Pathogenesis of calcium pyrophosphate deposition disease

Calcium pyrophosphate deposition disease is defined by the presence of calcium pyrophosphate (CPP) crystals in articular cartilage and is the fourth most common type of arthritis in adults. Despite its high prevalence, the etiology of CPPD disease remains unclear and no specific therapies currently exist. It has been known for several decades that abnormalities of cartilage pyrophosphate metabolism are common in patients with CPPD disease, and this classic work will be reviewed here. Recent studies of rare familial forms of CPPD disease have provided additional novel information about its pathophysiology. This work suggests that CPPD disease occurs through at least two unique and potentially intertwined biomolecular pathways. We are hopeful that a detailed understanding of the components and regulation of these pathways will lead to improved therapies for this common disease.     

Review: Outcome measures in calcium pyrophosphate deposition

This review highlights outcomes for patients with calcium pyrophosphate deposition (CPPD) reported in prior studies and underscores challenges to assessing outcomes of this condition. Prior clinical studies of interventions for CPPD focused on joint damage and calcification on imaging tests, joint pain, swelling, and inflammatory biomarkers. Qualitative interviews with patients with CPPD and healthcare providers additionally identified flares, overall function, and use of analgesic medications as important outcomes. Imaging evidence of joint damage and calcification is likely to be outcomes in future clinical studies of CPPD, though reliability and sensitivity to change in CPPD require further testing for several imaging modalities. Challenges to outcome measurement in CPPD include questions of attribution of signs and symptoms to CPPD versus co-existing forms of arthritis, lack of therapies to prevent or dissolve calcium pyrophosphate crystal deposition, absence of validated patient- or physician-reported CPPD outcome measures, and scarcity of large cohorts in which to study outcomes of different clinical presentations of CPPD.     

Subcutaneous tendon rupture of extensor tendons on bilateral wrists associated with calcium pyrophosphate dihydrate crystal deposition disease

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a well-recognized inflammatory joint disorder. Extensor tendon rupture associated with CPPD deposition has rarely been described. We report herein the case of a 58-year-old woman who underwent reconstruction for subcutaneous extensor tendon ruptures of the extensor tendons for the ring and little fingers on both wrists associated with CPPD deposition. The significance of this case is the occurrence at an earlier age compared to previous papers and the appearance on bilateral wrists.     

Pathogenesis of calcium pyrophosphate crystal deposition disease

Calcium pyrophosphate dihydrate deposition (CPPDD) disease is an increasingly common form of arthritis affecting the elderly. It is characterized by the formation of CPPD crystals in articular cartilage and usually results in severe cartilage destruction with loss of joint function. This article discusses our understanding of how and why these crystals form, highlighting recent developments in the field.     

Febrile presentation of calcium pyrophosphate dihydrate deposition disease

Three patients were found to have calcium pyrophosphate dihydrate deposition disease (CPPD) as the cause of prolonged fever and elevated sedimentation rate. All responded to treatment. CPPD should be considered in evaluating patients with fever and high sedimentation rate.     

Wrist arthropathy in calcium pyrophosphate dihydrate deposition disease

Calcium pyrophosphate dihydrate deposition disease is associated with chondrocalcinosis and a characteristic radiographic abnormality. In the wrist this abnormality consists of radiocarpal joint narrowing, sclerosis, and subchondral cystic degeneration of the carpal bones. These changes sometimes occur in the absence of chondrocalcinosis. To investigate the significance of this occurrence, 18 patients with the radiographic abnormality of radiocarpal joint narrowing, sclerosis, and subchondral cystic degeneration were examined. Six had neither local wrist nor distant chondrocalcinosis. Five of the latter had wrist arthrocentesis and 4 had calcium pyrophosphate dihydrate crystals. Calcium pyrophosphate dihydrate deposition disease can occur in the absence of chondrocalcinosis and the diagnosis is strongly suggested by a characteristic radiographic picture.     

Diseases associated with calcium pyrophosphate deposition disease.

Although many metabolic and endocrine diseases have been reported to predispose to calcium pyrophosphate dihydrate crystal deposition, the validity of many of these associations remains unclear. A critical review of the literature relating to these associations, with illustrative cases and data derived from the authors' own experience, is presented. It is concluded that there is good evidence to associate hypophosphatasia, hypomagnesemia, and hyperparathyroidism with chondrocalcinosis and acute attacks of "pseudogout." Meta-analysis also suggests a small but significant association between hypothyroidism and chondrocalcinosis. Hemochromatosis stands alone in clearly associating not only with chondrocalcinosis but also with structural change and chronic arthropathy. The biochemical mechanisms that may produce these various associations are discussed. Recommendations are made concerning appropriate screening for metabolic and endocrine disease in patients with chondrocalcinosis.     

Sacroiliac joint abnormalities in calcium pyrophosphate crystal deposition disease

Summary Three cases of generalized calcium pyrophosphate dihydrate deposition disease and roentgenographic sacroiliac abnormalities (chondrocalcinosis, inflammatory change and degenerative change) are described.     

Sclerochoroidal calcifications associated with early-onset calcium pyrophosphate deposition disease

Clinical Rheumatology -     

Familial calcium pyrophosphate dihydrate deposition disease and the ANKH gene

The crystal deposition arthropathies comprise a host of disorders that may occur idiopathically or as secondary manifestations of associated diseases. Rarely, crystal deposition presents as a familial disorder. Most affected family members display radiographically detectable crystals of calcium pyrophosphate dihydrate in their joint spaces. In genetic studies of familial calcium pyrophosphate dihydrate deposition disease, a region on the short arm of chromosome 5 was found to be genetically linked to the phenotype displayed by several of these families. Among the positional candidates at this locus was ANKH, the human homolog of a gene that is responsible for the phenotype of progressive ankylosis (ank) in the mouse. ANKH codes for a transmembrane protein that appears to regulate the transport of inorganic pyrophosphate. It was analyzed as a potential positional candidate gene for calcium pyrophosphate dihydrate deposition disease, and in several unrelated families, sequence variants were identified that segregated with the calcium pyrophosphate dihydrate deposition disease phenotype among affected members. A discussion of ANKH as the familial calcium pyrophosphate dihydrate deposition disease gene is presented.     

Tophaceous calcium pyrophosphate dihydrate deposition disease of the temporomandibular joint

Tophaceous pseudogout is a rare manifestation of calcium pyrophosphate dihydrate (CPPD) deposition disease that particularly affects the temporomandibular joint (TMJ). We describe a case of tophaceous pseudogout and review the literature. Thirty-four cases of chronic CPPD deposition disease affecting the TMJ are described. Symptoms usually included pain and swelling. Most patients required surgery because of extensive crystal deposits, usually localized to the joint and adjacent structures but occasionally invasive. For many patients, malignancy was the preoperative diagnosis. Although patients with acute pseudogout of the TMJ may have involvement of other joints, tophaceous pseudogout was predominantly isolated to the TMJ.     

Olecranon bursitis related to calcium pyrophosphate dihydrate crystal deposition disease

A case of olecranon bursitis in an 81-year-old patient is presented. Analysis of the bursal fluid revealed positive birefringent crystals; radiographs showed calcifications in the distal triceps tendon. A bursectomy was performed. X-ray diffraction analyses demonstrated calcium pyrophosphate dihydrate patterns in a subcutaneous "tophus" and in a specimen of the tendon. On histologic examination, there was a bursitis with positive birefringent crystals on the bursa's inner surface; histologic images of "chondrocalcinosis" were observed in and around the tendon. It is concluded that bursitis may be part of the extraarticular manifestations of calcium pyrophosphate dihydrate crystal deposition disease.     

Extensor tendon rupture related to calcium pyrophosphate crystal deposition disease

We report a rare case of spontaneous rupture of the extensor tendons at the wrist which was shown histologically to be related to calcium pyrophosphate crystal deposition disease. The causes of tendon rupture were chronic synovitis with crystal deposition and a dorsal prominence of the ulnar head.     

Formation of calcium pyrophosphate crystals in vitro: implications for calcium pyrophosphate crystal deposition disease (pseudogout)

Little is known about how calcium pyrophosphate dihydrate (CaPPD) crystals form in vivo and give rise to chondrocalcinosis or pseudogout (pyrophosphate arthropathy or calcium pyrophosphate crystal deposition disease). In this study a simple method has been devised to define the conditions necessary for the deposition of crystals in vitro. Crystal formation is monitored by ⁴⁵Ca in the presence of 1·5 mmol/l Ca and increasing concentrations of inorganic pyrophosphate (PPi) under simulated physiological conditions of pH and ionic strength. Concentrations of PPi required to initiate crystal formation were about 40 mmol/l in the absence and 175 mmol/l in the presence of 0·5 mmol/l Mg²⁺ at pH 7·4. Less PPi was required at higher pH values. The naturally occurring monoclinic and triclinic forms of CaPPD were produced after prolonged incubation in vitro, but the initial deposits were amorphous or orthorhombic. The physiological significance of these observations is discussed. Since much higher concentrations of PPi are required to form crystals in vitro than are found to occur naturally in synovial fluids from patients with pyrophosphate arthropathy, it is suggested that crystals are more likely to deposit initially within cartilage and that nucleating mechanisms may be important in vivo. Since other workers have observed a slow interconversion of other calcium pyrophosphate crystal forms into monoclinic and triclinic allomorphs under laboratory conditions, the reason why only these 2 forms occur under clinical conditions may reflect the long time available in vivo for the formation of crystals.     

Calcium pyrophosphate dihydrate gout and other crystal deposition diseases.

The number of crystal or birefringent particles associated with arthritis is increasing, and a uniform taxonomy is needed. The term gout has been proposed as a generic term for these diseases based on historical, clinical, and crystallographic reasons. Calcium pyrophosphate dihydrate gout follows monosodium urate gout in frequency, and its spectrum of clinical manifestations continues to grow. Familial calcium pyrophosphate dihydrate gout was described for the first time in kindreds studied in England and Tunisia; new Jewish and Spanish kindreds were also reported. Type I collagen was shown to nucleate nativelike calcium pyrophosphate dihydrate crystals, and pyrophosphate elaboration was explored in cartilage explants in an attempt to reproduce the in vivo metabolic or endocrine disorders associated with calcium pyrophosphate dihydrate gout. The effect of pyrophosphatase and different cofactors such as magnesium in dissolving calcium pyrophosphate dihydrate crystals was investigated. High-resolution electron microscopy was used to study the interrelation between apatite and other basic calcium phosphate crystals in apatite gout. Raman microscopy was applied for the first time to identify crystals in biologic specimens. A simple and specific technique for basic calcium phosphate crystal identification is necessary to understand the relationship between different calcium phosphate crystals and osteoarthritis. Several reports about children and young patients with primary oxalate gout described the effect of oxalate on eyes, periodontal tissues, and bone. Multicenter studies showed poor results of renal transplantation, but favored combined liver and renal transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Management of calcium pyrophosphate crystal deposition disease: A systematic review

ObjectiveCalcium pyrophosphate crystal deposition disease (CPPD) is a common cause of acute and chronic arthritis, especially in the elderly population. There is a paucity of data regarding the management of CPPD disease, which is currently based on expert opinion and evidence derived from the treatment of gout. We conducted a systematic literature review in order to identify the available treatment options for CPPD, and describe their efficacy and safety.Material and methodsOnline databases were searched from inception to May of 2020 using the search terms: (CPPD [Title/Abstract] OR CPDD [Title/Abstract] OR calcium pyrophosphate [Title/Abstract] OR chondrocalcinosis [Title/Abstract]) AND (treatment [Title/Abstract] OR management [Title/Abstract] OR therapy [Title/Abstract]). Articles evaluating the use of specific treatment agents for CPPD were eligible for inclusion. Case reports were excluded.ResultsA total of 22 eligible studies and 403 unique patients were selected. We identified only 3 randomized, double-blind, controlled trials (RCTs) evaluating the use of methotrexate, hydroxychloroquine, and magnesium carbonate in CPPD, and these therapeutic options, with the exception of methotrexate, have shown efficacy and reduction of pain intensity. Further, 10 case series and 9 cohort studies were included. Intramuscular and intra-articular glucocorticoids, ACTH, as well as the biologic agents anakinra and tocilizumab appear to be efficacious in CPPD. Intra-articular injections of glycosaminoglycan polysulphate, hyaluronic acid and yttrium, as well as synovial membrane destruction by laser irradiation were associated with symptomatic improvement. Due to significant study heterogenicity, direct comparison between studies was not possible.ConclusionThere are a limited number of studies evaluating the treatment of CPPD. High quality evidence is rather limited, while commonly administered agents such as NSAIDs, colchicine and corticosteroids have not been evaluated by RCTs. The need for high quality evidence supporting specific treatment modalities is urgent for this common yet neglected form of arthritis.