Crystal-induced Arthropathies Research Articles

In Defense of Research into the Crystal Induced Arthropathies

To the Editor: We were most interested to read Prof. Pritzker’s assessment of the state of research into the crystal induced arthropathies1. We wish to assure Prof. Pritzker and the wider rheumatology community that, rather than being a “dwindling endangered species whose interests are seen to be peripheral to those of most rheumatologists,” those researchers involved in studying the crystal induced arthropathies are enthusiastic, energetic, and productive. In recent years, work in this field has led to critical advances in our understanding of the basic science and epidemiology of crystal induced arthropathies2-6. Further, the prospect of new agents to treat ...

Acute pseudogout arthritis in a patient with chronic renal failure: a case report

Articular involvement such as osteodystrophy, osteonecrosis, dialysis-related amyloidosis, septic arthritis, malignancy and various crystal-induced arthropathies among patients with chronic renal failure is common. Cases of pseudogout (calcium pyrophosphate deposition disease) in patients with renal failure have been seen rarely in the literature. In these cases, acute pseudogout arthritis in only one joint such as an elbow, a wrist or an ankle in uremic patients has been reported. In our case, unlike the previously reported cases, pseudogout is found for the first time as the cause of arthritis which is concomitant in both knee and wrist joints in an uremic patient.

Crystal-Induced Arthropathies: Gout, Pseudogout and Apatite-Associated Syndromes

Crystal-Induced Arthropathies: Gout, Pseudogout and Apatite-Associated Syndromes

Reactive oxygen species and superoxide dismutases: Role in joint diseases

Reactive oxygen species (ROS) are produced in many normal and abnormal processes in humans, including atheroma, asthma, joint diseases, aging, and cancer. The superoxide anion O 2 − is the main ROS. Increased ROS production leads to tissue damage associated with inflammation. Superoxide dismutases (SODs) convert superoxide to hydrogen peroxide, which is then removed by glutathione peroxidase or catalase. Thus, SODs prevent the formation of highly aggressive ROS, such as peroxynitrite or the hydroxyl radical. Experimental models involving SOD knockout or overexpression are beginning to shed light on the pathophysiological role of SOD in humans. Although the antiinflammatory effects of exogenous native SOD (orgotein) are modest, synthetic SOD mimetics hold considerable promise for modulating the inflammatory response. In this review, we discuss new knowledge about the role of the superoxide anion and its derivates as mediators of inflammation and the role of SODs and SOD mimetics as antioxidant treatments in joint diseases such as rheumatoid arthritis, osteoarthritis, and crystal-induced arthropathies.

Monoclonal B Cell Expansion and Antigen-driven Somatic Hypermutation of Ig VH Genes in Synovial Membrane of Patients with Crystal-Induced Arthritis (129.3)

Abstract The mechanisms underlie the inflammation in crystal-induced arthropathies (CyA) is not fully understood. Inflammatory mediators, like crystal-specific antibodies and macrophages have been explored as possible factors in the generation or progression of CyA. To examine whether B cells are involved in the pathogenesis of CyA, we analyzed immunoglobulin (Ig) heavy chain variable region (VH) genes of B cells from synovial membrane of five CyA patients. Using a RT-PCR technique, we could detect rearrangements of Ig VH genes in all five cases. Sequence analysis of CDR3 region of rearranged VDJ genes revealed a monoclonal B cell expansion in four out of five CyA patients. The nucleotide sequences of VH genes from clonally expanded B cells demonstrated the heterogeneous usage of the Ig VH gene family. All expanded B cell clones showed somatic mutations in the CDRs with a high replacement-to-silent ratio (> 2.9) and were distributed in a way suggesting that these B cells had been positively selected through their antigen receptor. The intraclonal variations is also common, indicate that consistent antigen stimulation is close related to CyA development. These data demonstrate that there are antigen-driven clonal accumulations of B cells in CyA synovial membrane. Whether these antibodies are specific to crystal epitopes is currently under investigation. This study was supported by the NIH Grant RO1 AI 54911.

Differential diagnosis of chronic synovitis

This review presents an algorithm for the standardised histopathological diagnostics of synovial biopsies and synovectomy specimens. In general, changes of the synovium can be inflammatory or non-inflammatory. To the latter group belong certain benign tumors such as the diffuse variant of the tenosynovial giant cell tumor, lipoma or synovial chondromatosis, additionally the rare group of storage diseases should be kept in mind. Inflammatory diseases can be discriminated into crystal-induced arthropathies such as gout and pseudogout, into granulomatous diseases such as tuberculosis, sarcoidosis and foreign-body inoculation, and into the large group of non-granulomatous synovitis. This group is by far the most common, and it often causes difficulties in assigning the histopathological findings to a concrete diagnosis. Therefore, the synovitis-score should be applied as a diagnostic device in these cases, leading to the diagnosis of a low-grade synovitis (which is associated with degenerative arthropathies) or of a high-grade synovitis (associated with rheumatic diseases), the sensitivity and specificity being 60.5% and 95.5%, respectively.

Crystal-induced arthropathies: recent investigative advances

To highlight recent investigations that have stimulated renewed interest in crystal-induced arthropathies. Specific diet-related and alcohol-related risks for gout have been clarified, and alternative urate-lowering treatments likely to benefit patients with difficult-to-treat gout are in development. Progress toward understanding mechanisms underlying the renal deficits defining most cases of gout includes characterization of a urate-specific renal tubule transporter explaining many aspects of renal uric acid handling and identification of mutations in the UMOD gene, resulting in altered uromodulin protein in the gout-associated disorders familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type 2. A genetic marker associated with the risk for severe allopurinol toxicity has been reported. Hyperuricemia and gout are increasing in incidence, as is complicated gout, especially among the elderly and patients with cardiovascular and renal comorbidities, organ transplants, or complex concomitant medication regimens. Asymptomatic hyperuricemia is clearly associated with hypertension, chronic kidney disease, cardiovascular disease, and the insulin resistance syndrome, and the pathogenetic significance of these associations is under intensive study. Mutation in the ANKH gene has been found among some patients with sporadic as well as familial calcium pyrophosphate deposition disease. The results of these clinical, epidemiologic, experimental, and therapeutic investigations presage advances in the management of crystal-induced arthropathies.

Inflammation and tissue damage in crystal deposition diseases

The crystal-induced arthropathies are characterized by self-limiting episodes of acute inflammation and chronic tissue damage. This review summarizes recent advances in the understanding of the cellular responses to monosodium urate, calcium pyrophosphate dihydrate and basic calcium phosphate crystals. Factors such as the myeloid related proteins, endothelin-1 and the complement membrane attack complex have been recently identified as mediators of acute crystal-induced inflammation. In addition, signalling pathways involved in both acute inflammation and tissue damage in crystal arthropathies have been further clarified. The potential of macrophage-derived transforming growth factor beta1 to play a key role in the resolution phase of acute gout has also been demonstrated. Recent work has provided new insights into the regulation of both acute and chronic articular responses to inflammatory microcrystals. Further analysis of these responses may identify potential therapeutic targets for management of the crystal-induced arthropathies.

Calcium pyrophosphate dihydrate and basic calcium phosphate crystal-induced arthropathies: update on pathogenesis, clinical features, and therapy.

Calcium-containing crystals are the most common class for the osteoarthritic joint. They are responsible for acute periarthritis and destructive arthropathies, and for tissue deposits mimicking tumor-like masses. These crystals encompassed mainly calcium pyrophosphate dihydrate and basic calcium phosphate crystals, with the latter being related to hydroxyapatite, carbonate-substituted apatite, and octacalcium phosphate. Calcification deposit mechanisms will be reviewed with respect to extracellular inorganic pyrophosphate dysregulation mainly caused by modulation of specific membrane channel disorders. Genetic defects have been extensively studied and identified mutation of specific genes such as ANKH and COL. Pathogenesis of crystal-induced inflammation is related to synovial tissue and direct cartilage activation. Besides classical knee or wrist pseudogout attacks or Milwaukee shoulder arthropathies, clinicians should be aware of other specific common presentations, such as erosive calcifications, spinal cord compression by intraspinal masses, ligamentum flavum calcification, or atypical calcified tophus. Promising clinical results for preventing calcium crystal deposits and cartilage degradation are lacking. Practical imaging tools are needed to monitor reduction of calcification of fibrocartilage and articular cartilage as markers of drug efficacy.

Crystal-induced arthritis: An overview

The most common crystal-related arthropathies-gout, calcium pyrophosphate dihydrate disease or "pseudogout," and calcific periarthritis/tendinitis-may be appropriately diagnosed and managed by the primary care physician. Definitive diagnosis via synovial tap is recommended, as the clinical picture may not identify some cases. The acute pain and swelling of attacks, regardless of etiology, generally respond to treatment with nonsteroidal anti-inflammatory drugs and local or occasionally systemic corticosteroids. Once a causative crystal has been identified and a diagnosis established, a plan for long-term management and prevention of recurrences may be devised. Thus, uric-acid-lowering therapy may be indicated in a patient who has experienced recurrent attacks of gout, whereas control of serum phosphate levels might be effective in some individuals with hyperphosphatemia and hydroxyapatite-associated periarthritis or arthritis. Crystal deposits in joints can be destructive as well as painful. Treatment, therefore, has two objectives: To relieve the pain of the acute attack, thus restoring normal function, and to prevent the accumulation of crystals that can lead to degenerative disease. Identification and subsequent treatment of preventable or correctable underlying disorders may be one of the most gratifying aspects of managing crystal-induced arthropathies.

Treatment of gout and crystal arthropathies and uses and mechanisms of action of nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory agents have anti-inflammatory, analgesic, and antipyretic actions. Nonsteroidal anti-inflammatory drugs are the preferred class of agents for the treatment of gout and other crystal-induced arthropathies. The use of colchicine for other than the prophylaxis of acute attacks is discouraged owing to side effects, which include death. The inhibition of the enzyme prostaglandin H synthase by most nonsteroidal anti-inflammatory drugs explains many of their effects and toxicities. However, it is likely that additional biologic actions are important. These include the inhibition of the transcription of the gene for prostaglandin H synthase, a direct central effect on peripheral inflammation, and the modulation of the functions of a variety of cells (eg, neutrophils, lymphocytes, and chondrocytes). This review focuses on the current controversy in the treatment of gout and discusses the recent literature on the actions of nonsteroidal anti-inflammatory drugs.

Cephaloconiosis: A free radical perspective on the proposed particulate-induced etiopathogenesis of alzheimer's dementia and related disorders

By analogy to the etiology of the pneumoconioses, exogenous dust-induced diseases of the lung, and endogenous crystal-induced arthropathies such as gout, it is proposed that Alzheimer's dementia and allied disorders are causally related to the accumulation of fibriform inorganic deposits within the brain. Hence the neonosological term ‘Cephaloconiosis’. It is proposed that: 1) either by the extrinsic migration or intrinsic formation and deposition of insoluble and persistent inorganic reactive nidi, the particle-induced generation of tissue-damaging free-radical oxygen metabolites by stimulated brain glial macrophage-type and allied phagocytic cells, provides a rationale for the etiopathogenesis of neurodegenerative processes; 2) the modulation of the injurious oxidative metabolic reaction by micronutrient and pharmacological antioxidant agents is a rational and potentially feasible strategy for future therapeutic clinical investigations.

Control of Crystal-Induced Arthropathies

Present approaches to the treatment to crystal-induced arthropathies and indications for their use are reviewed. Successes and limitations of such therapy are discussed and potential new approaches to treatment are discussed. Treatment of gout hyperuricemia is generally effective if appropriately applied and is likely to be improved principally by better application of presently available drugs. New approaches to treatment may improve care for those patients in whom present approaches to management remain unsatisfactory.

Protection of crystal-induced polymorphonuclear leukocyte membranolysis by phosphocitrate

The protection afforded by phosphocitrate, a phosphorylated polycarboxylic acid, against crystal-induced membrane damage to polymorphonuclear leukocytes was studied in vitro. Membranolysis was assessed by nitro blue tetrazolium salt reduction, lactate dehydrogenase release, and scanning electron microscopy. Phosphocitrate protected strongly against hydroxyapatite crystal-induced damage, an action attributable to crystal surface binding of phosphocitrate rather than to the membrane. The ability of phosphocitrate to prevent hydroxyapatite crystallization, together with its membrane protective effect against preformed crystals, would suggest that the compound might have a useful future role against crystal-induced arthropathies.

Chondrocalcinosis and Other Calcifications

Less than 30 years ago, McCarty and others first described a syndrome which presented with gout-like attacks of arthritis but was due to CPPD crystals instead of urate crystals. They termed the condition "pseudogout." It was noted that this was often associated with chondrocalcinosis and it was commonly held that cartilage calcification had to be present if the diagnosis was to be suggested on the basis of the radiographic findings. Subsequently, a clinical and radiographic pattern has emerged in which the diagnosis of CPPD deposition disease can be suggested in the absence of chondrocalcinosis. This condition is termed pyrophosphate arthropathy and is differentiated from degenerative disease by the pattern and distribution of the joint disease. It is important to recognize CPPD deposition disease because of its association with other diseases, such as hemochromatosis and hyperparathyroidism. Although painful periarticular tendinous calcification (peritendinitis calcarea) resulting from the deposition of calcium HA crystals has long been recognized, it has only recently been discovered that intra-articular HA can be associated with an acute inflammatory synovitis. Additionally, patients are now being identified who have CPPD deposition at one anatomic location and HA deposition at another. Differentiation of these various types of crystal-induced arthropathies should lead to more effective therapy in the future.

Gout and pseudogout: Crystal-induced arthropathies

Gout and pseudogout: Crystal-induced arthropathies