Crystal-associated arthropathies: what's new in old joints

Degenerative arthritis in the aged includes two major disease categories--osteoarthritis and the crystal-associated arthropathics. The crystals chiefly involved are monosodium urate (gout) and calcium pyrophosphate dihydrate (CPPD), although several others (e.g., cholesterol, brushite and apatite) have been implicated. This report illustrates how the newer diagnostic techniques such as polarized-light microscopy, analytical electron microscopy and x-ray microdiffraction have augmented knowledge concerning diseases associated with articular crystal deposition. For example, diffraction techniques are required for accurate identification of the apatite crystals found in synovial fluid effusions and in the matrix vesicles of degenerate cartilage. According to ultrastructural studies, monosodium urate crystals found in tophi, joint surfaces and effusions show a distinct morphology. Present in inactive joints, the crystal surfaces are bare; in acute gout, the crystals are covered with mucin, confirming the observation that protein binding to crystals is necessary for inflammation to proceed. CPPD disease is by far the most common crystal-associated arthropathy affeting the aged. The incidence of CPPD deposits in articular tissues increases with age but, in contrast to gout, affects both men and women. The pathogenesis of CPPD disease is a mystery, but factors under investigation include matrix abnormalities, ionic imbalances, and enzyme disorders.     

A comparative analysis of serologic parameters and oxidative stress in osteoarthritis and rheumatoid arthritis: reply to Mishra and colleagues

In chronic diseases such as rheumatoid arthritis and osteoarthritis, the progression of the disease is characterized by stress oxidative, inflammation, and elevated levels of cholesterol. In mevalonate kinase deficiency, an auto-inflammatory disease, the correlation between inflammation and cholesterol levels is opposite. The metabolic pathway that underlies the production of cholesterol is the mevalonate pathway; it is also essential for the biosynthesis of isoprenoids involved in the control of several cell functions. This divergence of cholesterol levels, associated with these two inflammatory disorders, is probably due to a different etiology, pathogenesis, and progression.     

Cholesterol crystals pericarditis]

Cholesterol pericarditis is an uncommon, specific form of pericardial disease that is characterized by the presence of cholesterol crystals in pericardial fluid. The etiology may be either idiopathic or in association with systemic disorders such as tuberculosis, rheumatoid arthritis, myxedema or hypercholesterolemia. We report a case of cholesterol pericarditis in a 51-year-old male who was diagnosed with chronic renal failure due to polycystic kidney disease. To our knowledge no similar cases have been reported to date in the literature.     

Inhibitory effect of low density lipoprotein on the inflammation-inducing activity of calcium pyrophosphate dihydrate crystals.

OBJECTIVE: It has been proposed that low density lipoprotein (LDL) plays a role in the self-limiting nature of pseudogout inflammation. We investigated changes of LDL concentration in rat air pouch fluid during periods of acute and subsiding inflammation to evaluate whether LDL contributes to inhibiting inflammation of pseudogout. We examined whether LDL binds to calcium pyrophosphate dihydrate (CPPD) crystals as a possible mechanism for reduction of inflammation. METHODS: In this in vivo study, 5 mg suspensions of CPPD crystals and saline were injected into the rat air pouch. Fluid samples were taken from rat air pouch at 0, 3, 6, 12, 24, and 48 h after injection. White blood cells in the samples were counted; the remaining fluid was centrifuged and concentrations of beta-glucuronidase and PGE2 in the supernatant were measured as inflammatory markers. LDL in the supernatant was immunochemically identified by Western blotting, then pellets containing crystals were examined by the same technique. RESULTS: LDL was identified in the air pouch 3 h after CPPD crystal injection, and its concentration increased and reached a peak level after 24 h. Inflammatory markers reached maximal level from 6 to 12 h, then decreased after 24 h. In the pellets containing crystals, LDL could not be identified in every specimen. CONCLUSION: LDL in the rat air pouch increased during the inflammatory course induced by CPPD crystal and the inflammation subsided as the LDL increased. Since some reports indicate LDL was related to reduction of crystal induced inflammation such as gout or pseudogout, we concluded that LDL could contribute to the resolution of acute pseudogout arthritis in vivo with or without binding to CPPD crystals.     

Polyarticular Clostridium perfringens pyoarthritis

A woman with rheumatoid arthritis presented with an abdominal mass and Clostridium perfringens septic arthritis in both wrists and shoulders. We believed this to be the first reported case of polyarticular septic arthritis due to Clostridium perfringens. Apatite, lipid, and cholesterol crystals in the shoulder joint effusions were a potential source of diagnostic confusion.     

Inflammatory responses to intradermal crystals in healthy volunteers and patients with rheumatic diseases

Summary The inflammatory response to intradermal injections of urate, pyrophosphate and hydroxyapatite crystals in human forearm skin is described. Patients with rheumatoid arthritis responded normally to urate crystals, and patients with osteoarthritis or pyrophosphate arthropathy responded normally to hydroxyapatite and pyrophosphate crystals respectively. These results suggest that variation in host response to crystals cannot explain the different patterns of crystal-induced disease seen in man. The model, however, is recommended as a safe, simple ethical and reproducible test of inflammation in human subjects.     

Changes in the proteins coating monosodium urate crystals during active and subsiding inflammation. immunogold studies of synovial fluid from patients with gout and of fluid obtained using the rat subcutaneous air pouch model

Objective. In this in vivo study, we investigated changes in the proteins that coat monosodium urate (MSU) crystals in human synovial fluid samples and rat air pouch fluid samples obtained sequentially during periods of active and resolving inflammation, in order to evaluate whether in vivo findings are consistent with hypotheses on roles of protein coating based on in vitro findings. Methods. Crystals from patients with gout were isolated from joint fluids with acute inflammation, and subsequently from the same joints at the time inflammation was resolving. Crystals were also obtained using the rat subcutaneous air pouch model. Immunogold was used to label proteins coating MSU crystals, for light microscopy (LM) and transmission electron microscopy (TEM) studies. Results. Dense immunogold–silver labeling for IgG was observed under LM on crystals from fluid with acute inflammation, whereas other proteins (apolipoproteins [Apo], fibronectin, fibrinogen, albumin) were not labeled significantly. Apo B became strongly positive on crystals as the inflammation subsided, whereas other proteins were only weakly positive and IgG became absent or weakly positive. Quantitative TEM evaluation confirmed the LM observations. Conclusion. This study provides the first in vivo evidence supporting the notion derived from previous in vitro studies that proteins coating MSU crystals change as inflammation evolves. Protein coatings may play an important role in the self-limited nature of gouty inflammation. IgG coating MSU crystals may enhance the inflammation. As the inflammation subsides, Apo B could displace the IgG by competitively coating sites on crystals and could contribute in part to the resolution of the acute gouty arthritis.     

Hydroxyapatite deposition disease of the joint

Basic calcium phosphate (BCP) crystals include partially carbonate-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate. They may form deposits, which are frequently asymptomatic but may give rise to a number of clinical syndromes including calcific periarthritis, Milwaukee shoulder syndrome, and osteoarthritis, in and around joints. Recent data suggest that magnesium whitlockite, another form of BCP, may play a pathologic role in arthritis. Data from the past year have provided further understanding of the mechanisms by which BCP crystals induce inflammation and degeneration. There remains no specific treatment to modify the effects of BCP crystals. Although potential drugs are being identified as the complex pathophysiology of BCP crystals is unraveled, much work remains to be done in order to translate research advances to date into tangible clinical benefits.     

Arthritis associated with apatite crystals.

Needle-shaped crystals of 75 to 250 A diameter have been identified by transmission electron microscopy in clumps within synovial fluid mononuclear cell vacuoles in a variety of joint diseases. These crystals, similar to those previously associated with calcific periarthritis, were seen in acute undiagnosed arthritis and in exacerbations of osteoarthritis where they may be inducing a synovitis similar to that seen with urate and pyrophosphate crystals in gout and pseudogout. By light microscopy purple staining cytoplasmic inclusions or extracellular globules can suggest the presence of clumps of these crystals. Apatite clumps can also occasionally appear as small birefringent chunks or rods and thus might mimic urate or calcium pyrophosphate. Ultrastructural appearance, electron probe analysis, and X-ray diffraction pattern were those of apatite. Experimental injection of hydroxyapatite crystals into dog knee joints produces inflammation supporting the potential role for these crystals in joint disease.     

New knowledge on the pathophysiology and therapy of gout

Gout is caused by the deposition of monosodium urate crystals (MSU) in tissue and provokes a local inflammatory reaction. It is the most common form of inflammatory arthritis in the elderly. The formation of MSU crystals is facilitated by hyperuricemia. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into uric acid metabolism in the kidneys as well as possible links between hyperuricemia and hypertension. MSU crystals provoke inflammation by activating leukocytes to produce inflammatory cytokines and other inflammatory mediators. The uptake of MSU crystals by monocytes involves interactions with Toll-like receptors (TLR-2 and TLR-4) and CD14, components of the innate immune system. Intracellularly, MSU crystals activate inflammasomes to activate pro-IL-1 (interleukin 1) processing to yield mature IL-1beta. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances provide new therapeutic targets to treat hyperuricemia and gout.     

Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis

BACKGROUND: Rheumatoid arthritis is characterised by inflammation and an increased cardiovascular risk. It was recently shown that active early rheumatoid arthritis is associated with dyslipidaemia, which may partially explain the enhanced cardiovascular risk. However, it is unknown when this dyslipidaemia starts. OBJECTIVE: To investigate the progression of the lipid profile over time and the influence of inflammatory parameters on this lipid profile, in people who later developed rheumatoid arthritis. METHODS: Levels of total cholesterol, high-density lipoprotein cholesterol (HDLc), triglycerides, apolipoprotein AI (apo AI), apolipoprotein B (apo B) and lipoprotein(a) (Lp(a)) were determined in 1078 stored, deep-frozen, serial blood bank samples, collected between 1984 and 1999, of 79 blood donors who later developed rheumatoid arthritis. These samples were compared with 1071 control samples of unselected blood donors, matched for age, sex and storage time. RESULTS: Samples of patients who later developed rheumatoid arthritis showed, on average, 4% higher total cholesterol, 9% lower HDLc, 17% higher triglyceride and 6% higher apo B levels than matched controls (p< or =0.05). The magnitude of the differences in lipid levels between groups, explained by C reactive protein (CRP), was limited. For example, only 3.6% of the difference in HDLc levels between the groups was explained by the CRP concentrations. CONCLUSION: Patients who later develop rheumatoid arthritis have a considerably more atherogenic lipid profile than matched blood donors at least 10 years before onset of symptoms. As inflammation only marginally explains the differences between the two groups, a modulating effect of lipids on inflammatory processes is hypothesised.     

Neue Erkenntnisse zur Pathophysiologie und Therapie der Gicht

Gout is caused by the deposition of monosodium urate crystals (MSU) in tissue and provokes a local inflammatory reaction. It is the most common form of inflammatory arthritis in the elderly. The formation of MSU crystals is facilitated by hyperuricemia. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into uric acid metabolism in the kidneys as well as possible links between hyperuricemia and hypertension. MSU crystals provoke inflammation by activating leukocytes to produce inflammatory cytokines and other inflammatory mediators. The uptake of MSU crystals by monocytes involves interactions with Toll-like receptors (TLR-2 and TLR-4) and CD14, components of the innate immune system. Intracellularly, MSU crystals activate inflammasomes to activate pro-IL-1 (interleukin 1) processing to yield mature IL-1β. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances provide new therapeutic targets to treat hyperuricemia and gout.     

T-cell function is critical for murine cholesterol gallstone formation

BACKGROUND & AIMS: The formation of cholesterol gallstones is a complex process involving contributions from genes and environmental factors. Although gallbladder inflammation is believed to be common during cholelithogenesis, the role of immunologic factors is unknown. METHODS: The role of adaptive immunity in cholesterol cholelithogenesis was analyzed utilizing immunocompetent Helicobacter spp.-infected and -uninfected BALB/c and congenic immunodeficient Rag2(-/-) (Rag) mice. Lymphocyte transfer studies were performed to determine which cellular subset was responsible for cholesterol gallstone formation. Also, gallbladder inflammation was quantified to determine the nature of the inflammatory response associated with cholelilithogenesis. RESULTS: When fed a lithogenic diet for 8 weeks, wild-type mice developed significantly more cholesterol gallstones (27%-80% prevalence) than Rag mice ( approximately 5%, P < .05). Helicobacter spp.-infected BALB/cJ mice displayed statistically significant increases in cholesterol gallstone prevalence compared with uninfected mice (81% vs. 39%; P < .05). Transfer of splenocytes or T lymphocytes to Rag2(-/-) mice increased stone prevalence markedly (26% and 40% respectively; P < .05), whereas transfer of B cells was not appreciably cholelithogenic (13%). The adaptive immune response increased the expression of gallbladder Muc genes and accumulation of mucin gel. In addition, T cells and cholesterol monohydrate crystals induced proinflammatory gene expression in the gallbladder, which likely contributes to gallbladder dysfunction. CONCLUSIONS: These studies indicate that T cells are critical in murine cholesterol cholelithogenesis. Furthermore, cholesterol monohydrate crystals induce expression of proinflammatory cytokines in a T-cell-dependent fashion. Acquired immunity and inflammation are likely to be crucial factors in cholesterol gallstone pathogenesis, rather then merely the result of cholelithogenesis.     

Serum cholesterol and vitamins A and E in juvenile chronic arthritis

Serum total cholesterol is decreased during acute infections and in adults with rheumatoid arthritis, probably partly because of enhanced lipid peroxidation. Oxidative stress also causes augmentation of inflammation and tissue damage in arthritic synovium. Therefore, concentrations of serum total cholesterol and the antioxidant vitamins A and E were studied in 125 children with juvenile chronic arthritis. Total serum cholesterol was significantly lower in the patients than in healthy children in most age groups and correlated with the markers of disease activity, haemoglobin and the erythrocyte sedimentation rate. In age- and sex-adjusted stepwise multiple linear regression, serum zinc had a significant predictive value for cholesterol. The vitamin A concentrations in the sera of the patients was virtually the same as in the healthy controls, though serum vitamin E concentrations were low (22.8 +/- 15.2 vs 30.5 +/- 4.3 mumol/l, p less than 0.001). The deficiency in vitamin E was not compensated for by another lipoperoxide antioxidant, glutathione peroxidase. Only serum cholesterol had an independent explanatory significance for vitamin E in multiple linear regression analysis (partial correlation 0.554, p less than 0.001). It is suggested that low vitamin E and impairment of the anti-oxidant protection further contribute to low serum cholesterol values in JCA.     

Levels of plasma lipid peroxide products and antioxidant status in rheumatoid arthritis

Oxygen free radicals have been implicated as mediators of tissue damage in patients with rheumatoid arthritis. The aim of our study was to assess the lipid peroxide products and antioxidant status in rheumatoid arthritis patients (RA). The study involved determination of two plasma lipid peroxide products, malondialdehyde (MDA) and conjugated dienes (CD), two plasma antioxidant vitamins (C and E) in 91 RA patients and 26 healthy subjects. The results showed that rheumatoid patients had increased plasma CD but not MDA and decreased plasma vitamin E, when properly expressed per unit cholesterol and triglyceride. This finding suggested that RA patients had increased oxidant stress that might play a role in the tissue damage and inflammation process of this disease.     

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.     

11β-Hydroxysteroid dehydrogenase type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice

Glucocorticoids profoundly influence immune responses, and synthetic glucocorticoids are widely used clinically for their potent antiinflammatory effects. Endogenous glucocorticoid action is modulated by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). In vivo, 11β-HSD1 catalyzes the reduction of inactive cortisone or 11-dehydrocorticosterone into active cortisol or corticosterone, respectively, thereby increasing intracellular glucocorticoid levels. 11β-HSD2 catalyzes the reverse reaction, inactivating intracellular glucocorticoids. Both enzymes have been postulated to modulate inflammatory responses. In the K/BxN serum transfer model of arthritis, 11β-HSD1-deficient mice showed earlier onset and slower resolution of inflammation than wild-type controls, with greater exostoses in periarticular bone and, uniquely, ganglion cysts, consistent with greater inflammation. In contrast, K/BxN serum arthritis was unaffected by 11β-HSD2 deficiency. In a distinct model of inflammation, thioglycollate-induced sterile peritonitis, 11β-HSD1-deficient mice had more inflammatory cells in the peritoneum, but again 11β-HSD2-deficient mice did not differ from controls. Additionally, compared with control mice, 11β-HSD1-deficient mice showed greater numbers of inflammatory cells in pleural lavages in carrageenan-induced pleurisy with lung pathology consistent with slower resolution. These data suggest that 11β-HSD1 limits acute inflammation. In contrast, 11β-HSD2 plays no role in acute inflammatory responses in mice. Regulation of local 11β-HSD1 expression and/or delivery of substrate may afford a novel approach for antiinflammatory therapy.     

Relations between autoantibodies against oxidized low-density lipoprotein, inflammation, subclinical atherosclerosis, and cardiovascular disease in rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is associated with an unexplained increased cardiovascular risk. Autoantibodies recognizing oxidized low-density lipoprotein (oxLDL-ab) are associated with atherosclerosis in the general population and have been reported in several autoimmune diseases. We investigated relations between oxLDL-ab, inflammation, subclinical atherosclerosis, and cardiovascular disease (CVD) in patients with RA. METHODS: In a nested case-control study, serum concentrations of oxLDL-ab were measured in 140 RA patients. Ultrasound examination of the carotid artery [i.e., carotid intima-media thickness (CIMT)] was performed in a third of these patients. Correlations were calculated for oxLDL-ab, C-reactive protein (CRP), and high-density lipoprotein (HDL) cholesterol. Regression analyses were used to examine associations between oxLDL-ab and prevalent CVD, and oxLDL-ab and CIMT. RESULTS: OxLDL-ab were positively correlated with CRP (r = 0.33, p < 0.001) and negatively correlated with HDL cholesterol (r = -0.28, p = 0.001). An indication for interaction was found (p = 0.09), suggesting that inflammation modifies the relation between HDL cholesterol and oxLDL-ab. OxLDL-ab were independently associated with intimal thickening, but not associated with prevalent CVD. CONCLUSION: OxLDL-ab were strongly related with the degree of inflammation and may predispose to a higher risk for CVD, as they were independently associated with subclinical atherosclerosis in patients with RA.     

Psoriatic arthritis associated with adult polycystic kidney disease,seminal vesicle,and epididymal cysts

Patients with seminal vesicle and epididymal cysts are mostly asymptomatic. To date, only one patient presenting with bloody ejaculate and acute scrotum has been reported. Different extrarenal manifestations and the association of adult polycystic kidney disease (APKD) with some connective tissue diseases are known. We report on a 60-year-old male patient with bloody ejaculate and acute scrotum who had been diagnosed as having APKD 1 year earlier and whose past medical history revealed inflammatory low back pain, psoriasis, and the diagnosis of psoriatic arthritis. Cultures of urine and ejaculate were sterile, and the patient's renal functions were normal. Ultrasound showed epididymal and seminal vesicle cysts in addition to hepatic and renal cysts. Our case is the first in which psoriatic arthritis accompanied APKD, seminal vesicle cysts, and epididymal cysts. We also review other APKD cases that have accompanied seminal vesicle cysts.     

Crystal-induced neutrophil activation: X. Proinflammatory role of the tyrosine kinase Tec

OBJECTIVE: Monosodium urate monohydrate (MSU) crystals are among the most potent proinflammatory stimuli, and an innate immune inflammatory response to the crystal surface is involved in the pathogenesis of gouty arthritis. Release of the crystals into the joint cavity promotes an acute inflammation characterized by massive infiltration of neutrophils, which leads to tissue damage. The aim of the present study was to assess the involvement of the tyrosine kinase Tec in MSU crystal-initiated transduction events in human neutrophils. METHODS: Immunoprecipitation and immunoblotting techniques were used for the cellular signaling studies. Chemotaxis and enzyme-linked immunosorbent assay techniques were used for the functional studies. Silencing of Tec expression using specific small interfering RNA was also performed. RESULTS: MSU crystals induced the phosphorylation and activation of Tec in a Src-dependent manner. This activation was necessary for the MSU crystal-induced secretion of interleukin-1beta (IL-1beta) and IL-8 and for the generation of chemotactic activity in supernatants of MSU crystal-stimulated neutrophils. In addition, colchicine, an effective drug for the treatment of gout, inhibited the MSU crystal-induced tyrosine phosphorylation of Tec, thus modulating its kinase activity. CONCLUSION: Our findings show that Tec is the principal kinase of the Tec family that plays a major role in the responses of human neutrophils to MSU crystals, which are likely to be involved in the initiation and perpetuation of gout. Our results suggest that the specific inhibition of Tec during the acute phase of MSU crystal-induced inflammation may be considered for the treatment of gouty arthritis.