Search

Objective. To determine the prevalence, clinical picture, and disease burden of arthritis in patients with hereditary hemochromatosis. Methods. In this cross-sectional observational study of 199 patients with hemochromatosis and iron overload, demographic and disease-specific variables, genotype, and organ involvement were recorded. The prevalence, intensity, and localization of joint pain were assessed, and a complete rheumatologic investigation was performed. Radiographs of the hands, knees, and ankles were scored for joint space narrowing, erosions, osteophytes, and chondrocalcinosis. In addition, the number and type of joint replacement surgeries were recorded. Results. Joint pain was reported by 72.4% of the patients. Their mean SD age at the time of the initial joint symptoms was 45.8 13.2 years. If joint pain was present, it preceded the diagnosis of hemochromatosis by a mean SD of 9.0 10.7 years. Bony enlargement was observed in 65.8% of the patients, whereas synovitis was less common (13.6%). Joint space narrowing and osteophytes as well as chondrocalcinosis of the wrist and knee joints were frequent radiographic features of hemochromatosis. Joint replacement surgery was common, with 32 patients (16.1%) undergoing total joint replacement surgery due to severe OA. The mean SD age of these patients was 58.3 10.4 years at time of joint replacement surgery. Female sex, metacarpophalangeal joint involvement, and the presence of chondrocalcinosis were associated with a higher risk of early joint failure (i.e., the need for joint replacement surgery). Conclusion. Arthritis is a frequent, early, and severe symptom of hemochromatosis. Disease is not confined to involvement of the metacarpophalangeal joints and often leads to severe damage requiring the replacement of joints.

Objective To evaluate the effectiveness of methotrexate (MTX), which works not only as an immunosuppressant, but also as a potent antiinflammatory agent, as an alternative therapeutic option for patients with severe calcium pyrophosphate deposition disease (CPDD) who fail to respond to standard therapy with nonsteroidal antiinflammatory drugs and/or glucocorticoids. Methods We analyzed, in 2 university hospitals in Switzerland, consecutive patients with CPDD that was resistant to classic treatment and were subsequently treated with MTX. Before and after initiation of MTX therapy, we quantified the frequency of pseudogout attacks, pain intensity, the number of swollen and tender joints, and inflammatory biomarkers. Clinical and biologic side effects of MTX and patients satisfaction with MTX treatment were also evaluated. Results The study included 5 patients treated with low dosages of MTX (5–20 mg/week). The mean followup time with MTX was 50.4 months (range 6–81 months). All patients reported an excellent clinical response, with marked improvement within a mean period of 7.4 weeks. A significant decrease in pain intensity (P < 0.0001), swollen and tender joint counts (P < 0.0001), and frequency of attacks was observed. The biomarkers of inflammation decreased markedly when systematically analyzed (3 patients). No significant side effects were reported. Conclusion This study suggests that MTX could be a valuable therapeutic option for severe CPDD that is refractory to conventional therapy.

A patient referred to us for recurrent chest wall gouty tophus, but who was determined to actually have a chylous cyst, is described herein. Chylous cysts of the neck or chest wall can be caused by thoracic duct injury. Chyle contains 4-40 gm/liter of lipids, mostly triglycerides, and these can form birefringent crystals upon drying, leading to a false diagnosis of gout.

Objective. Twelve families that were multiply affected with diffuse idiopathic skeletal hyperostosis (DISH) and/or chondrocalcinosis, were identified on the island of Terceira, The Azores, potentially supporting the hypothesis that the 2 disorders share common etiopathogenic factors. The present study was undertaken to investigate this hypothesis. Methods. One hundred three individuals from 12 unrelated families were assessed. Probands were identified from patients attending the Rheumatic Diseases Clinic, Hospital de Santo Espirito, in The Azores. Family members were assessed by rheumatologists and radiologists. Radiographs of all family members were obtained, including radiographs of the dorsolumbar spine, pelvis, knees, elbows, and wrists, and all cases were screened for known features of chondrocalcinosis. Results. Ectopic calcifications were identified in 70 patients. The most frequent symptoms or findings were as follows: axial pain, elbow, knee and metacarpophalangeal (MCP) joint pain, swelling, and/or deformity, and radiographic enthesopathic changes. Elbow and MCP joint periarticular calcifications were observed in 35 and 5 patients, respectively, and chondrocalcinosis was identified in 12 patients. Fifteen patients had sacroiliac disease (ankylosis or sclerosis) on computed tomography scans. Fifty-two patients could be classified as having definite (17%), probable (26%), or possible (31%) DISH. Concomitant DISH and chondrocalcinosis was diagnosed in 12 patients. Pyrophosphate crystals were identified from knee effusions in 13 patients. The pattern of disease transmission was compatible with an autosomal-dominant monogenic disease. The mean age at which symptoms developed was 38 years. Conclusion. These families may represent a familial type of pyrophosphate arthropathy with a phenotype that includes peripheral and axial enthesopathic calcifications. The concurrence of DISH and chondrocalcinosis suggests a shared pathogenic mechanism in the 2 conditions.

Objective. The ank/ank mouse develops a phenotype similar to ankylosing spondylitis (AS) in humans. ANKH, the human homolog of the mutated gene in the ank/ank mouse, has been implicated in familial autosomal-dominant chondrocalcinosis and autosomal-dominant craniometaphyseal dysplasia. This study was undertaken to investigate the role of ANKH in susceptibility to and clinical manifestations of AS. Methods. Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls. Linkage to the ANKH locus was assessed in 185 affected-sibling-pair families. Results. Five single-nucleotide polymorphisms were identified within the coding region and flanking splice sites. No association between either susceptibility to AS or its clinical manifestations and these novel polymorphisms, or between disease susceptibility and 3 known promoter variants, was seen. No linkage between the ANKH locus and AS was observed. Multipoint exclusion mapping rejected the hypothesis of a locus of a magnitude lambdagreater than or equal to1.4 (logarithm of odds score 10% to the AS sibling recurrence risk ratio) within this area contributing to AS. Conclusion. These findings indicate that ANKH is not significantly involved in susceptibility to or clinical manifestations of AS.

Objective Excess accumulation of extracellular inorganic pyrophosphate (ePPi) in aged human cartilage is crucial in calcium pyrophosphate dihydrate (CPPD) crystal formation in cartilage matrix. Two sources of ePPi are ePPi-generating ectoenzymes (NTPPPH) and extracellular transport of intracellular PPi by ANK. This study was undertaken to evaluate the role of NTPPPH and ANK in ePPi elaboration, by investigating expression of NTPPPH enzymes (cartilage intermediate-layer protein [CILP] and plasma cell membrane glycoprotein 1 [PC-1]) and ANK in human chondrocytes from osteoarthritic (OA) articular cartilage containing CPPD crystals and without crystals. Methods Chondrocytes were harvested from knee cartilage at the time of arthroplasty (OA with CPPD crystals [CPPD], n = 8; OA without crystals [OA], n = 10). Normal adult human chondrocytes (n = 1) were used as a control. Chondrocytes were cultured with transforming growth factor β1 (TGFβ1), which stimulates ePPi elaboration, and/or insulin-like growth factor 1 (IGF-1), which inhibits ePPi elaboration. NTPPPH and ePPi were measured in the media at 48 hours. Media CILP, PC-1, and ANK were determined by dot-immunoblot analysis. Chondrocyte messenger RNA (mRNA) was extracted for reverse transcriptase–polymerase chain reaction to study expression of mRNA for CILP, PC-1, and ANK. NTPPPH and ANK mRNA and protein were also studied in fresh frozen cartilage. Results Basal ePPi elaboration and NTPPPH activity in conditioned media from CPPD chondrocytes were elevated compared with normal chondrocytes, and tended to be higher compared with OA chondrocytes. Basal expression of mRNA for CILP (chondrocytes) and ANK (cartilage) was higher in both CPPD chondrocytes and CPPD cartilage extract than in OA or normal samples. PC-1 mRNA was less abundant in CPPD chondrocytes and cartilage extract than in OA chondrocytes and extract, although the difference was not significant. CILP, PC-1, and ANK protein levels were similar in CPPD, OA, and normal chondrocytes or cartilage extracts. Both CILP and ANK mRNA expression and ePPi elaboration were stimulated by TGFβ1 and inhibited by IGF-1 in chondrocytes from all sources. Conclusion CILP and ANK mRNA expression correlates with chondrocyte ePPi accumulation around CPPD and OA chondrocytes, and all respond similarly to growth factor stimulation. These findings suggest that up-regulated CILP and ANK expression contributes to higher ePPi accumulation from CPPD crystal–forming cartilage.

Objective Elevated cartilage inorganic pyrophosphate (PPi) production and PPi-generating nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity are strongly linked with aging-related cartilage calcification in meniscal and articular cartilages. We hypothesized that there were divergent relationships of 3 NTPPPH isozymes with cartilage matrix calcification and sought to identify them. Methods We studied knee medial meniscal expression in situ of 3 NTPPPH isozymes of the phosphodiesterase nucleotide pyrophosphatase (PDNP) family: plasma cell membrane glycoprotein 1 (PC-1, or PDNP1), autotaxin (ATX, or PDNP2), and B10/PDNP3. We also used complementary DNA transfection to assess differential functions in matrix calcification of each NTPPPH isozyme in vitro in meniscal cells. Results We observed diffuse cell-associated ATX and B10/PDNP3 expression in central (chondrocytic) and, to a lesser degree, peripheral (fibroblastic) regions of normal, degenerative uncalcified, and degenerative calcified menisci. In contrast, PC-1 expression was only robust at sites of apoptotic cells and calcification in central regions of degenerative menisci. Only PC-1 was abundant at the perimeter of meniscal cells and in association with meniscal cell–derived matrix vesicles (MVs). Because each PDNP-family isozyme was expressed by cells near calcifications, we transfected the isozymes in nonadherent knee meniscal cells cultured with ascorbic acid, β-glycerophosphate, and dexamethasone supplementation to stimulate them to calcify the matrix. PC-1, but not ATX or B10/PDNP3, consistently promoted increased MV NTPPPH, MV-associated PPi, and extracellular PPi. PC-1 also increased matrix calcification (with hydroxyapatite crystals) by meniscal cells. ATX uniquely induced alkaline phosphatase activity, but promoted only moderately increased matrix calcification. Conclusion We identified divergent effects of 3 PDNP-family NTPPPH isozymes on meniscal cell matrix calcification. Increased expression of PC-1 is both a marker and a potential pathogenic factor for knee meniscal cartilage matrix calcification.

Objective Diagnosis of the crystal-induced arthritides is primarily based on microscopic identification of crystals in synovial fluid. Therefore, we aimed to estimate the operating characteristics of this test and demonstrate its clinical use. Methods Medline was searched for relevant studies. Sensitivity and specificity of identification of crystals were calculated, as were measures of interobserver agreement. Likelihood ratios were calculated and curves constructed using the solutions to the Bayesian equations. Results Four studies were identified. The rates of interobserver agreement were low; the false-negative rates in identifying calcium pyrophosphate crystals were particularly high. Only one study allowed calculation of the test operating characteristics, and this was a study that used synthetic crystals and therefore may not be directly useful in a clinical setting. Conclusion There is a paucity of data about the accuracy of crystal identification. As it is clearly not a perfectly sensitive and specific test, the most prudent diagnostic strategy, as with essentially all diagnostic tests, is to establish a posterior probability of disease from a prior probability, based on the clinical features of the patient. Determining the operating characteristics of this test in conventional and reference laboratories should be a research priority for high quality clinical research on crystal arthropathies.

Objective To map the gene for human cartilage intermediate layer protein (CILP) in order to assess its involvement in some familial forms of calcium pyrophosphate dihydrate (CPPD) deposition disease. Methods A radiation hybrid panel was analyzed for chromosomal assignment of the CILP gene within a 1-cM limit of resolution. The location of the gene for CILP was confirmed to reside at the observed radiation hybrid locus by fluorescence in situ hybridization. Results The human CILP gene resides at chromosome 15q21. Conclusion This map location definitively excludes mutations in the CILP gene as the cause of certain familial forms of CPPD deposition disease that have been genetically mapped to chromosomes 8q and 5p.

Objective To determine whether the osteoarticular changes associated with genetic hemochromatosis could be explained by metabolic parathyroid hormone (PTH) disorders. Methods The study involved 210 patients with liver iron overload syndromes. Osteoarticular changes were numerically scored as the number of damaged joints. PTH 1–84 and 44–68 were assayed. Results An increase in serum PTH 44–68 levels was found in one-third of untreated patients who had no calcium or PTH 1–84 abnormalities. Serum PTH 44–68 levels correlated positively with serum ferritin levels. In multivariate analyses, the number of affected joints correlated positively with age, serum PTH 44–68 levels, and serum ferritin levels. Conclusion Liver iron overload syndromes, especially genetic hemochromatosis, are associated with elevated circulating levels of PTH fragments containing the 44–68 region, which appears to play a role in osteoarticular changes. This increase seems to be a consequence of iron overload.

We describe herein the case of a 63-year-old man with pseudogout affecting multiple joints that was resistant to treatment with allopurinol, steroids, and antiinflammatory drugs. Based on recent data on the molecular mechanism of pseudogout that demonstrated overproduction of interleukin-1 (IL-1), we treated the patient with anakinra, an IL-1 receptor antagonist. The patient responded to treatment with anakinra within 2 weeks, with resolution of the signs and symptoms of pseudogout and normalization of levels of inflammation markers.

Objective. To investigate the effects of chronic calcium pyrophosphate dihydrate (CPPD) synovitis on the development of osteoarthritic (OA) lesions in an animal model. Methods. OA was induced in the right knees of 30 male New Zealand white rabbits by partial lateral meniscectomy and section of the fibular collateral and sesamoid ligaments (PLM/LS), followed by 8 weekly intraarticular (IA) injections of 1 mg (low-dose) or 10 mg (high-dose) of CPPD crystals in 3 sets of experiments (10 rabbits each). The contralateral left knees served as controls: experiment 1 PLM/LS alone, experiment 2 8 weekly IA injections of CPPD crystals alone, and experiment 3 sham surgery plus 8 weekly IA injections of CPPD crystals. Results. At 8 weeks, repeated IA injections of low-dose and high-dose CPPD crystals into meniscectomized right knees resulted in more severe OA than in meniscectomized but noninjected left knees (experiment 1) (P = 0.003 and P = 0.001, respectively). One-fourth of the meniscectomized knees (11 of 40), both CPPD-injected and noninjected, showed embedded synovial cartilage shards. Conclusion. The data demonstrate a worsening effect of chronic CPPD crystal-induced synovitis on experimental OA produced in the rabbit knees by PLM/LS, and support a possible role for CPPD microcrystalline inflammation in the progression of OA lesions in clinical CPPD crystal deposition disease.

Objective. To characterize a kindred of Chiloe Islanders with spondyloepiphyseal dysplasia tarda (SEDT), brachydactyly, precocious osteoarthritis (OA), and intraarticular calcification. Methods. Sixteen family members underwent a complete physical examination, anthropometric measurements, radiographic studies of the spine and peripheral joints, and analysis of the type II procollagen gene (COL2A1). Results. Seven family members presented with SEDT, brachydactyly, precocious OA, and periarticular calcification while 2 others had the same syndrome but without brachydactyly. The inheritance was autosomal dominant, and the disease cosegregated with a base substitution in the COL2A1 gene. Conclusion. The syndrome of SEDT, precocious OA, and brachydactyly in a kindred of Chiloe Islanders is associated with a point mutation in 1 allele of the COL2A1 gene. The relationship of this type of SEDT to familial calcium pyrophosphate dihydrate deposition disease and idiopathic hip dysplasia, both endemic in Chiloe Islanders, needs to be further investigated.

Objective. To determine the major source of eicosanoid release in arthritic joint tissues and to examine the modulation of this release by indomethacin and diclofenac. Methods. Release of prostaglandin E2 (PGE2), 6-keto-PGF1α, leukotriene B4 (LTB4), and LTC4 was measured in supernatants of synovial tissue, cartilage, and bone incubates from patients with osteoarthritis, active rheumatoid arthritis (RA), inactive RA, and pseudogout. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. Results. Addition of the divalent cation ionophore A23187 resulted in significant release of all eicosanoids measured from synovial tissue, but not from cartilage, cortical bone, or cancellous bone. PG release was significantly inhibited by the addition of indomethacin or diclofenac at either 10–5 moles/liter or 10–7 moles/liter. The amount of LTC4 released from cartilage and bone was only slightly above the detection limit of the RIA, whereas large amounts were released from synovial tissue. Neither indomethacin nor diclofenac had an effect on LTC4 release. LTC4 release from synovial tissue of patients with inactive RA was significantly decreased in comparison with the levels from synovial tissue of patients with the other joint diseases. There was no significant difference in PG release among patients in the various disease groups. Conclusion. Synovial tissue appears to be the major source of eicosanoids in synovial fluid. Indomethacin and diclofenac inhibit the release of PG, but not LT, from various joint tissues.

Objective. Reasons for apparent primary deposition of calcium pyrophosphate dihydrate (CPPD) crystals in some synovial membranes have not been systematically examined. We undertook the present study to investigate for and compare possible cellular and matrix factors related to the presence of these crystals in synovium and cartilage. Methods. Ten synovial membrane specimens and 6 cartilage specimens were obtained at the time of joint surgery from 10 patients with CPPD crystal deposition disease, for light microscopic (LM) and electron microscopic (EM) studies. Results. In all synovial and cartilage specimens, we found many of the small CPPD crystals aligned on or in parallel to collagen fibers, as seen by EM. In 9 of the 10 crystal-containing synovia, we found foci of chondrometaplasia adjacent to CPPD, by LM. In 7 of the synovia, including the one without LM evidence of chondrometaplasia, we observed the presence of chondrocyte-like cells by EM. We did not note any predictable relationship between the crystals and matrix vesicles, either in synovium or in cartilage. Conclusion. Our EM findings provide evidence of the relationship of small CPPD-like crystals, presumably early forms, to collagen fibers both in synovium and in cartilage. By LM and EM, we also demonstrate evidence of a close association between chondrometaplasia and CPPD deposits in synovium. We suggest that chondrometaplasia might be responsible for synovial CPPD formation in predisposed patients. Both the collagen fibers and chondrocyte-like cells seem to be involved in the primary formation of CPPD deposits in the synovium as well as in the cartilage.

Objective The purpose of this study was to determine the effect of transforming growth factor beta 1 (TGF beta 1) on inorganic pyrophosphate (PPi) elaboration from articular tissues to better understand the pathophysiology of calcium pyrophosphate dihydrate (CPPD) crystal deposition in the joint. Methods PPi was measured in the media of adult porcine articular tissue in organ culture and monolayer cultures. Results TGF beta 1 strongly stimulated PPi elaboration by porcine fibrocartilage and hyaline cartilage. It modestly increased PPi elaboration by ligament, and had no effect on PPi elaborated by synovium. Of all cell types tested in cell culture, only chondrocytes responded to TGF beta 1 by significantly increasing PPi elaboration. Conclusion TGF beta 1 stimulates PPi elaboration from hyaline cartilage, fibrocartilage, and ligament, indicating that there is in situ CPPD crystal formation in these tissues. The ability of tissues to respond to TGF beta 1 by increasing PPi elaboration correlates with the prevalence of CPPD crystal deposition found clinically. The unique response of chondrocyte monolayers to TGF beta 1 reinforces the key role of the chondrocyte in PPi elaboration in the joint. These findings support an etiologic role for responsiveness to TGF beta 1 in CPPD disease.

Fine linear extraarticular calcium deposits were found in X-rays of 7 of 52 patients with articular chondrocalcinosis (ACC). Seven Achilles tendons, seven quadriceps tendons, and one plantar fascia were affected. In a control group of comparable age and sex, without ACC but with generalized osteoarthritis, no calcifications were found in the tendons. On a biopsy specimen of Achilles tendon with such calcium deposits, X-ray diffraction showed that they had the characteristics of calcium pyrophosphate dilhydrate. Isolated small foci of crystals were observed on some segments of tendon bundles. The presence of fine linear calcifications on X-rays of the Achilles or quadriceps tendons may be a useful aid in the radiologic diagnosis of so-called articular chondrocalcinosis.

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. Two 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.

The existence of articular chondrocalcinosis was documented in 9 members of 3 generations of a Quebec family. No associated or secondary forms of the disease were found. The clinical manifestations appeared early in life, and extensive radiologic involvement was apparent. We determined that genetic transmission was dominant, either autosomal or sex-linked, and not related to the HLA system.

In a study of 45 adults in a family of Mexican-Indian ancestry, it was found that 22 (49%) had joint symptoms resembling those of degenerative joint disease. Eleven family members had radiographic evidence of chondrocalcinosis, and 1 adult and 3 adolescents had clinical histories and examinations consistent with the familial arthropathy, but no radiographic evidence of disease. The cause of the arthritis in the affected family members is calcium pyrophosphate crystal deposition. The mode of inheritance appears to be autosomal dominant with a high degree of penetrance. The disease is characterized by onset in the second to fifth decades of either episodes of acute inflammatory arthritis or degenerative joint disease. A unique finding of this study was a "halo" surrounding chondrocytes in 1 patient's cartilage, demonstrating loss of the proteoglycans.

Inorganic pyrophosphatase activity has been partially characterized in joint fluid and determined in patients with sporadic and familial chondrocalcinosis and their controls. Optimal pH was established at 3.5 and Km values were estimated. Ca-2 and Mg-2 did not affect this activity whereas orthophosphate (Pi) strongly inhibited it. In the clinical study no significant differences were found among groups. This suggests that if a pyrophosphatase defect is present it might be localized in joint tissue and not be reflected in synovial fluid.

Deposition of crystalline triclinic (t) and monoclinic (m) calcium pyrophosphate dihydrate (CPPD) in fibrocartilage and articular cartilage is the hallmark of chondrocalcinosis. Using biologic grade gelatin to model this crystal growth process, t-CPPD, m-CPPD, amorphous calcium pyrophosphate, orthorhombic calcium pyrophosphate tetrahydrate (o-CPPT), and 3 mixed calcium/sodium pyrophosphate salts were grown at physiologic pH. Amorphous and o-CPPT appeared to be kinetic precursor crystals in the formation of t-CPPD and m-CPPD. Optimal concentration ranges for the different crystals were determined.

Because cleavage products of the third component of complement augment inflammation and may contribute to arthritis, we used a competitive inhibition radioimmunoassay to measure levels of the low molecular weight cleavage products of the third component of complement, C3a and C3adesArg, in 72 synovial fluid samples. Mean levels of C3a/C3adesArg were more than sevenfold higher in 41 patients who had rheumatoid arthritis than in 15 patients who had degenerative joint disease or 5 patients who had traumatic arthritis. Striking elevations were also present in 2 patients who had acute gouty arthritis. A calculation of the fraction of intraarticular C3 cleaved showed that the patients with rheumatoid arthritis had a mean C3 cleavage of 11.6 +/- 11.0%, which was significantly higher than values of less than 1.5% for patients with degenerative joint disease or traumatic arthritis. In rheumatoid arthritis and gouty arthritis, specific immunoassay identified substantial quantities of the initial C3 cleavage fragments.

The American Rheumatism Association sub-committe on classification criteria for gout analyzed data from more than 700 patients with gout, pseudogout, rheumatoid arthritis, or septic arthritis. Criteria for classifying a patient as having gout were a) the presence of characteristic urate crystals in the joint fluid, and/or b) a topus proved to contain urate crystals by chemical or polarized light microscopic means, and/or c) the presence of six of the twelve clinical, laboratory, and X-ray phenomena listed in Table 5.

A comprehensive review of the roentgenographic features of calcium pyrophosphate crystal deposition disease (pseudogout) is presented. The roentgenographic techniques are reviewed. Those recommended as optimal are as follows: for small peripheral joints, industrial Type M film with contact exposure; for large central joints, direct radiographic magnification (3-4 X) with a microfocus tube. The classic appearances of articular chondrocalcinosis in fibrocartilage, hyaline cartilage, and capsular structures are discussed. Distinctive features of pyrophosphate arthropathy, including the distribution of involvement and the degree of destruction, are emphasized. Finally, the relationship among articular chondrocalcinosis, arthropathy, microscopic crystals, and symptoms is discussed.

Adenosine triphosphate pyrophosphohydrolase (ATPPPH) and neutral inorganic pyrophosphatase activities were assayed in synovial fluids (SF) from 37 patients with a variety of arthropathies. ATPPPH activity was detected in all fluids, but was highest in patients with chronic chondrocalcinosis; its activity in patients with osteoarthritis was higher than that in patients with rheumatoid arthritis, gout, or pseudogout. ATPPPH activity correlated positively with SF pyrophosphate concentration and negatively with SF white blood cell count. Pyrophosphatase activity did not correlate with diagnosis, pyrophosphate level, or white blood cell count.

DNA levels were measured in synovial fluids and sera of 106 patients with rheumatoid arthritis (RA), osteoarthritis (OA), gout, pseudogout, and posttraumatic arthritis (TRA). In synovial fluids, the highest concentration was found in rheumatoid arthritis (mean +/- SE 18 +/- 3 microgram/ml for seropositive and 9 +/- 1 microgram/ml for seronegative variants), gout and pseudogout (17 +/- 3 microgram/ml). In contrast, the levels in patients with OA or acute TRA were very low: 0.8 +/- 0.1 microgram/ml an 1.1 +/- 0.2 microgram/ml, respectively. The differences between the means of the first disease group and OA or TRA is statistically significant. A similar pattern was observed for DNA levels in the circulation: in rheumatoid arthritis, the mean concentration was 135 +/- 28 ng/ml and 164 +/- 39 ng/ml for seropositive and seronegative RA, respectively. Again the levels in OA and TRA were much lower, 52 +/- 18 ng/ml and 0 ng/Ml, respectively. The latter are not significantly different from the mean levels of 95 normal, healthy controls (14 +/- 3 ng/ml), whereas the concentration of DNA in the serum of RA patients is significantly higher than in OA, TRA, or normal controls. Serial determinations of DNA and other criteria of disease activity (leukocytes and protein levels in synovial fluid, blood sedimentation rate) in individual patients revealed a strong correlation of elevated values with active episodes. THe results suggest that these parameters reflect tissue damage.

A gene in the heterozygous state appears responsible for a 2-fold increase in pyrophosphate content of both fibroblasts and lymphoblasts cultured from patients who have dominantly inherited chondrocalcinosis. Cells from unaffected family members of this large kindred showed a pyrophosphate content in the same range as was found in unaffected, unrelated controls. Similar cells from individuals homozygous for the gene would be useful in delineating the precise biochemical abnormality responsible for the increased pyrophosphate content.

The first-degree consanguineous relatives of 46 patients with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease were examined for the presence of articular chondrocalcinosis. In 5 cases the process was familial, with 17 persons in the oldest living generation (mean age 69 +/- 7.4) showing radiographic evidence of calcified cartilage. The clinical syndrome was characterized by a female predominance, late onset of symptoms with mild arthritic manifestations, and oligoarticular chondrocalcinosis. These data suggest that the familial type of CPPD crystal deposition disease is more frequent than formerly thought.

A negative correlation between rheumatoid arthritis (RA) and calcium pyrophosphate dihydrate (CPPD) crystal deposition was demonstrated in separate controlled radiographic and synovial fluid surveys of RA patients aged 55–75 years. Knee chondrocalcinosis was detected in 14% of 135 normal controls and 28% of 87 post-meniscectomy (“joint damage”) controls (P < 0.05), but only 3% of 100 RA patients (P < 0.01). Microscopic examination of fluids from symptomatic knees of an additional 100 RA and 75 osteoarthritis patients revealed CPPD crystals in 1% and 23%, respectively (P < 0.01). Ten subjects with coexistent RA and CPPD deposition were also studied; 7 showed radiographic features atypical of RA, including patchy, asymmetric disease, retained bone density, prominent osteophytosis, well-corticated cysts, and paucity of progressive erosive disease. It is suggested that rheumatoid joint damage, unlike that in osteoarthritis, is not conducive to CPPD crystal formation. When RA and CPPD coexist, atypical radiographic features reflecting a hypertrophic reparative response may occur.

Incubates of articular cartilage from young but not mature rabbits, as well as growth plate cartilage, elaborated PPi into basel Eagle's medium during a 4-hour period. Control rabbit synovial membrane and ear cartilage elaborated negligible amounts of PPi. The PPi was shown to be nondialyzable but could be dissociated from the alkaline phosphatase by ultracentrifugation. In 16 patients with osteoarthritis a substantial output of PPi by samples of articular cartilage from the knee was demonstrated. The present authors believe that either rapid cell division and matrix synthesis found in the base of ulcerating osteoarthritic cartilage or remodeling calcified sites comprise the origin of the PPi in such osteoarthritic cartilage. They further theorize that this PPi output accounts for a considerable fraction, if not all, of the elevated PPi levels found in synovial fluid of patients with osteoarthritis.