Calcium Pyrophosphate Dihydrate Deposition (CPPD) Disease

Definition, Etiology, PathogenesisTop

Calcium pyrophosphate dihydrate deposition (CPPD) disease, also known as pseudogout and pyrophosphate arthropathy, refers to a group of diseases caused by accumulation of calcium pyrophosphate dihydrate (CPP) crystals. CPPD disease most commonly occurs in articular fibrocartilage and hyaline cartilage. Chondrocalcinosis is caused by deposits of calcium salts (not only CPP) in joint cartilage; these are identified using imaging studies or during histologic examination.

The etiology of CPPD disease remains unknown. The disease may be familial with an autosomal dominant inheritance. Secondary generalized (polyarticular) CPPD may develop in patients with the following associated pathologies:

1) Endocrine disorders (thyrotoxicosis, hypothyroidism, hyperparathyroidism).

2) Hematologic disorders (hemochromatosis).

3) Electrolyte-related disorders (hypomagnesemia, hypophosphatemia).

4) Joint disorders (gout, previous joint injury).

5) Exogeneous factors (persons receiving glucocorticoid therapy).

Localized CPPD may be associated with joint instability, prior resection of a joint meniscus, amyloid deposits, and biochemical abnormalities of cartilage matrix. This form of CPPD may be initiated by aging or injury and is mediated by factors such as transforming growth factor beta.

CPP crystals formed in cartilage may move to synovium and synovial fluid and cause inflammation. The underlying mechanism is the same as in gout (see Gout). Arthritis is often accompanied by degenerative lesions involving cartilage and bone.

Clinical Features and Natural HistoryTop

CPPD disease rarely occurs before the age of 50 years. It is most frequently asymptomatic (isolated chondrocalcinosis or chondrocalcinosis coexisting with osteoarthritis) but may also cause symptoms of arthritis.

The following is a 6-phase classification for CPPD-related arthritis:

1) Acute CPP arthritis: Typically monoarticular, involving large joints (eg, knee).

2) Chronic CPP arthritis: Typically polyarticular, involving small and large joints.

3) Osteoarthritis with CPPD with an inflammatory component (chronic polyarticular arthritis with superimposed inflammatory acute arthritic episodes).

4) Osteoarthritis with CPPD without an inflammatory component (chronic polyarticular arthritis but without an inflammatory component).

5) Asymptomatic CPPD: Articular CPPD without signs or symptoms.

6) Pseudoneuropathic CPPD: Severe destructive arthropathy resembling neuropathic arthritis.

Episodes of acute CPPD arthritis are similar to those of gout, but symptoms develop less rapidly, over 6 to 24 hours, and pain is less severe. Joint pain lasts from 1 day to 4 weeks and most frequently affects the knees, with occasional involvement of shoulders, wrists, and the first metatarsophalangeal (MTP) joint of the foot.

Chronic CPPD arthritis may involve several joints concurrently and resemble rheumatoid arthritis. Episodes of acute arthritis may be superimposed on chronic arthritic disease.

CPPD-associated osteoarthritis most often affects the knee, although wrists, MTP joints, elbows, shoulders, hips, ankles, the tarsus, and the metatarsus may also be involved. Changes are typically symmetric. Unlike in osteoarthritis without CPPD, patients usually have narrowing of the lateral joint space of the knee and osteophytes and inflammation are more frequent. In addition to peripheral joints, CPPD may also involve the lumbar spine, causing symptoms similar to ankylosing spondylitis. Peripheral joint involvement may resemble joint changes caused by peripheral neuropathy (Charcot joints).

DiagnosisTop

A complete history is of key importance and should include symptoms, chronicity and pattern of arthritis, associated conditions, and records of previous treatment. The accompanying physical examination should include a complete joint examination as well as close observation of the skin and examination for other extra-articular signs of inflammatory arthritis.

The diagnosis of CPPD disease requires the documented presence of CPP crystals in synovial fluid. CPPD can be diagnosed on the basis of joint lesions found on imaging studies and histologic examination; the absence of deposits on radiographs does not exclude the diagnosis.

Diagnostic Tests

1. Synovial fluid examination: Definitive diagnosis relies on the identification of CPP crystals based on synovial fluid examination. During an attack of acute arthritis, synovial fluid may be milky, slightly blood-stained, and inflammatory. CPP crystals are present in the sediment and are often visible in the cytoplasm of granulocytes, macrophages, or both. When carefully examined under polarized light microscopy, CPP crystals may reveal weakly positively birefringent rhomboid-shaped crystals (although the absence of birefringence does not exclude CPPD arthritis).

2. Radiography: CPP crystal deposits may be found in hyaline cartilage and fibrocartilage, tendons, ligaments, fascia, and joint capsules. Most often deposits present as punctate linear radiodense areas within the cartilage of the knee, hip, or elbow joints, and often also in the wrists. In the knee, triangular deposits are often seen within the menisci. In the spine, deposits may be found within the intervertebral cartilage. Radiographic examination of the knees, pelvis, and wrist should be conducted in all patients with suspected polyarticular CPPD. Plain radiographs are valuable to confirm a diagnosis of CPPD, but the absence of chondrocalcinosis should not be used to exclude the diagnosis.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to significant imprecision and indirectness. Utsinger PD, Resnick D, Zvaifler NJ. Wrist arthropathy in calcium pyrophosphate dihydrate deposition disease. Arthritis Rheum. 1975 Sep-Oct;18(5):485-91. PubMed PMID: 172092. Louthrenoo W, Sukitawut W. Calcium pyrophosphate dihydrate crystal deposition: a clinical and laboratory analysis of 91 Thai patients. J Med Assoc Thai. 1999 Jun;82(6):569-76. PubMed PMID: 10443078.

3. Ultrasonography and computed tomography (CT): Ultrasonography and other imaging modalities such as CT may detect small deposits that are sometimes missed by plain radiographs. Deposits may appear as hyperechoic streaks in hyaline cartilage and “shiny” punctate lesions in fibrocartilage. The diagnostic properties of the tests are, at best, moderate and their clinical utility is unclear.Evidence 2Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Zufferey P, Valcov R, Fabreguet I, Dumusc A, Omoumi P, So A. A prospective evaluation of ultrasound as a diagnostic tool in acute microcrystalline arthritis. Arthritis Res Ther. 2015 Jul 22;17:188. doi: 10.1186/s13075-015-0701-7. Erratum in: Arthritis Res Ther. 2015;17:255. Pascal, Zufferey [corrected to Zufferey, Pascal]. PubMed PMID: 26198435; PubMed Central PMCID: PMC4511437.

4. Biochemistry: Blood tests may reveal elevated serum levels of calcium, parathyroid hormone, alkaline phosphatase, ferritin, iron, and total iron-binding capacity. Hypomagnesemia may be present. Serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels may be elevated, as with most inflammatory conditions, but they are of little diagnostic value, given their lack of specificity. Rheumatoid factor is positive in ~10% of CPPD patients.

Differential Diagnosis

The differential diagnosis of CPPD includes acute arthritis associated with gout (CPP may coexist with gout; 20% of patients with CPPD also have hyperuricemia), acute septic arthritis, osteoarthritis, rheumatoid arthritis (positive rheumatoid factor in ~10% of patients), Charcot joints, polymyalgia rheumatica, and Milwaukee shoulder syndrome (apatite-associated destructive arthritis).

TreatmentTop

General Measures

As per the 2011 European League Against Rheumatism (EULAR) CPPD guidelines, optimal management requires both nonpharmacologic and pharmacologic treatments that are tailored to clinical features, general risk factors, and predisposing metabolic disorders.

No currently available treatment modifies CPP crystal formation or deposition.

In patients with secondary CPPD, treatment of the underlying condition is necessary. The goals of treatment include pain reduction and improved function of the affected joints.

Treatment of associated conditions (eg, hyperparathyroidism, hemochromatosis, hypomagnesemia) should be considered as part of the management plan for CPPD.

Treatment goals and strategies for CPPD with comorbid osteoarthritis are the same as without osteoarthritis.

Treatment of Acute Arthritis

1. Local therapy: Cold compresses (eg, ice packs, cool gel packs), temporary rest, synovial fluid aspiration, and intra-articular long-acting glucocorticoid injections may provide sufficient analgesia.

2. Initial systemic therapy: Systemic therapy with oral colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs) may provide rapid relief,Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and sparse data. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev. 2014 Aug 15;(8):CD006190. doi: 10.1002/14651858.CD006190.pub2. Review. PubMed PMID: 25123076. Wechalekar MD, Vinik O, Moi JH, et al. The efficacy and safety of treatments for acute gout: results from a series of systematic literature reviews including Cochrane reviews on intraarticular glucocorticoids, colchicine, nonsteroidal antiinflammatory drugs, and interleukin-1 inhibitors. J Rheumatol Suppl. 2014 Sep;92:15-25. doi: 10.3899/jrheum.140458. Review. PubMed PMID: 25180124.van Durme CM, Wechalekar MD, Buchbinder R, Schlesinger N, van der Heijde D, Landewé RB. Non-steroidal anti-inflammatory drugs for acute gout. Cochrane Database Syst Rev. 2014 Sep 16;(9):CD010120. doi: 10.1002/14651858.CD010120.pub2. Review. PubMed PMID: 25225849. but their use may be limited by toxicity and comorbidities in some patients.

3. Other systemic therapy: In patients not responding to intra-articular glucocorticoid injections, short-term oral or parenteral glucocorticoids in doses tapered over time are a reasonable alternative to colchicine and NSAIDs. Parenteral adrenocorticotropic hormone may also be considered in this setting.

Long-Term Treatment

1. Asymptomatic CPPD requires no treatment.

2. Frequent recurrences of acute arthritis: Low-dose colchicine in doses 0.5 to 1 mg/d or NSAIDs may be used to prevent relapses.

3. Chronic arthritis: Drugs that may be used are (in the order of choice): oral NSAIDs, low-dose colchicine (0.5-1 mg/d), or both; low-dose glucocorticoids; methotrexate; and hydroxychloroquine. Nevertheless, the efficacy of this approach is poorly documented.

4. Osteoarthritis associated with CPPD: Treatment is similar to that of osteoarthritis without CPPD. Note that intra-articular hyaluronic acid should not be used, as it may precipitate acute arthritis.