older adult population. We generally prefer nonselective NSAIDs over other agents because they are inexpensive, readily available to patients at the onset of an attack (some without a prescription), and, in our experience, as effective and at least as safe as other agents. A cyclooxygenase 2 (COX-2) selective inhibitor (celecoxib dosed as a single dose of 400 mg followed by an additional 200 mg daily) has been described as an alternative to nonselective NSAIDs for gout flare therapy [13] but has not been studied in randomized trials for acute CPP crystal arthritis.

The NSAID dose may be reduced after a significant reduction in symptoms has occurred, but the frequency of dosing should be maintained for several more days for optimal antiinflammatory effect. NSAIDs can be discontinued one or two days after clinical signs have completely resolved. Typically, the total duration of NSAID therapy for an acute attack is five to seven days.

Contraindications – There are important contraindications to NSAIDs, including active duodenal or gastric ulcer, poorly controlled hypertension, moderate to severe or uncompensated heart failure, use of anticoagulants, chronic kidney disease (especially with an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), cirrhosis, and NSAID allergy. They should also be used with caution in patients with cardiovascular disease, particularly heart failure or hypertension that is difficult to control. (See "NSAIDs: Adverse cardiovascular effects" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities' and "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

Adverse effects – Adverse effects are uncommon with brief courses of therapy but may include gastrointestinal intolerance and worsening of kidney function. A more detailed description of adverse effects with NSAIDs are described elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs: Adverse cardiovascular effects" and "Overview of COX-2 selective NSAIDs", section on 'Reduction in toxicities with COX-2 selective NSAIDs (coxibs)'.)

Concurrent use of a proton pump inhibitor may be required for patients who have an increased risk of gastropathy from NSAIDs. Strategies for primary or secondary prevention of gastroduodenal toxicity related to NSAIDs are provided elsewhere. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

Colchicine — Colchicine is an option for systemic antiinflammatory therapy in patients with acute CPP crystal arthritis affecting three or more joints, or one to two joints that are not amenable to arthrocentesis. It may also be used as antiinflammatory therapy in patients for whom there is concern for a concomitant septic joint. (See 'Selection of agent' above.)

Dosing and duration – When using colchicine for acute CPP crystal arthritis, we administer a "low-dose" oral regimen of no more than 1.8 mg of colchicine in the first 24 hours of treatment, followed by 0.6 mg colchicine taken twice daily until the attack abates [14]. IV colchicine is no longer available due to increased risk of severe adverse outcomes.

Contraindications – Contraindications to the use of colchicine include:

Presence of combined kidney and hepatic impairment

Use of colchicine (eg, for prophylaxis) within the prior 14 days in patients with severe hepatic impairment or severe kidney function impairment (eGFR of <30 mL/min/1.73 m2)

Concomitant or very recent use of a medication that strongly inhibits the cytochrome P450 system component CYP3A4 (table 3) or that inhibits the membrane P-glycoprotein multidrug resistance transporter (P-gp) in the presence of kidney or hepatic impairment [14].

History of allergy or severe reaction to colchicine

Adverse effects – Gastrointestinal symptoms (diarrhea, abdominal pain, nausea and vomiting) are the most common adverse effects of colchicine. Diarrhea and abdominal cramping are less likely in patients who receive a total of 1.8 mg or less on the first day compared with patients receiving higher doses (eg, 0.6 mg every one to two hours until symptom relief or intolerance, as was historically employed) [15]. The peripheral neuropathy sometimes caused by colchicine is rare in patients taking colchicine for short periods of time. More severe and potentially life-threatening colchicine toxicities, such as blood cytopenias, rhabdomyolysis or myopathy, peripheral neuropathy, liver failure, or severe cutaneous eruption, have only rarely been reported in patients receiving brief administration of this agent [16].

Anti-interleukin 1 therapy — Anti-IL-1 agents (eg, anakinra, canakinumab) may be beneficial in patients who cannot use, do not tolerate, or do not respond to NSAIDs, colchicine, and glucocorticoids (see 'Selection of agent' above). We use anakinra to allow for the shortest course possible, usually dosed as 100 mg via subcutaneous injection daily until symptoms have improved. Canakinumab is an alternative that is given as a one-time dose of 150 mg via subcutaneous injection.

Adverse effects of anakinra include injection site reactions, infection, hepatitis, and neutropenia. Patients must be screened for latent infections, including tuberculosis, prior to initiating therapy. It must be adjusted for patients with advanced kidney function impairment (eGFR of <30 mL/min/1.73 m2). Limited observational data has not noted a significant infection risk in patients receiving short courses of anakinra for crystalline arthropathy, even when used in patients with other risk factors including organ transplantation and recent surgery [17]. A more complete description of potential adverse effects is detailed elsewhere. (See "Interleukin 1 inhibitors: Biology, principles of use, and adverse events", section on 'Adverse effects'.)

Resistant disease — We consider patients to have resistant disease if they have moderate to severe symptoms that are persistent or worsening despite 48 to 72 hours of treatment. Truly resistant disease is uncommon and most acute flares of acute CPP crystal arthritis resolve within 7 to 14 days. However, some attacks may resolve slowly, especially if treatment is not started early or if prior flares have led to a chronic arthropathy with nearly continuous joint inflammation. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Acute CPP crystal arthritis'.)

In patients with symptoms that are not improving as expected, the diagnosis should be reevaluated. If it was not already performed, arthrocentesis may be required to exclude other causes of a flare of acute inflammatory arthritis, including infection. The patient's adherence to the treatment program should also be assessed. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Differential diagnosis'.)

The management of patients with persistent symptoms depends upon the prior initial therapy used and upon the risks of various therapies for an individual patient. Our approach is outlined below (algorithm 2):

In patients who received initial therapy with intraarticular glucocorticoids, we switch to systemic antiinflammatory therapy with oral glucocorticoids, NSAIDs, or colchicine. IV glucocorticoids may be used for patients who cannot take oral medications. Selection of an oral antiinflammatory agent should be based on an evaluation of the risks of therapy and history of treatment response in prior flares. (See 'Selection of agent' above.)

In patients who received initial therapy with an oral antiinflammatory agent, we either add a second antiinflammatory agent or switch to an alternative antiinflammatory agent, depending upon the patient’s response to initial therapy. If the patient has had some improvement with initial therapy and is tolerating it well, we prefer to add a second agent when possible instead of switching therapy. As with initial therapy, the choice of agent should depend on an evaluation of the risks of a particular therapy for the patient.

If colchicine was used initially, we switch to or add an NSAID or oral glucocorticoids. (See 'NSAIDs' above and 'Systemic glucocorticoids' above.)

If an NSAID was used initially, we switch to or add colchicine or switch to oral glucocorticoids. Glucocorticoids should not be added to an NSAID due to an increased risk of gastrointestinal complications. (See 'Colchicine' above and 'Systemic glucocorticoids' above and "Major adverse effects of systemic glucocorticoids", section on 'Gastrointestinal effects'.)

If oral glucocorticoids were used initially, options include continuing oral glucocorticoids and adding colchicine; switching the route of glucocorticoids from oral to IV or IM; or switching the route of glucocorticoids and adding colchicine. If IV therapy is used, the IV route should be continued until symptoms are improving. The management of recurrent (or "rebound") attacks may require slower tapering of the glucocorticoid dose with extension of the course to 10 to 14 or even 21 days if needed. (See 'Colchicine' above and 'Systemic glucocorticoids' above.)

In patients who received initial therapy with IV glucocorticoids and have an ongoing inability to take oral medications, we increase the dose of glucocorticoids if tolerated (to a maximum dose of methylprednisolone 80 mg daily) or switch to IL-1 inhibitor therapy. In patients who are able to take oral medications, we also increase the dose of IV glucocorticoids and add colchicine if it is not otherwise contraindicated. (See 'Anti-interleukin 1 therapy' above and 'Colchicine' above.)

Prophylaxis for acute CPP crystal arthritis — Certain patients with frequent episodes of acute CPP crystal arthritis may benefit from prophylactic therapy, where antiinflammatory therapy is administered for a longer period of time with the goal of preventing or decreasing the frequency of acute flares. For patients with three or more attacks of acute CPP crystal arthritis annually, we suggest prophylactic therapy rather than limiting treatment to the period of each acute attack. We continue therapy until patients have not had a flare of acute CPP crystal arthritis for at least two years; we then taper and discontinue therapy as symptoms allow.

For most patients, we suggest colchicine as initial prophylactic therapy. In patients with an intolerance or contraindication to colchicine, NSAIDs are an alternative option. For patients who do not respond to or have a contraindication to both NSAIDs and colchicine, we use low-dose glucocorticoids. If the patient does not respond to or cannot use any of these agents, we use anti-IL-1 therapy. Contraindications to and adverse effects of these therapies are summarized in the table (table 2). We do not use methotrexate (MTX) as prophylactic therapy due to limited data and uncertain benefit [18].

If colchicine is used, we administer colchicine 0.6 mg twice daily. The dose can be reduced to 0.6 mg once daily or even every other day for patients with gastrointestinal symptoms (eg, diarrhea). Notable contraindications to and adverse effects of colchicine are described in detail elsewhere. (See 'Colchicine' above and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Colchicine prophylaxis'.)

If the patient does not have an adequate response to prophylactic therapy with colchicine, we add NSAIDs unless they are contraindicated.

If NSAIDs are used, we administer the lowest dose needed to control symptoms. Notable contraindications to and adverse effects of NSAIDs are described in detail elsewhere. Patients at increased risk for NSAID gastropathy and gastrointestinal bleeding may require addition of prophylactic therapy (eg, proton pump inhibitor). (See 'NSAIDs' above and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities' and "NSAIDs: Adverse cardiovascular effects".)

If glucocorticoids are used, we use the lowest dose possible and do not exceed 7.5 to 10 mg daily. Contraindications to and adverse effects of glucocorticoids are described in detail elsewhere. Low-dose glucocorticoids may be used with colchicine. (See 'Systemic glucocorticoids' above.)

If anti-IL-1 therapy is used, we use the same dosing as described for the treatment of acute CPP crystal arthritis; contraindications and adverse effects are outlined above. (See 'Anti-interleukin 1 therapy' above.)

There are no prophylactic therapies for CPPD disease that act on the CPP crystal itself. This is in contrast to prophylactic therapy in gout, where urate-lowering therapy is used to reduce serum uric acid and therefore subsequent crystal deposition and gout flares.

Several reports indicate that oral colchicine taken chronically may be effective as a prophylactic agent at this dose. In one series of 10 patients with recurrent episodes, colchicine treatment was associated with a reduction in the number of episodes at one year compared with the year prior to the initiation of therapy (10 versus 32 episodes) [19]. Evidence for reduction of acute CPP crystal arthritis flare incidence with doses lower than 0.6 mg twice daily is lacking.

CHRONIC FORMS OF CPPD DISEASE — Chronic forms of calcium pyrophosphate crystal deposition (CPPD) disease include chronic calcium pyrophosphate (CPP) crystal inflammatory arthritis and osteoarthritis (OA) or severe joint degeneration with evidence of CPPD. Treatment of chronic forms of CPPD disease depend on the patient's symptoms. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Chronic CPP crystal arthritis'.)

Chronic CPP crystal inflammatory arthritis — A small proportion of patients with CPP crystal-related inflammatory arthritis exhibit features of chronic joint inflammation that may mimic rheumatoid arthritis (RA). Patients may experience persistent oligo- or polyarticular synovitis involving small joints of the extremities, sometimes in a symmetric distribution, and typically lack rheumatoid factor or anti-citrullinated peptide antibodies. In such patients, our approach is to treat initially with antiinflammatory agents as outlined below and to proceed to disease-modifying agents as necessary. Many patients will require a combination of therapies to control the disease. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Chronic CPP crystal inflammatory arthritis'.)

Initial therapy with NSAIDs — For patients with chronic CPP crystal inflammatory arthritis, we suggest initial therapy with nonsteroidal antiinflammatory drugs (NSAIDs) rather than other antiinflammatory agents. We use the lowest NSAID dose needed to control symptoms (eg, naproxen 250 to 500 mg two times daily) and modify the dose as needed to minimize risk of adverse effects based on the patient age, comorbidities, and concomitant medications. Patients at increased risk for NSAID gastropathy and gastrointestinal bleeding may require addition of prophylactic therapy (eg, proton pump inhibitor). (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)

Inadequate response to NSAIDs — In patients with an inadequate response to NSAIDs alone after several weeks of therapy, we use one of several second-line therapeutic options. In the absence of strong evidence to support one approach over another, we choose second-line therapy based on the potential contraindications to and adverse effects of therapies in an individual patient. In many cases, combination therapy may be helpful and should be based on the compatibility of various agents as outlined below.

Second-line agents include the following:

Colchicine – In patients with an inadequate response or contraindication to NSAIDs, we prescribe a trial of colchicine (0.6 mg twice daily or lower, according to patient tolerance and accompanying disorders and medications). Colchicine may be used alone or in combination with NSAIDs. Contraindications to and adverse effects of colchicine are described elsewhere. (See 'Colchicine' above.)

Glucocorticoids – In patients whose symptoms are not controlled with NSAIDs or colchicine, or in whom there are contraindications to these agents, we use low-dose oral glucocorticoids such as prednisone in doses not exceeding 7.5 to 10 mg daily. We continue glucocorticoids for several months before slowly tapering to find the lowest possible dose that provides symptomatic relief. Low-dose glucocorticoids may be used alone or combined with colchicine. Adverse effects of glucocorticoids are discussed in detail elsewhere. (See "Pharmacologic use of glucocorticoids" and "Major adverse effects of systemic glucocorticoids".)

Hydroxychloroquine – A trial of hydroxychloroquine (HCQ) is an alternative option for patients who have uncontrolled symptoms on or contraindications to the above therapies. HCQ is dosed at 200 mg twice daily (not to exceed 5 mg/kg of patient weight) and given for six months to assess treatment efficacy, by analogy with its use in RA. HCQ may be used alone or combined with NSAIDs or colchicine. The dosing, use, monitoring, and adverse effects of HCQ are described in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease".)

There are only very limited published data available regarding the treatment of this population. Our approach, which is consistent with the recommendations of the European Alliance of Associations for Rheumatology (EULAR) consensus panel [6], is based primarily upon our clinical experience and the limited available data.

Resistant to initial and second-line therapies — Patients who do not respond to any of the above initial and second-line therapies may benefit from a trial of methotrexate (MTX), anakinra, or tocilizumab. Data supporting the efficacy of these treatments for chronic CPP crystal arthritis are very limited, and the choice of agent should therefore be based on potential adverse effects and contraindications for an individual patient.

Methotrexate – MTX may provide benefit in patients with an inadequate response to initial and second-line therapies. The dosing, monitoring, and adverse effects of MTX are the same as when it is used for RA and are described in detail separately. We continue treatment for at least three months to assess efficacy. MTX may be used alone or in combination with HCQ and/or NSAIDs. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate" and "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)

The benefits of MTX are uncertain in these patients, but limited observational studies involving a total of 15 patients suggest that low-dose MTX (administered once weekly in doses comparable to those recommended for RA) may be useful in instances of refractory CPP crystal-induced inflammation, presenting either as recurrent acute CPP crystal arthritis or as a more chronic inflammatory arthritis resembling RA [18,20,21]. By contrast, a lack of efficacy was seen in a smaller experience with three patients and in a small randomized trial with a mixed population of patients with recurrent acute attacks and chronic persistent polyarthritis [22,23].

Interleukin 1 beta inhibitorsAnakinra can be used for refractory persistent inflammation in CPPD. Dosing, contraindications, and adverse effects are the same as those outlined for their use in treatment of acute CPP crystal arthritis. Serious infections are the major barrier to its use. It may be used alone or in combination with low-dose glucocorticoids. Longer-acting interleukin 1 (IL-1) inhibitors such as canakinumab and rilonacept may be useful in CPPD but have not been studied. (See 'Anti-interleukin 1 therapy' above.)

TocilizumabTocilizumab has also been proposed for the treatment of refractory chronic CPP crystal arthritis. Dosing, contraindications, and adverse effects are the same as those described for RA (see "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'). Very preliminary case collections showed some efficacy but also an increased risk for major infection [24].

Osteoarthritis with CPPD — Some patients with CPPD have concomitant OA without symptomatic episodes of inflammatory arthritis, which is classified as OA with CPPD. As an example, a patient with knee pain attributed to OA may have a knee radiograph demonstrating chondrocalcinosis suggestive of CPPD or a noninflammatory joint effusion that shows CPP crystals on microscopy. The treatment approach for patients with OA with CPPD is the same as that for OA without CPPD, as discussed in detail elsewhere. (See "Overview of the management of osteoarthritis" and "Overview of surgical therapy of knee and hip osteoarthritis".)

Severe joint degeneration — Patients with severe joint degeneration in the presence of CPPD are treated with the same approach used for patients with neuropathic joint disease (Charcot arthropathy) based upon a lack of clinical or research evidence to inform any alternative approach. (See "Diabetic neuroarthropathy", section on 'Treatment'.)

TREATMENT OF ASSOCIATED DISEASES — Patients who have a disease associated with calcium pyrophosphate crystal deposition (CPPD) (table 1) should receive specific therapy directed at the underlying disorder; however, such interventions usually do not reverse CPPD disease.

Among patients with metabolic disorders associated with CPPD, like hemochromatosis and hyperparathyroidism, successful treatment of the metabolic disorder has not resulted in reversal of cartilage calcification and new calcifications have developed in some individuals [25-28]. However, there are reports of improvement in meniscal calcification and symptoms due to chronic CPPD disease in patients being treated for hypomagnesemia [29,30]. Evaluation and treatment of hypomagnesemia is discussed in detail elsewhere. (See "Hypomagnesemia: Evaluation and treatment".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gout and other crystal disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Calcium pyrophosphate deposition disease (The Basics)")

Beyond the Basics topics (see "Patient education: Calcium pyrophosphate crystal deposition (CPPD) disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

General approach – The approach to treatment of calcium pyrophosphate crystal deposition (CPPD) disease depends on the subtype, which is based on clinical manifestations and acuity. Asymptomatic patients with evidence of cartilage calcification (also called chondrocalcinosis) on imaging do not need any specific treatment. (See 'General approach' above.)

Acute CPP crystal arthritis (pseudogout) – Treatment for acute calcium pyrophosphate (CPP) crystal arthritis consists of supportive measures for symptomatic relief (eg, applying ice, resting the affected area, taking analgesic medications) as well as antiinflammatory therapy for most patients. (See 'Supportive measures for all patients' above.)

Initial antiinflammatory therapy – We use antiinflammatory therapy for most patients with acute CPP crystal arthritis. While supportive measures may provide some relief, they are often insufficient. (See 'Selection of agent' above.)

Concomitant septic arthritis can be present; suggestive features may include signs and symptoms of systemic inflammation (eg, fever), rash, and a nearby foci of infection (eg, cellulitis). In patients with possible acute CPP crystal arthritis and septic joint, we treat with colchicine rather than with other antiinflammatory therapies. Patients should be evaluated and treated as appropriate for septic joint, as detailed elsewhere. (See 'Colchicine' above and "Septic arthritis in adults".)

For patients with low suspicion of a septic joint, we use the following approach (algorithm 1):

-For patients with one or two affected joints that are amenable to arthrocentesis, we suggest thorough joint aspiration and treatment with intraarticular glucocorticoids rather than systemic antiinflammatory therapy (Grade 2C). (See 'Intraarticular glucocorticoids' above.)

-For patients with a presentations that is not amenable to arthrocentesis (eg, multiple joints, knuckles) and when an experienced clinician is not available to perform this procedures, reasonable alternatives include we use oral glucocorticoids, nonsteroidal antiinflammatory drugs (NSAIDs), or colchicine. Selection of therapy should be based on the patient’s prior treatment response and an evaluation of the potential adverse effects and contraindications (table 2). (See 'Systemic glucocorticoids' above and 'NSAIDs' above and 'Colchicine' above.)

If the patient cannot take oral medications, we treat with intravenous (IV) glucocorticoids in the inpatient setting or intramuscular (IM) glucocorticoid injection in the outpatient setting. (See 'Systemic glucocorticoids' above.)

We reserve treatment with interleukin 1 (IL-1) inhibitors (eg, anakinra, canakinumab) for patients who cannot receive glucocorticoids, NSAIDs, or colchicine; clinical experience with these drugs is more limited. (See 'Anti-interleukin 1 therapy' above.)

Resistant disease – We consider patients to have resistant disease if they have moderate to severe symptoms that are persistent or worsening despite 48 to 72 hours of treatment. The management of such patients depends upon the prior initial therapy used and the risks of various therapies for an individual patient (algorithm 2). (See 'Resistant disease' above.)

Prophylaxis – For patients with three or more attacks of acute CPP crystal arthritis annually, we suggest prophylactic therapy with colchicine rather than limiting treatment to the period of each acute attack (Grade 2C). In patients with an intolerance or contraindication to colchicine, NSAIDs are an alternative option. (See 'Prophylaxis for acute CPP crystal arthritis' above.)

Chronic CPP crystal inflammatory arthritis – For patients with chronic CPP crystal inflammatory arthritis, we suggest initial therapy with NSAIDs rather than other antiinflammatory agents (Grade 2C). In patients with an inadequate response to NSAIDs alone after several weeks of therapy, second-line therapies include colchicine, low-dose oral glucocorticoids, and hydroxychloroquine (HCQ). (See 'Chronic CPP crystal inflammatory arthritis' above.)

Treatment of associated diseases – Patients who have a disease associated with CPPD (table 1) should receive specific therapy directed at the underlying disorder; however, such interventions usually do not reverse CPPD disease. (See 'Treatment of associated diseases' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Michael A Becker, MD, and Lawrence Ryan, MD, who contributed to an earlier version of this topic review.

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