Diagnose und Therapie der Kalziumpyrophosphatkristall-induzierten Arthropathie

Calcium pyrophosphate dihydrate deposition (CPPDD) disease is the term used to describe a group of common and potentially severe metabolic arthropathies. In these, CPPD crystals form and are deposited in the cartilage matrix (chondrocalcinosis) and induce inflammatory and/or destructive mechanisms. Most cases are idiopathic, but hyperparathyroidism, hemochromatosis, hypomagnesemia and hypophosphatemia can promote or cause chondrocalcinosis. Early disease (with onset before the age of 60 years) thus requires that the patient be examined for these metabolic conditions, particularly hemochromatosis. The prevalence of CPPDD disease in the general population increases with age, being 10–15% in the age group 65–75 years and more than 40% in the over-80s. Although frequently asymptomatic, chondrocalcinosis can involve severe acute attacks of inflammatory arthritis (pseudogout) and also various types of chronic arthropathy including pseudorheumatoid arthritis, pseudo-osteoarthritis, and pseudoneuropathic joint disease. CPPD crystals can also be deposited in the bursae, ligaments, and tendons and generate inflammation and/or ruptures. The diagnosis is based on synovial fluid analysis (positively birefringent CPPD crystals visualized by compensated polarized light microscopy) and X-rays (punctate and linear radiodense areas in fibrocartilage and hyaline cartilage). Treatment is primarily symptomatic, since there is no known drug that can prevent progression of the joint destruction). Nonsteroid anti-inflammatory drugs (NSAIDs) and intra-articular or systemic glucocorticoids (amounts must be only small if use is prolonged) are the most useful treatments. Colchicine can be effective in recurring pseudogout, and magnesium can be used prophylactically. In a small uncontrolled series methotrexate was effective and aroused interest; it can be used when other treatments fail.     

Chondrokalzinose durch Kalziumpyrophosphat-Dihydrat-Ablagerung (CPPD)

If acute arthritis occurs in the elderly in addition to typical degenerative, load-related joint complaints, this is often induced by crystal deposition. The crystals lead to activation of the immune system resulting in acute inflammation. In addition to gout, calcium pyrophosphate deposition (CPPD) disease in particular must also be taken into consideration. Diagnostically important are imaging techniques, e.g. early specific alterations of cartilage can be shown by joint sonography and later calcium pyrophosphate crystals can be detected as cartilage calcification (chondrocalcinosis) by radiography. Important for the diagnosis of crystal arthropathy is usually the microscopic detection of specific crystals in the synovial fluid and is supported by exclusion of septic arthritis by arthrocentesis. In contrast to gout, which can be well controlled by the pharmaceutical lowering of uric acid levels, there is no causal therapy for CPPD disease so far. As CPPD may occur as a secondary effect in metabolic disorders, such as hyperparathyroidism or hemochromatosis, it seems to be important to search for the underlying disease. The following article presents the current knowledge on clinically relevant aspects of the pathogenesis, diagnosis and therapy of CPPD disease.     

Pseudogout of the acromioclavicular joint: report of two cases and review of the literature

Abstract

Although calcium pyrophosphate dehydrate (CPPD) deposition disease, including pseudogout, is a relatively common disease affecting the major joints, especially the knee, pseudogout in the acromioclavicular (AC) joint is very uncommon. We describe two cases of acute pseudogout attacks of the AC joint in elderly patients. Radiological findings showed chondrocalcinosis in the AC joints. Microscopically, aspirated articular synovial fluid demonstrated CPPD crystals. Conservative therapy with non-steroidal anti-inflammatory drugs completely resolved all symptoms within 1 week.     

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.     

Pseudogout of the acromioclavicular joint: report of two cases and review of the literature

Although calcium pyrophosphate dehydrate (CPPD) deposition disease, including pseudogout, is a relatively common disease affecting the major joints, especially the knee, pseudogout in the acromioclavicular (AC) joint is very uncommon. We describe two cases of acute pseudogout attacks of the AC joint in elderly patients. Radiological findings showed chondrocalcinosis in the AC joints. Microscopically, aspirated articular synovial fluid demonstrated CPPD crystals. Conservative therapy with non-steroidal anti-inflammatory drugs completely resolved all symptoms within 1 week.     

Acute pseudogout in chronic renal failure.

Acute pseudogout (calcium pyrophosphate dihydrate deposition disease [CPPD disease]) developed in two patients with chronic renal failure. The disease had atypical features. The calcification of the involved joints was more diffuse than the usual linear stippled calcification. The first patient, age 39, was young to have pseudogout. The second patient had pseudogout and chondrocalcinosis limited to the elbow. Review of wrist roentgenograms of 82 patients (mean age, 49.0 years), undergoing hemodialysis for chronic renal failure revealed three patients (a 3.7% incidence) with chondrocalcinosis. The incidence increased to three of 19 (15.8%) in the patients over the age of 60. Although considered uncommon, pseudogout may cause acute arthritis in chronic renal failure more often than previously suspected. Joint aspiration and identification of CPPD cystals with compensated polarized light microscopy will establish the diagnosis of pseudogout.     

CRYSTAL SHEDDING IN SEPTIC ARTHRITIS: CASE REPORTS AND IN VIVO EVIDENCE IN AN ANIMAL MODEL

Abstract Two cases of coexisting septic and crystalline joint disease are reported. In one patient polyarticular septic artaritis occurred simultaneously with gout and pseudogout. In a second patient septic arthritis preceded the appearance of calcium pyrophosphate dihydrate (CPPD) crystals in the joint fluid, supporting an earlier postulate that lysosomal enzymes released during sepsis lead to shedding of crystals from cartilage and synovium into the joint space. This sequence was demonstrated in a rat air pouch model of synovium, in which CPPD crystals embedded in facsimile synovial tissue were released after injection of pyogenic bacteria. Coexisting septic arthritis should always be considered when crystals are identified in inflamed joints, particularly in elderly patients with concurrent infections.     

Interaction of polymorphonuclear leukocytes with calcium pyrophosphate dihydrate crystals deposited in chondrocalcinosis cartilage

Summary Electron microscopy was used to investigate the characteristics of calcium pyrophosphate dihydrate (CPPD) crystals in chondrocalcinosis (pseudogout syndrome). Crystals in midzone cartilage were frequently seen adjacent to chondrocytes. Great variation in crystal size and shape was observed. Most of the pyrophosphate crystals that had been phagocytosed by polymorphonuclear leukocytes of synovial fluid from patients with acute pseudogout were small (1 m), indicating that small crystals can cause intense inflammation. Large numbers of polymorphonuclear leukocytes became attached to the eroded articular surface and phagocytosed microcrystals. Interaction of polymorphonuclear leukocytes with CPPD crystals in the superficial region of articular cartilage may stimulate the release of inflammatory mediators.     

Crystal shedding and acute pseudogout. An hypothesis based on a therapeutic failure

Four patients with chondrocalcinosis of the knees volunteered for joint lavage. Preliminary experiments indicated that disodium EDTA and magnesium ions were potent solubilizers of CPPD crystals. The procedure was a therapeutic failure in that insignificant amounts of CPPD were removed and all 4 subjects developed postlavage attacks of pseudogout. It is hypothesized that the acute attack of pseudogout is a result of crystal shedding and may be triggered by any factor that enhances CPPD solubility.     

Calcium pyrophosphate deposition disease: clinical manifestations

Calcium pyrophosphate deposition (CPPD) disease is an arthropathy caused by calcium pyrophosphate dihydrate (CPP) crystal deposits in articular tissues, most commonly fibrocartilage and hyaline cartilage. According to EULAR, four different clinical presentations can be observed: 1) asymptomatic CPPD; 2) osteoarthritis (OA) with CPPD; 3) acute CPP crystal arthritis; 4) chronic CPP inflammatory crystal arthritis. Acute CPP crystal arthritis is characterized by sudden onset of pain, swelling and tenderness with overlying erythema, usually in a large joint, most often the knee, wrist, shoulder, and hip. Occasionally, ligaments, tendons, bursae, bone and the spine can be involved. CPPD of the atlanto-occipital joint (crowned dens syndrome) can cause periodic acute cervico-occipital pain with fever, neck stiffness and laboratory inflammatory syndrome. Chronic inflammatory arthritis is characterized by joint swelling, morning stiffness, pain, and high ESR and CRP. The relationship between OA and CPPD is still unclear. The main problem is whether such crystals are directly involved in the pathogenesis of OA or if they are the result of joint degeneration. Diagnosis is based on evaluation of history and clinical features, conventional radiology, and synovial fluid examination. Non-polarized light microscopy should be used initially to screen for CPPD crystals based upon their characteristic morphology, and compensated polarized light microscopy, showing the crystals to be weakly positive birefringent, is recommended for definitive identification, although this last pattern only occurs in about 20% of samples. The main goals of CPPD therapy are control of the acute or chronic inflammatory reaction and prevention of further episodes.     

Calciumpyrophosphatdihydrat (CPPD)—Kristallarthropathie (Arthropathie bei Chondrocalcinose)

Calcium pyrophosphate dihydrate (CPPD) crystal induced arthropathy (CPPD-CA; systemic articular chondrocalcinosis) characterized by deposition of CPPD-crystals in fibro- and hyaline cartilage, joint capsule and periarticular tissues is associated with a variable clinical spectrum of inflammatory degenerative and occasionally destructive joint and vertebral manifestations including neurologic complications and rarely tophaceous-tumoral tissue calcifications. Microcrystal formation in the extracellular matrix of cartilage and tendons is based on genetic and acquired dysregulation of chondrocyte pyrophosphate metabolism and presumably linked to gene mutants on the short arm of chromosome-5 (gene locus 5p15.1 and ANKH gene). Idiopathic disease occurs rarely in hereditary-familial and frequently in sporadic manifestation with increasing prevalence due to aging; a secondary form is significantly related to endocrine and metabolic disorders (as to hyperparathyroidism, hemochromatosis etc.). The impact of the clinical syndrome in practice is important in differential diagnosis of age related conditions like acute mono- or oligoarthritis, systemic osteoarthritis and polymyalgia rheumatica. Actual treatment ignores established prevention of systemic cartilage calcification and is oriented to symptomatic relief.     

Transforming growth factor beta 1 stimulates inorganic pyrophosphate elaboration by porcine cartilage.

The overproduction of inorganic pyrophosphate (PPi) by cartilage is thought to be a key element in the formation of calcium pyrophosphate dihydrate (CPPD) crystals in joints, and the subsequent development of pseudogout or chondrocalcinosis. We report herein that transforming growth factor beta 1 (TGF beta 1), alone and in synergy with epidermal growth factor (EGF) or TGF alpha, markedly stimulates PPi elaboration by porcine articular cartilage in organ culture and monolayer culture. This effect is not seen with platelet-derived growth factor, basic fibroblast growth factor, or insulin-like growth factor types 1 and 2, substances which also affect chondrocyte metabolism or are mitogenic. TGF beta 1 produces only a modest increase in nucleoside triphosphate pyrophosphohydrolase (NTPPPH), a chondrocyte ectoenzyme that produces PPi; this implies the existence of other pathways for PPi elaboration. TGF beta 1 is present in joint fluid and cartilage. TGF beta 1, TGF alpha, and EGF are the first known physiologic modifiers of cartilage PPi production. They provide a novel model for the study of CPPD crystal formation in cartilage, as well as new insights into the pathogenesis of this common affliction of aging.     

The prevalence of chondrocalcinosis (CC) of the acromioclavicular (AC) joint on chest radiographs and correlation with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease

Digital imaging combined with picture archiving and communication system (PACS) access allows detailed image retrieval and magnification. Calcium pyrophosphate dihydrate (CPPD) crystals preferentially deposit in fibrocartilages, the cartilage of the acromioclavicular (AC) joint being one such structure. We sought to determine if examination of the AC joints on magnified PACS imaging of chest films would be useful in identifying chondrocalcinosis (CC). Retrospective radiographic readings and chart reviews involving 1,920 patients aged 50 or more who had routine outpatient chest radiographs over a 4-month period were performed. Knee radiographs were available for comparison in 489 patients. Medical records were reviewed to abstract demographics, chest film reports, and diagnoses. AC joint CC was identified in 1.1 % (21/1,920) of consecutive chest films. Patients with AC joint CC were 75 years of age versus 65.4 in those without CC (p?<?0.0002). Four hundred eighty-nine patients had knee films. Six of these patients had AC joint CC, and of these, five also had knee CC (83 %). Of the 483 without AC joint CC, 62 (12 %) had knee CC (p?=?0.002). Patients with AC joint CC were more likely to have a recorded history of CPPD crystal deposition disease than those without AC joint CC (14 versus 1 %, p?=?0.0017). The prevalence of AC joint CC increases with age and is associated with knee CC. A finding of AC joint CC should heighten suspicion of pseudogout or secondary osteoarthritis in appropriate clinical settings and, in a young patient, should alert the clinician to the possibility of an associated metabolic condition.     

Hypomagnesemia and chondrocalcinosis in short bowel syndrome

Chondrocalcinosis is a result of deposition of calcium pyrophosphate dihydrate (CPPD) crystals in cartilage and fibrocartilage. Chondrocalcinosis is usually sporadic but has also been associated with a variety of metabolic diseases including hypomagnesemia. Reported cases of hypomagnesemia associated chondrocalcinosis were mostly due to renal genetic disorders such as Bartter's or Gitelman's syndrome. We describe 3 patients with chronic hypomagnesemia induced by short bowel syndrome who developed symptomatic chondrocalcinosis. CPPD crystals were identified by polarizing light microscopy in one patient. The underlying intestinal pathology was radiation enteritis in 2 patients and mesenteric arterial thrombosis in the third. Our observations strengthen the hypothesis of a role for magnesium in CPPD crystal deposition disease.     

Calcium pyrophosphate dihydrate deposition disease without chondrocalcinosis.

The pseudogout syndrome is usually associated with radiographic evidence of articular cartilage calcification. Eight patients who had joints containing calcium pyrophosphate dihydrate crystals were studied. Extensive radiographic evaluation was obtained in seven patients and a limited evaluation in the other. None had evidence of chondrocalcinosis. Six had distinctive radiographic abnormalities of the wrists consisting of radiocarpal joint space narrowing and sclerosis, and subchondral cystic degeneration of the carpal bones. We conclude that calcium pyrophosphate dihydrate deposition disease and pseudogout can occur without radiographic evidence of chondrocalcinosis and that the diagnosis can be suggested by characteristic radiographic abnormalities of the wrists.     

Synovial osteochondromatosis and pseudogout

A middle aged male developed recurrent episodic inflammatory effusions of the right knee associated with radiographic findings consistent with osteochondromatosis. Calcium pyrophosphate dihydrate (CPPD) crystals were identified by polarized light and electron microscopy, although chondrocalcinosis was not demonstrated radiographically in this joint or any other locations. Analysis of noninflammatory fluid from the left knee demonstrated apatite crystals. The unique association of CPPD crystals and synovial osteochondromatosis without evidence of chondrocalcinosis and the relationship of these 2 entities is discussed.     

Pseudogout presenting with low synovial fluid glucose: identification of crystals by gram stain

A man developed acute monoarticular ankle arthritis caused by calcium pyrophosphate dihydrate (CPPD) crystals. The clinical syndrome resembled that of a pyogenic arthritis. Synovial fluid analysis revealed a glucose concentration of 13 mg/dL and 99,000 white blood cells/mm3. Only one other report of an extremely low synovial fluid glucose associated with pseudogout could be found. The diagnosis of pseudogout was initially suggested when rhomboidal forms were seen during synovial fluid Gram stain examination. Synovial fluid examination with polarized microscopy was initially negative, but revealed numerous CPPD crystals when repeated on the third hospital day. This case serves to illustrate how pseudogout can mimic pyogenic arthritis in both clinical presentation and low synovial fluid glucose concentration. The examination of Gram-stained synovial fluid can reveal the rhomboidal forms of CPPD crystals. The appearance of these crystals is documented in this report.     

Inflammatory microcrystals stimulate interleukin-6 production and secretion by human monocytes and synoviocytes

Crystal-related joint diseases are often associated with systemic inflammatory manifestations, including increased levels of acute-phase proteins, leukocytosis, and fever. Recently, interleukin-6 (IL-6) has been identified as a pluripotent mediator of inflammatory and immunologic responses and the major hepatocyte-stimulating factor. In this study, we demonstrated that monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals, and to a lesser extent, hydroxyapatite crystals, increased IL-6 production by synoviocytes and monocytes in vitro. Immunoprecipitation experiments showed that MSU and CPPD crystals, but not hydroxyapatite crystals, were able to increase the release of newly synthesized IL-6. Crystal-induced IL-6 stimulated acute-phase protein synthesis, immunoglobulin production, and hybridoma cell proliferation, which was neutralized by a specific antibody to IL-6. High levels of IL-6 were found in synovial fluid from patients with gout and pseudogout. These results demonstrate that MSU and CPPD crystals can induce IL-6 production in synoviocytes and monocytes, and that synovial fluid from patients with gout and pseudogout contains high levels of IL-6. Crystal-induced IL-6 is likely to be an important mediator of inflammatory responses in acute gout and pseudogout.     

Pseudogout in ochronosis

Calcium pyrophosphate dihydrate crystals were identified in synovial fluid white blood cells during an episode of acute arthritis in a patient with ochronosis and chondrocalcinosis. Review of the histories and radiographs of 5 other patients with ochronosis demonstrated two additional instances of chondrocalcinosis. Both of these patients had episodes of arthritis consistent with pseudogout. This suggests that pseudogout, which has been found in increased incidence in some metabolic diseases, may also be more common in ochronosis.     

Chondrocalcinosis and hypomagnesemia: clinical and radiological progression

Hypomagnesemia is a rare secundary metabolic disorder associated with calcium pyrophosphate dihydrate cristal deposition disease in joint structures and may cause asymptomatic chondrocalcinosis (linear calcification of cartilage), pseudogout, and chronic arthropathy. We report 2 young men with relapsing acute knee monoarthritis with chondrocalcinosis and hypomagnesemia. After follow-up clinical and radiological events al least for 5 years and treatment with magnesium lactate, these patients have not shown new pseudogout attacks. We discuss knee radiological evolution in both patients, outstanding major knee radiological deterioration in the patient with early symptoms and a familial chondrocalcinosis association, in spite of clinical asymptomatic status.