Pyrophosphate arthropathy.

A scanning electron microscopic study of six cases of pyrophosphate arthropathy has been conducted. In the majority of cases the crystals were rectangular. In some cases giant crystals were present. In one case, the crystals were pyramidal. It is concluded that many geometrically different forms of calcium pyrophosphate crystal exist and that the scanning electron microscope is a useful tool in the differentiation of pyrophosphate arthropathy from other forms of crystal synovitis.     

Kristallarthropathien

Crystal arthropathies represent a heterogenic group of skeletal diseases associated with the deposition of mineralised material within joints and periarticular soft tissues. Gout is the most common and pathogenetically best understood crystal arthropathy, followed by basic calcium phosphate and calcium pyrophosphate dihydrate deposition diseases, and, in very rare cases, calcium oxalate crystal arthropathy. These crystals are responsible for different rheumatic syndromes, including acute or chronic synovial inflammation, and also contribute to cartilage degeneration. This review gives an overview of the pathological and clinical changes of these arthropathies.     

Hereditary pyrophosphate arthropathy (familial articular chondrocalcinosis) in Sweden

Genealogical links between three Swedish families with hereditary pyrophosphate arthropathy were found in the 18th century, indicating a possible founder effect, similar to earlier findings in Slovakia, France and Chile. However, no connection between the Swedish and other European families with the disease has so far been found. In accordance with other reported familial aggregations of pyrophosphate arthropathy, the transmission of the disease in the Swedish families appeared to be autosomal dominant with incomplete penetrance and variable expressivity. Severe symptoms related to homozygotic cases reported in some other families were not found in Sweden.     

Needle biopsy in gout and pseudogout (author's transl)]

Introduction: Radiological and morphological findings in advanced arthritis urica and pyrophosphate arthropathy are well known. In contrast, the early changes of synovial membrane in these disturbances of metabolism pose diagnostic problems. With the assistance of various cytological techniques and polarizing microscopical as well as electron microscopical investigation it was examined to what extent needle biopsies can be helpful in the differential diagnosis of gout and pseudogout. Material and Methods: In 8 patients with gout and 11 patients with pseudogout synovial fluid and small tissue specimens could be obtained with the aid of the Parker-Pearson needle. Both fluid and tissue specimens were investigated light and electron microscopically. Cell counts were evaluated in a Rosenthal chamber. The differentiation of the cells in stained smears was done by counting 200-600 cells per case. Crystals were identified by polarizing microscopy in wet preparations of freshly aspirated synovial fluid. Results: Polarizing microscopy of synovial fluid detected intra- as well as extracellular urate and pyrophosphate crystals. The wedge-shaped urate crystals and the larger partly polygonal pyrophosphate crystals showed different polarizing microscopical properties and a negative birefringence. The absolute cell counts in gout were higher than those in pseudogout. The relative cell counts of the different cell types in synovial fluid showed more variation in gout than in pseudogout. Cases with acute gout developed a relative leukocytosis in contrast to a relative lymphocytosis in chronic gout. A relative leukocytosis was constant in all patients with pseudogout. Sclerosed areas with scarce and plump villi as well as sometimes hyperplastic and polymorphous synovial cell layers could be demonstrated histologically in the tissue specimens of the needle biopsies in cases with gout. Urate crystals were less frequent in specimens fixed in formalin. The histological alterations in pseudogout were uniform, 2-4 rows of slightly pleomorphic synovial cells lined the inner surface of the joint capsule, sclerosing alterations were less frequent. Pyrophosphate crystals and calcified particles were seen within the synovial lining cells, the connective tissue and the enodthelial cells of the blood vessels in pseudogout specimens. Intra- as well as extracellular crystals could also be demonstrated with the aid of scanning electron microscopy in sediments of synovial fluid in gout and pseudogout. Transmission electron microscopical investigations of synovial tissue specimens detected proliferated and pleomorphic synovial lining cells in gout in contrast to a more monomorphic appearance of these cells in pseudogout. The crystals were washed out during the preparation techniques for transmission electron microscopy so that needle-like empty spaces resulted within cytoplasm of the phagocytic cells. These clefts were surrounded by phagosomal structures and densified cytoplasmic ground substance; sometimes they were also lined by membranes...     

Arthropathy in calcium pyrophosphate dihydrate crystal deposition disease. Pathologic study of 12 cases

The pathologic features of calcium pyrophosphate crystal deposition disease (CPDD), particularly the synovial abnormalities, have not been adequately described or depicted in textbooks or journals; this report details the findings in 12 cases. Attention is drawn to the practical reasons for distinguishing CPDD arthropathy from other arthropathies, particularly osteoarthritis; clinical and gross pathologic features that should suggest CPDD arthropathy in cases that are not suspected preoperatively; and characteristics of the tophaceous deposits in CPDD.     

The clinical significance of cytoplasmic inclusions(CPI) in synovial fluid examination.

The clinical significance of cytoplasmic inclusions(CPI) in synovial fluid(SF) examination was evaluated. We examined SF specimens collected from major rheumatology clinics in the Philadelphia area during the period of January to December 1995. Among 759 patients in the initial study group, 419 cases with established diagnoses and full synovial analyses were included. Their diagnoses and SF analysis results including leukocyte counts, differential counts and wet preparations were collected and analysed. Ninety seven of the 419 SF specimens were found to have CPI. CPI were found in SF from almost all rheumatic diseases. They were most likely to be found in inflammatory arthropathy including rheumatoid arthritis(RA, 46%), juvenile rheumatoid arthritis(JRA, 78%) and psoriatic arthritis(55%). On the contrary, CPI were least common in crystal-induced arthropathy among the inflammatory arthropathy. CPI were found 8 out of 98 gout cases(8%) and 2 among 53 calcium pyrophosphate dihydrate(CPPD) deposition disease(4%). In noninflammatory arthropathy, CPI were found in only 6 cases(6%) out of the 103 osteoarthritis(OA). In RA cases with non-inflammatory SF, 4 of the 20 SF(20%) had CPI while only 6% of OA SF had CPI. OA SF with CPI were all noninflammatory SF. In summary, CPI were a common finding on SF examination. CPI were more likely to be found in inflammatory arthropathy than noninflammatory. Among inflammatory arthropathy, CPI can favor non-crystal arthropathy than crystal arthropathy. Awareness of the presence of CPI is suggested as an addendum to routine SF analysis. Renewed investigation of the several types of CPI may add further to the understanding of joint disease.     

Acute hyperuricemic nephropathy in rats. An electron microscopic study.

Hyperuricemia and uricosuria were induced in rats fed uric acid and oxonic acid. Kidneys then were studied by light and electron microscopy. After 1 day of hyperuricemia, animals had deposits of uric acid and urate crystals within collecting tubules of the renal papillae, and tubular cells were altered. By 10 days, there was an exudative response with further injury to epithelium. Clear spaces within lumens, epithelium, and neutrophils suggested the presence of crystals; however, there was no direct ultrastructural evidence that neutrophils or epithelial cells ingested crystals and suffered injury. Presumably, crystals readily seen in frozen, unfixed tissue were lost during preparation for electron microscopy. Nonetheless, the ultrastructural findings indicated that hyperuricemic nephropathy was initiated in a fashion analogous to urate arthropathy. Urate crystals formed within collecting tubules, epithelial cells were altered, and most likely there was chemotaxis of neutrophils which underwent degranulation and vacuolation followed by lysis freeing any ingested urate. Release of ingested crystals plus precipitation of new crystals both might serve to sustain the nephritis.     

Investigations on the synthesis and crystallization of hydroxyapatite at low temperature

An easy method to crystallize homogenous HAP at physiological pH as well as powders of HAP and CPP at low temperature are described. Platy and spherulitic crystals of HAP were crystallized at the physiological pH using single diffusion method. Well-defined platy crystals of hydroxyapatite were obtained at the physiological temperature and pH. These crystals were found to be pure and homogenous form of HAP without any contamination from the crystallizing medium. Spherulitic crystals of HAP of approximately 3 mm in diameter were obtained in the presence of Fe at 47 degrees C. A sol-gel technique involving agarose is described for the preparation of hydroxyapatite and calcium pyrophosphate. Pure form of HAP was synthesised at 85 degrees C and its sintering properties were also studied. At a temperature of 1200 degrees C, the material gets completely converted to alpha-calcium pyrophosphate. The samples were analysed by XRD, IR, TGA and SEM. The particle size of the synthesised powders was measured using the dynamic light scattering experiments.     

Calcium pyrophosphate dihydrate (CPPD) deposition in ochronotic arthropathy

The post-mortem examination of an unsuspected case of alkaptonuria revealed extensive ochronosis. Histological examination of undecalcified sections of tracheal, costal, femoral and patellar cartilage revealed, in addition to ochronotic pigment, extensive calcium pyrophosphate dihydrate (CPPD) deposition. Similar deposits were present in intervertebral discs and were related to ossification of the discs resulting in partial or complete ankylosis. The calcific deposits were present around chondrocytes in the articular cartilage and this may be an important factor in the initiation of the osteoarthrotic process which characterises ochronotic arthropathy as it affects large diarthrodial joints.     

Tumors and diseases of the joint

A variety of different diseases affect the synovium, including infection, noninfectious immunologic inflammatory conditions, degenerative arthroses, crystal deposits, trauma, and tumors. Tumors of the synovium are relatively uncommon. Any mesenchymal tumor may arise in the synovium, but most recapitulate its normal counterpart including synoviocytes, blood vessels, fat, and fibrous tissue. These tumors can arise in any synovial lined structures both within joints and in extraarticular locations. Most synovial tumors are benign. Malignant tumors are rare but important to recognize because many are aggressive and must be treated appropriately. Among common nonneoplastic conditions that affect the synovium and surrounding structures are crystal deposits such as monosodium urate crystals, calcium pyrophosphate dihydrate crystals, and hydroxyapatite crystals. These crystal deposits may be asymptomatic or cause severe pain or chronic joint destruction. Their accurate identification is important to guide appropriate therapy.     

The relation of cyclic AMP levels to phagocytosis and enzyme release in acute inflammation in vivo.

The effect of altering endogenous leucocyte cyclic AMP levels on phagocytosis and lysosomal enzyme release was studied in vivo. Acute pleural exudates were produced in rats using either calcium pyrophosphate dihydrate crystals or rat serum. Despite marked increases in leucocyte cyclic AMP concentration produced by injection of dibutyryl cyclic AMP and theophylline, there was no reduction in crystal phagocytosis or in enzyme discharge.     

A mechanism of action for non-steroidal anti-inflammatory agents in calcium pyrophosphate dihydrate (CPPD) crystal induced arthritis

The acute inflammatory response to calcium pyrophosphate dihydrate crystals follows the meeting of neutrophils and crystals. The ensuing phagocytosis leads to the generation of a glycoprotein chemotactically active for neutrophils and to the release of lysosomal enzymes. Indomethacin and phenylbutazone, at therapeutic concentrations, impaired phagocytosis of the crystals and generation of chemotactic factor activity. Colchicine had no effect upon phagocytosis but significantly impaired the appearance of chemotactic factor activity.Supported by U.S. Public Health Service Grant AM-19349, and by an Arthritis Foundation Clinical Research Center Grant.     

Sclerochoroidal calcification associated with Gitelman syndrome and calcium pyrophosphate dihydrate deposition

Sclerochoroidal calcification is an uncommon condition. Metabolic evaluation and clinical examination are important to exclude associated systemic conditions such as the Bartter and Gitelman syndromes. It has been suggested that the lesions seen in sclerochoroidal calcification are calcium pyrophosphate dihydrate crystals. This report describes the first documented case in the UK of sclerochoroidal calcification associated with Gitelman syndrome and calcium pyrophosphate dihydrate deposition.     

Kinetics of IL1 beta mRNA and protein accumulation in human mononuclear cells.

Interleukin 1 beta (IL1 beta) is an inducible polypeptide with many roles in host defence and homoeostasis. It has also been implicated as a mediator of infectious, inflammatory and autoimmune diseases, and the kinetics of its production are relevant to an understanding of the pathogenesis of these conditions. We report here the time-course of IL1 beta production in human adherent monocytes. Both IL1 beta protein and mRNA were measured following cell activation with bacterial endotoxin (lipopolysaccharide; LPS), and pro-inflammatory crystals of monosodium urate (MSU), which cause arthritis and kidney disease. We also tested other crystal types associated with arthritis, namely hydroxylapatite and calcium pyrophosphate dihydrate. IL1 was absent from unstimulated cells, but IL1 beta mRNA accumulated rapidly after LPS or MSU stimulation and was associated with the later appearance of intracellular IL1 beta protein which was subsequently released from the cells (60% at 9 h). The other crystals failed to induce significant IL1 production. Our findings support the view that production of IL1 beta in human mononuclear cells is based on rapid translation of an inducible pool of mRNA and that no pre-formed mRNA or intracellular protein exists in normal blood monocytes. Further, although IL1 beta is translated without a conventional leader sequence, it is translocated extracellularly with the kinetics of a secretory protein.     

Fine needle aspiration of tophi in asymptomatic gout--a case report

Gout, a chronic hyperuricemic crystal induced arthropathy, may produce soft tissue masses (tophi). Tophi may be found in synovial membranes, periarticular ligaments, tendons, soft tissues as well as internal organs. We present a case in which diagnosis of gout was made by fine needle aspiration of tophus. The patient had a painless nodule over right ankle which was progressively increasing in size. He gave a past history of painful arthropathy, but serum uric acid levels were within normal limits. At this juncture, FNAC of the ankle tophus was performed which revealed aggregated and innumerable dissociated needle-shaped negatively birefringent crystals of monosodium urate (MSU) on polarization microscopy.     

Tissue changes detectable by sonography before radiological evidence of elbow chondrocalcinosis

Chondrocalcinosis is a joint disease caused by deposits of calcium pyrophosphate dihydrate (CPPD) crystals with manifestations that may include intermittent attacks of acute arthritis or enthesitis. If no crystals are found on synovial analysis, the diagnosis in clinical practice is based on typical radiographic findings, although it is now recognized that some signs of the disease could also be seen by ultrasound. We studied six patients with elbow enthesopathy without radiographic evidence of CPPD that presented ultrasound findings suggesting joint calcification. On the basis of these echographic findings, the diagnosis was then ascertained by x-ray examination of the most commonly involved joints. Ultrasound is a method of proven interest in the evaluation of rheumatic patients and could be an important tool in diagnosing CPPD.     

Calcium pyrophosphate dihydrate deposition disease: morphological and microanalytical features

The light microscopic and polarization appearances of calcium pyrophosphate dihydrate crystal deposits in tissues are reviewed. In routine sections haematoxylinophilic crystalline deposits with a feathery or brush-like pattern are typical of calcium pyrophosphate dihydrate. Short rhomboidal crystals showing positive birefringence are seen on polarization; X-ray microanalytical and infrared spectroscopic data support the specificity of these appearances. The appearances of the crystal deposits in decalcified specimens are also described. We include six cases of calcium pyrophosphate dihydrate deposition within periarticular bone; to the best of our knowledge this has not previously been described.     

Tumoural calcium pyrophosphate dihydrate crystal deposition disease presenting clinically as a malignant soft tissue mass diagnosed on fine needle aspiration biopsy

Tumoural calcium pyrophosphate dihydrate crystal deposition is a rare manifestation of calcium pyrophosphate deposition disease (CPPD). We present the case of a 75-year-old male with a previously resected rectal adenocarcinoma who developed a 5-cm right-sided mass at the base of his neck. Clinically and radiologically the lesion was suspicious for malignancy, possibly of metastatic origin. A bedside fine needle aspirate was performed and the smears were mildly cellular showing histiocytes with numerous intracellular and extracellular crystals. These colourless crystals were mostly short and rhomboid shaped and demonstrated weakly positive birefringence. A diagnosis of tumoural CPPD was made. This case is only the second in the English literature diagnosed on fine needle aspiration biopsy. Tumoural CPPD is well known to be a clinical, radiological and occasionally pathological mimic of malignancy. Several cases have been reported where unnecessary radical surgery was performed for this condition. Fine needle aspiration biopsy, as in this case, can provide a rapid and accurate diagnosis of CPPD, avoiding the need for invasive procedures. Polarisation microscopy is a vital adjunct to confirm this diagnosis.     

Histological study of a case of recurrent olecranon bursitis with mixed calcium pyrophosphate dihydrate and apatite crystal deposits

Summary This is the report of a light and transmission electron microscopic study of an olecranon bursitis and of the adjacent distal tricipital tendon in an 83 year-old man. The data are compared with those of a similar study in the same patient performed 2 years ago.Calcium pyrophosphate dihydrate crystals were observed in the bursal fluid, in the inner part of the bursal wall (extracellular localization and intracellular phagocytosis) as well as in the peripheral part of the tendon. In addition, small apatite deposits were observed in the bursa and tendon by electron microscopy. The origin of these bursal deposits is discussed; it is suggested that they may be related to an exchange from the tendon to the remodelled bursal wall.This study was partially subsidized by the Swiss Federal Commission for Rheumatic Diseases (Bern)