INTRODUCTION — Precipitation of crystals of calcium pyrophosphate dihydrate (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 — The names traditionally used for the varying clinical manifestations of calcium pyrophosphate (CPP) crystal deposition (CPPD) disease include pseudogout, chondrocalcinosis, and pyrophosphate arthropathy. Each of these terms has both useful and problematic features [4,5] (see "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Terminology'). A European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) consensus panel rigorously reviewed the literature regarding CPP crystal deposition and proposed changes in nomenclature, summarized levels of evidence regarding diagnosis, and made recommendations for management [6,7]. A commentary has also been published concerning the EULAR committee recommendations, authored by experts from the United States, that generally supports use of the EULAR terminology [4], with calcium pyrophosphate deposition disease (also abbreviated as CPPD disease) as the umbrella term for all instances of CPP crystal occurrence.
In view of its wider acceptance in the literature, we will place primary emphasis on the EULAR task force terminology [6,7] in the discussion below. Nevertheless, despite their limitations, the clinical syndromes and findings implied by the traditional terms are likely to be retained by some clinicians on the basis of their resemblances to common clinical disorders familiar to the clinician. Familiarity with the older nomenclature may, in addition, be useful in instances where literature searches using only the EULAR task force terms overlook citations indexed under the traditional terms. For these reasons, the traditional terms appear in parentheses following the EULAR designation:
●Asymptomatic CPPD disease (asymptomatic CPPD)
●Acute CPP crystal arthritis (pseudogout) (see 'Acute CPP crystal arthritis ('acute pseudogout')' below)
●Chronic CPP crystal arthritis
•Chronic CPP crystal inflammatory arthritis (pseudo-rheumatoid arthritis) (see 'Chronic CPP crystal inflammatory arthritis ('pseudo-rheumatoid arthritis')' below)
•Osteoarthritis (OA) with CPPD, with or without superimposed acute attacks (pseudo-OA) (see 'Joint degeneration ('OA with CPPD')' below)
●Severe joint degeneration (pseudo-neuropathic joint disease) (see 'Severe joint degeneration/Pseudo-neuropathic joint disease' below)
●Spinal involvement
GENERAL APPROACH — The treatment of acute calcium pyrophosphate (CPP) crystal arthritis ("acute pseudogout") is aimed at reducing the pain and disability associated with the inflammatory response to CPP crystal deposition (CPPD) and is modeled on the treatment of gout flare (acute monosodium urate crystal deposition disease), the other major form of acute crystalline arthritis (see 'Acute CPP crystal arthritis ('acute pseudogout')' below and 'Prophylaxis for acute CPP crystal arthritis' below). However, the evidence directly examining and supporting this approach is quite limited. In patients in whom a disease associated with CPPD is present, specific therapy directed at the underlying disorder should be initiated; 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'.)
Approaches to the treatment and prophylaxis of acute CPP crystal arthritis, and for the treatment of chronic CPP crystal inflammatory arthritis or degenerative joint disease, are utilized as necessitated by the clinical presentation (see 'Acute CPP crystal arthritis ('acute pseudogout')' below and 'Chronic CPP crystal inflammatory arthritis ('pseudo-rheumatoid arthritis')' below and 'Chronic and progressive calcium pyrophosphate crystal deposition (CPPD)' below and 'Joint degeneration ('OA with CPPD')' below). These treatment approaches are based upon clinical experience and not upon controlled trials. The aforementioned European Alliance of Associations for Rheumatology (EULAR) panel has made a careful analysis of the scant literature supporting treatment strategies, as has a subsequent review [6-8]. In general, their recommendations concur with ours, but the limitations of these recommendations and the importance of further clinical research in CPPD disease have also been noted.
ACUTE CPP CRYSTAL ARTHRITIS ('ACUTE PSEUDOGOUT') — One approach or, more often, a combination of approaches, including local and systemic measures, is appropriate for the treatment of attacks of acute calcium pyrophosphate (CPP) crystal arthritis. The initial treatment interventions depend upon the number of involved joints and whether joint injections are feasible. (See 'Initial treatment/one or two joints' below and 'Initial treatment/more than two joints' below.)
Initial treatment/one or two joints — Our preferred treatment for acute CPP crystal arthritis includes the administration of antiinflammatory medication, usually by intraarticular injection, supported by local measures to reduce symptoms:
●In patients with acute CPP crystal arthritis with no more than two acutely inflamed joints, we suggest thorough joint aspiration and intraarticular glucocorticoid injection as initial treatment rather than using oral antiinflammatory agents. In patients in whom joint injection is not feasible, alternative measures should be used. (See 'Initial treatment/more than two joints' below.)
Joint 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, rash, and associated foci of infection, and the absence of local signs such as a purulent appearing synovial fluid. In patients suspected of infection, glucocorticoid injection should be deferred until synovial fluid culture is negative, and interventions other than glucocorticoid injection should be employed. Absence of infection is further supported by a lack of microorganisms on Gram stain, and by sterile synovial fluid and blood cultures. (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. However, the occurrence of a worsening of symptoms shortly after aspiration and injection, a failure to achieve even a partial response within 48 to 72 hours, or the development of additional inflamed joints may necessitate use of the same measures used in patients with multiple involved joints, such as a brief addition of an oral antiinflammatory medication (a nonsteroidal antiinflammatory drug [NSAID], colchicine, or a glucocorticoid), with prompt discontinuation as the flare subsides (see 'Initial treatment/more than two joints' below). Patients resistant to these approaches may require additional or alternative measures. (See 'Resistant disease' below.)
●Supportive measures used for symptomatic relief include application of ice or cool packs and immobilization and resting of the joint by restriction of weightbearing or routine joint use in all patients for 48 to 72 hours, employing splints when necessary. The use of these strategies is based largely upon our clinical experience and the similar experience of other experts. (See "Joint aspiration or injection in adults: Technique and indications" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)
Initial treatment/more than two joints — When more than two joints are inflamed or small joints not amenable to intraarticular glucocorticoid injection are involved, focused joint injection is usually an impractical approach. In this setting, systemic antiinflammatory therapy is warranted, employing agents typically used for the treatment of acute gout (see "Treatment of gout flares"). These include: NSAIDs, which may, however, be contraindicated in older adults, the population especially susceptible to acute attacks of pseudogout (see 'NSAIDs' below); colchicine, which is particularly useful if a low-dose regimen is initiated within hours of attack onset (see 'Colchicine' below); and glucocorticoids, which are efficacious in patients unable to take NSAIDs or colchicine (see 'Unable to use oral NSAIDs and colchicine' below). The choice of which oral antiinflammatory to prescribe is largely determined by patient clinical features and history of the patient's current and prior flares rather than inherently superior efficacy of any one of these classes of antiinflammatory agents. (See "Treatment of gout flares", section on 'General therapeutic principles' and "Treatment of gout flares", section on 'Initial treatment'.)
Analgesic medications (such as acetaminophen or opioids) or NSAIDs at analgesic rather than antiinflammatory dose are frequently prescribed for acute crystal-induced arthritis but should not substitute for the use of medications with antiinflammatory properties at the doses provided.
NSAIDs — In patients with acute CPP crystal arthritis who are not treated with arthrocentesis and injection, we suggest NSAIDs administered in antiinflammatory doses (eg, naproxen 500 mg twice daily). Any NSAID can be used in this setting, although we avoid high-dose indomethacin because of its common adverse effects, particularly in this older adult population. Adverse effects are uncommon with brief courses of therapy but may include gastrointestinal intolerance and worsening of renal function.
There are important contraindications to NSAIDs, including:
●Chronic kidney disease with creatinine clearance (CrCl) of less than 60 mL/min per 1.73 m2 (see "Nonselective NSAIDs: Overview of adverse effects", section on 'Renal effects' and "Overview of the management of chronic kidney disease in adults", section on 'Definition and classification' and "Assessment of kidney function")
●Active duodenal or gastric ulcer (see "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity")
●Cardiovascular disease, particularly heart failure or hypertension that is difficult to control (see "NSAIDs: Adverse cardiovascular effects")
●NSAID allergy (see "NSAIDs (including aspirin): Allergic and pseudoallergic reactions")
●Ongoing treatment with anticoagulants (see "Nonselective NSAIDs: Overview of adverse effects", section on 'Interaction with antiplatelet agents and anticoagulants')
The approach to the use of NSAIDs is the same as in patients with gout flare, as described in detail separately (see "Treatment of gout flares", section on 'NSAID therapy'). Except in circumstances when treatment is initiated within 24 hours of flare onset, NSAID treatment is more likely than colchicine, in our experience, to provide pain relief and reduced disability within 24 to 48 hours in acute oligo- or polyarticular CPP crystal arthritis. In patients suited for NSAID use, a brief flare-limited course of NSAID agents achieves flare relief in about the same timeframe as oral glucocorticoids with less likelihood of rebound flares, as often occurs when glucocorticoid doses are rapidly tapered. We would consider failure to result in flare symptom relief in 48 to 72 hours as a sign of an inadequate response and an indication to switch to glucocorticoid treatment.
We also 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. NSAIDs are most effective if treatment is initiated within 48 hours of the onset of symptoms. The 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. High-dose celecoxib (a single dose of 400 mg followed by an additional 200 mg daily), a cyclooxygenase (COX)-2 selective inhibitor, is an alternative to nonselective NSAIDs for gout flare therapy [9] but has not been studied in randomized trials for acute CPP crystal arthritis.
The NSAID 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. It is likely to be shorter in patients treated within the first 24 hours of symptom onset and may be longer in patients in whom treatment is not begun until several days later.
Colchicine — In patients in whom treatment for acute CPP crystal arthritis is initiated within about 24 hours of onset and whose clinical and concomitant medication profiles permit its consideration, we suggest oral colchicine in a low-dose regimen as initially recommended for the treatment of gout flare, rather than using oral glucocorticoids [7,10]. For regimens using low-dose colchicine, no more than 1.8 mg of colchicine is taken orally in the first 24 hours of treatment, followed by 0.6 mg colchicine taken twice daily until the attack abates [10]. This strategy is based upon a treatment regimen for gout flare and not on studies of acute CPP crystal arthritis.
The benefit achieved by use of colchicine within the first 24 hours after flare onset is likely to be comparable to that with NSAIDs or glucocorticoids and less likely than oral glucocorticoids to result in rebound flares with discontinuation of treatment after attack resolution. The use of colchicine in acute CPP crystal arthritis is supported by similarities in the mechanisms of acute CPP crystal and acute monosodium urate crystal-induced inflammation, the recommendation of the EULAR expert consensus group [7], and our clinical experience.
The approach to the use of colchicine is the same as in patients with gout flare. The use of colchicine and its adverse effects and risks are described in detail separately. (See "Treatment of gout flares", section on 'Colchicine therapy'.)
Contraindications to the use of colchicine in usual doses and schedules of administration include:
●Use of colchicine (eg, for prophylaxis) within the prior 14 days in patients with severe hepatic impairment or severe renal impairment (CrCl of <30 mL/min)
●Concomitant use of a medication that strongly inhibits the cytochrome P450 system component CYP3A4 (table 1) or that inhibits the membrane P-glycoprotein multidrug resistance transporter (P-gp) in the presence of renal or hepatic impairment [11]. (See "Treatment of gout flares", section on 'Safety of colchicine'.)
Common adverse effects of colchicine may include diarrhea and abdominal cramping, but these are less likely in patients who receive no more than 1.8 mg in total on the first day compared with patients receiving higher doses, such as 0.6 mg every one to two hours until symptom relief or intolerance (as was historically employed) [12]. Gastrointestinal symptoms (diarrhea, abdominal pain, nausea and vomiting) are the most common adverse effects. A readily reversible peripheral neuropathy, another common toxicity, does not occur frequently during the brief period of colchicine administration for acute CPP crystal arthritis. More severe colchicine toxicities, which may include combinations of serious, life-threatening or fatal adverse events 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 [13].
Unable to use oral NSAIDs and colchicine — In patients in whom NSAIDs and colchicine are contraindicated, such as patients who are postoperative or have renal or hepatic dysfunction, we suggest systemic glucocorticoids for the treatment of acute attacks (see 'Acute CPP crystal arthritis ('acute pseudogout')' above and 'Initial treatment/one or two joints' above). The following approaches are described in detail elsewhere (see "Treatment of gout flares"):
●Not candidates for joint injection – Despite wide use in practice of oral glucocorticoids as first-line therapy for gout flare, it is largely since about 2007 to 2008 that randomized trials comparing glucocorticoid and NSAID therapy have confirmed similar efficacy and safety profiles for these two classes of antiinflammatory agents [14-16]. In patients who are not candidates for intraarticular glucocorticoid injection, therefore, we increasingly 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 10 to 14 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. If a response to oral glucocorticoid therapy is not evident, parenteral glucocorticoids may be required. Glucocorticoids should be used with caution in patients with heart failure, poorly controlled hypertension, or glucose intolerance, but they may be used in patients with moderate to severe renal insufficiency. (See "Treatment of gout flares", section on 'Oral glucocorticoids'.)
Since attacks of acute CPP crystal arthritis are self-limited, an alternative option is managing the symptoms using supportive measures until they resolve with analgesics, rest, splinting, and icing. (See 'Initial treatment/one or two joints' above.)
●Need for parenteral (non-intraarticular) therapy – In patients who are unable to take oral agents and who are not appropriate candidates for intraarticular injection, we use parenteral glucocorticoids in doses equivalent to those suggested above for oral glucocorticoids. Although corticotropin (adrenocorticotropic hormone [ACTH]) has been reported to be beneficial for acute gout flare treatment, cost and limited availability restrict the use of parenteral ACTH treatment for gout, and ACTH therapy has been less well-studied for acute CPP crystal arthritis than for gouty arthritis. (See "Treatment of gout flares", section on 'Parenteral glucocorticoids'.)
We do not administer colchicine intravenously, and we strongly advise against such use because of the risk of serious adverse effects, including death, which are associated with the intravenous administration of this drug. Although intravenous colchicine can reduce the inflammation of pseudogout, the potential dangers of this approach have led to withdrawal of approval in the United States for the distribution of colchicine for administration by the intravenous route.
Resistant disease — In patients with symptoms that are not improving as expected, the patient's adherence to the treatment program should be assessed. Also, alternative agents should be considered, depending upon what has already been tried, and the diagnosis should be reevaluated. If it was not already performed earlier in the attack, arthrocentesis may be required to exclude other causes of a flare of acute inflammatory arthritis, including infection. It is important not to become overly concerned if attacks do not begin to resolve within one to three days of starting treatment, because most acute flares of acute CPP crystal arthritis resolve within 7 to 14 days. Regardless of the type of therapy, resolution of the joint flare and the accompanying physical disability are much more rapid if the patient is treated early in the attack. Thus, truly resistant disease is uncommon, although 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' and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Differential diagnosis'.)
The management of patients with persistent symptoms due to a confirmed acute flare of pseudogout depends upon the prior therapy and upon the patients' comorbidities:
●In some patients being treated with NSAIDs, a more prolonged than usual course of therapy may be required, especially if treatment was not started until the flare was ongoing for several days. Patients with a flare that appears resistant to an adequate course of NSAID therapy may respond to treatment with glucocorticoids. (See 'Unable to use oral NSAIDs and colchicine' above.)
●In patients who are being treated with colchicine but who do not have contraindications to NSAIDs, it may be necessary to switch to NSAID therapy if no improvement is seen within several days, especially if the attack was not treated early. In patients in whom NSAIDs are contraindicated, glucocorticoids may be required. (See 'NSAIDs' above and 'Unable to use oral NSAIDs and colchicine' above.)
●The management of recurrent (or "rebound") attacks following treatment with glucocorticoids may require slower tapering of the glucocorticoid dose with extension of the course to 10 to 14 or even 21 days if needed. (See 'Unable to use oral NSAIDs and colchicine' above.)
●Interleukin (IL) 1 inhibitors show promise for suppressing crystal-induced inflammation, but data from large clinical trials are not available [17-19]. Anakinra, an IL-1 receptor antagonist protein, has been used in patients with frequent flares in whom all other available treatments have failed or in whom "rebound flares" occur even when glucocorticoid treatment is appropriately tapered [18]. Although IL-1 antagonist agents are available for the treatment of other conditions, such as anakinra for rheumatoid arthritis and canakinumab and rilonacept for cryopyrin-associated periodic syndromes, only the first two have shown clear efficacy in treatment of acute crystal arthritis (see "Treatment of gout flares", section on 'Investigational therapy'). Use of IL-1 inhibitors for acute crystal arthritis remains investigational in the United States.
Prophylaxis for acute CPP crystal arthritis — In patients with three or more attacks of acute CPP crystal arthritis annually, we suggest prophylaxis with colchicine (0.6 mg twice daily) rather than limiting treatment to the period of each acute attack. 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 marked reduction in the number of episodes at one year compared with the year prior to the initiation of therapy (10 versus 32 episodes) [20].
Particular attention should be given to comorbidities (including renal and hepatic dysfunction, drug intolerance, and potential drug interactions) that may limit the chronic use of this agent and that may be more common in the older adults at greater risk for acute CPP crystal arthritis. (See "Treatment of gout flares", section on 'Safety of colchicine' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Colchicine prophylaxis'.)
If the recommended dose of 0.6 mg twice daily results in abdominal distress or diarrhea, side effects that commonly occur among older patients, a reduction in dose to 0.6 mg once daily or even every other day may increase colchicine tolerability. However, evidence for reduction of acute CPP crystal arthritis flare incidence with doses lower than 0.6 mg twice daily is lacking.
In patients with an inadequate response to colchicine alone or intolerant of a lowered dose, but without contraindications to the use of an NSAID, these agents (eg, naproxen) may be used in place of or in addition to colchicine therapy.
Methotrexate has undergone very limited study as prophylactic therapy in patients with recurrent episodes of acute CPP crystal arthritis; its benefits remain uncertain, and its use for flare prevention is not advised [21]. (See 'Chronic CPP crystal inflammatory arthritis ('pseudo-rheumatoid arthritis')' below.)
CHRONIC CPP CRYSTAL INFLAMMATORY ARTHRITIS ('PSEUDO-RHEUMATOID ARTHRITIS') — A small proportion of patients with calcium pyrophosphate (CPP) crystal-related inflammatory arthritis exhibit features of chronic joint inflammation that may mimic rheumatoid arthritis, such as persistent oligo- or polyarticular synovitis involving small joints of the extremities, sometimes in a symmetric distribution; such patients typically lack rheumatoid factor or anti-citrullinated peptide antibodies (see "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Chronic CPP crystal inflammatory arthritis'). In such patients, our approach is to treat initially with antiinflammatory agents and, if necessary, to proceed to disease-modifying agents, in the following order of preference, with the goal of therapy being symptomatic control. We will often use combinations of therapies if this is required to control the disease:
●Initial treatment – We initiate treatment in this group of patients with nonsteroidal antiinflammatory drugs (NSAIDs; eg, naproxen 250 to 500 mg two to three times daily). When prescribing NSAIDs for chronic CPP crystal inflammatory arthritis, the prolonged need for treatment and consideration of patient age, comorbidities, and concomitant medications often indicates a need to modify dosing. Such issues should prompt efforts to use the lowest NSAID dose needed to control symptoms. Patients at increased risk for NSAID gastropathy and gastrointestinal bleeding may require cotherapy with a gastroprotective proton pump inhibitor as well. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)
●Inadequate response to NSAIDs – We use one of several second-line therapeutic options in patients with an inadequate response to NSAIDs alone. These include either:
•Colchicine – A trial of colchicine (0.6 mg twice daily or lower, according to patient tolerance and accompanying disorders and medications) for 8 to 12 weeks.
•Hydroxychloroquine – A trial of hydroxychloroquine (HCQ; usually 200 mg twice daily), which by analogy with its use in rheumatoid arthritis, requires administration for six months or more to document treatment efficacy. HCQ may also be combined with NSAIDs or colchicine. There is little clinical trial support for efficacy of this usually well-tolerated drug, but European Alliance of Associations for Rheumatology (EULAR) recommendations for treatment of pseudo-rheumatoid arthritis include support for the use of this widely used antirheumatic agent. The dosing, use, monitoring, and adverse effects of HCQ are described in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease".)
•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.
●Resistant to initial therapies and second-line therapeutic agents (third-line approaches) – Methotrexate (MTX) may provide benefit in patients with an inadequate response to NSAIDs, colchicine, low-dose glucocorticoids, and HCQ as the sole disease-modifying antirheumatic drug (DMARD). 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 rheumatoid arthritis) 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 rheumatoid arthritis [21-23]. 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 [24,25]. MTX may be used in combination with HCQ. The dosing, use, monitoring, and adverse effects of MTX are described in detail separately. (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'.)
Anakinra can be used for refractory persistent inflammation in CPPD, although serious infections are the major barrier to its use. There are some very preliminary studies on the use of tocilizumab for CPPD. These case collections showed some efficacy again balanced by increases in risks for major infection [26].
There are only very limited published data available regarding the treatment of this population; our approach is based upon our clinical experience and the limited available data, but is consistent with the recommendations of a consensus panel from the EULAR [7].
OTHER CHRONIC PRESENTATIONS
Chronic and progressive calcium pyrophosphate crystal deposition (CPPD) — In patients with persistent clinical manifestations of calcium pyrophosphate (CPP) crystal deposition (CPPD) disease despite correction of associated metabolic disorders, management of the joint disease follows the approaches used for idiopathic CPPD. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease", section on 'Post-diagnostic evaluation for associated diseases' and 'Acute CPP crystal arthritis ('acute pseudogout')' above and 'Chronic CPP crystal inflammatory arthritis ('pseudo-rheumatoid arthritis')' above and 'Joint degeneration ('OA with CPPD')' below.)
In contrast to the relatively routine success in the treatment of attacks of acute CPP crystal arthritis, there is no proven effective therapy to prevent progressive calcium pyrophosphate crystal deposition or to remove crystals already deposited. In this regard, the potential therapeutic use of probenecid, an inhibitor of transmembrane anion transport, to retard extracellular pyrophosphate elaboration [27,28] is an intriguing idea that is under investigation.
Even among patients with associated metabolic disorders, such as 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 [29-32]. However, some instances of treatment-associated resolution of the presumed CPP crystal deposits have been reported, including:
●Long-term administration of magnesium in some patients with chronic hypomagnesemia may decrease meniscal calcification [33]. (See "Hypomagnesemia: Evaluation and treatment".)
●Symptomatic improvement was noted in some patients with sporadic CPPD crystal deposition during a controlled trial of magnesium carbonate supplementation administered as 10 mEq three times daily, but radiographic improvement was not detected [34].
Joint degeneration ('OA with CPPD') — The treatment approaches for patients in whom joint degeneration is the major manifestation of CPPD disease and is unaccompanied by episodic acute CPP crystal arthritis are the same as those employed for osteoarthritis (OA). (See "Overview of surgical therapy of knee and hip osteoarthritis" and "Overview of the management of osteoarthritis".)
Severe joint degeneration/Pseudo-neuropathic joint disease — Patients with pseudo-neuropathic joint disease are treated with the same approach as 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'.)
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 and role of treating any underlying disorder – Treatment of calcium pyrophosphate crystal deposition (CPPD) disease is based largely upon clinical experience in both CPPD disease and gout, given the paucity of randomized trials in this disorder. In patients with an underlying disorder associated with CPP crystal deposition, specific therapy directed at the underlying disorder should also be initiated, although it usually does not reverse CPPD disease. (See 'General approach' above and 'Initial treatment/one or two joints' above and 'Chronic and progressive calcium pyrophosphate crystal deposition (CPPD)' above.)
●Choosing treatment for acute CPP arthritis – The initial treatment interventions for acute CPP crystal arthritis ("acute pseudogout") depend upon the number of involved joints, whether joint injections are feasible, and the potential risks of adverse events with a given agent due to patient characteristics. (See 'Acute CPP crystal arthritis ('acute pseudogout')' above.)
•Aspiration and injection if only one or two involved joints – In patients with acute CPP crystal arthritis with no more than two acutely inflamed joints, we suggest joint aspiration and intraarticular glucocorticoid injection as initial treatment rather than oral agents. For injections into large joints, including the knees and shoulders, we use triamcinolone acetonide (0.75 to 1 mL, 30 to 40 mg) mixed with 1 or 2 mL of 1% lidocaine. When smaller joints are involved in an acute attack, smaller doses of the respective glucocorticoid preparations can be utilized. In patients with features suggesting joint infection, we defer glucocorticoid injection until infection has been excluded by synovial fluid Gram stain and culture and treat as in patients who are unable to undergo arthrocentesis. (See 'Acute CPP crystal arthritis ('acute pseudogout')' above and 'Initial treatment/one or two joints' above.)
•Oral therapy with NSAID, colchicine, or glucocorticoids – In patients with acute CPP crystal arthritis who are not treated with arthrocentesis and injection, we suggest oral antiinflammatory therapy with: a nonsteroidal antiinflammatory drug (NSAID; eg, naproxen 500 mg twice daily); or oral colchicine in a low-dose regimen (eg, 1.2 mg followed by 0.6 mg one hour later, then 0.6 mg twice daily); or an oral glucocorticoid, such as prednisone (given as 30 to 50 mg once daily or in two divided doses until flare resolution begins and then tapered over 7 to 10 days or more). Selection among these agents is best made on an individualized assessment of patient medical history (including comorbidities and concomitant medications) and flare history (eg, duration prior to treatment, prior medication experience). Parenteral glucocorticoids may be utilized if oral glucocorticoid therapy is ineffective or not feasible. (See 'Acute CPP crystal arthritis ('acute pseudogout')' above and 'Initial treatment/more than two joints' above and 'NSAIDs' above and 'Colchicine' above.)
•Low dose oral colchicine for treatment within 24 hours of flare onset – In patients with acute CPP crystal arthritis in whom oral antiinflammatory treatment is initiated within 24 hours of flare onset, we often prescribe low-dose oral colchicine rather than an NSAID or an oral glucocorticoid. (See 'Acute CPP crystal arthritis ('acute pseudogout')' above and 'Colchicine' above.)
•Colchicine prophylaxis for multiple recurrent flares – We suggest prophylaxis with colchicine for patients with three or more attacks of acute CPP crystal arthritis annually rather than limiting treatment to the period of each acute attack, with appropriate dose adjustment for renal and hepatic dysfunction, drug intolerance, and potential drug interactions. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout" and 'Prophylaxis for acute CPP crystal arthritis' above.)
●Management of chronic CPP crystal inflammatory arthritis – In patients with chronic CPP crystal inflammatory arthritis ("pseudo-rheumatoid arthritis"), we use NSAIDs and/or colchicine, followed, if needed, by hydroxychloroquine (HCQ), low-dose glucocorticoids, and methotrexate (MTX). (See 'Chronic CPP crystal inflammatory arthritis ('pseudo-rheumatoid arthritis')' above.)
●Osteoarthritis with CPPD without acute flares – The treatment approaches for patients in whom osteoarthritis (OA) with CPPD ("joint degeneration") is the major manifestation of CPPD crystal deposition disease and is unaccompanied by episodic acute CPP crystal arthritis are the same as those employed for OA and other associated conditions. (See 'Chronic and progressive calcium pyrophosphate crystal deposition (CPPD)' above and 'Joint degeneration ('OA with CPPD')' 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.
