The role of calcium crystals and their effect on osteoarthritis pathogenesis.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive degeneration of articular cartilage. Due to its high prevalence and limited treatment options, OA has become one of the most disabling diseases in developed countries. In recent years, OA has been recognized as a heterogenic disease with various phenotypes. Calcium crystal-related endotypes, which are defined by either a distinct functional or pathobiological mechanism, are present in approximately 60% of all OA patients. Two different calcium crystals can accumulate in the joint and thereby calcify the cartilage matrix, which are basic calcium phosphate (BCP) and calcium pyrophosphate (CPP) crystals. The formation of these crystals depends mainly on the balance of phosphate and pyrophosphate, which is regulated by specific proteins controlling the pyrophosphate metabolism. Dysregulation of these molecules subsequently leads to preferential formation of either BCP or CPP crystals. BCP crystals, on the one hand, are directly associated with OA severity and cartilage degradation. They are mostly located in the deeper cartilage layers and are associated with chondrocyte hypertrophy. CPP crystal deposition, on the other hand, is a hallmark of chondrocalcinosis and is associated with aging and chondrocyte senescence. Therefore, BCP and CPP crystals are associated with different chondrocyte phenotypes. However, BCP and CPP crystals are not mutually exclusive and can coexist in OA, creating a mixed endotype of OA. Both crystals clearly play a role in the pathogenesis of OA. However, the exact impact of each crystal type on either driving the disease progression or being a result of chondrocyte differentiation is still to be elucidated.

Pathogenesis of calcium pyrophosphate deposition disease.

Calcium pyrophosphate deposition disease is defined by the presence of calcium pyrophosphate (CPP) crystals in articular cartilage and is the fourth most common type of arthritis in adults. Despite its high prevalence, the etiology of CPPD disease remains unclear and no specific therapies currently exist. It has been known for several decades that abnormalities of cartilage pyrophosphate metabolism are common in patients with CPPD disease, and this classic work will be reviewed here. Recent studies of rare familial forms of CPPD disease have provided additional novel information about its pathophysiology. This work suggests that CPPD disease occurs through at least two unique and potentially intertwined biomolecular pathways. We are hopeful that a detailed understanding of the components and regulation of these pathways will lead to improved therapies for this common disease.

Newly developed pseudogout arthritis after therapy with MAGE-A4 directed TCR T cells responded to treatment with tocilizumab.

With durable cancer responses, genetically modified cell therapies are being implemented in various cancers. However, these immune effector cell therapies can cause toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Pseudogout arthritis is an inflammatory arthritis induced by deposition of calcium pyrophosphate dihydrate crystals. Here, we report a case of pseudogout arthritis in a patient treated with MAGE-A4 directed T cell receptor T cells, for fallopian tube cancer. The patient developed CRS and ICANS 7 days after infusion of the T cells. Concurrently, the patient newly developed sudden onset of left knee arthritis. Synovial fluid analyses revealed the presence of calcium pyrophosphate dihydrate crystal. Notably, the pseudogout arthritis was resolved with tocilizumab, which was administered for the treatment of CRS and ICANS. Immunoprofiling of the synovial fluid showed that the proportion of inflammatory interleukin 17 (IL-17)-producing CD4+ T (Th17) cells and amount of IL-6 were notably increased, suggesting a potential role of Th17 cells in pseudogout arthritis after T-cell therapy. To the best of our knowledge, this is the first reported case of pseudogout arthritis after cell therapy. Clinicians, especially hematologists, oncologists and rheumatologists, should be aware that pseudogout arthritis can be associated with CRS/ICANS.

Bilateral hamstring origin calcification: rare presentation of Gitelman syndrome.

This case report is the first case to our knowledge of intratendinous or peritendinous calcification reported in Gitelman syndrome (GS) patients. GS represents the clinical manifestations of inactivation of the Slc12a3 genes encoding the thiazide-sensitive sodium chloride cotransporter and the Trpm6-Mg genes encoding the magnesium transporters in the distal convoluted tubule. Hence, the biochemical findings resemble those with thiazide diuretics such as hypokalaemia, hypomagnesaemia, hypocalciuria, metabolic alkalosis and low normal blood pressure. Serum calcium and phosphate levels are usually unaffected in GS unless associated with hyperparathyroidism or other hypercalcaemic aetiologies. We report a 69-year-old male patient with a history of GS who presented with bilateral ischial tuberosity tenderness. Further investigations confirmed the calcification of bilateral hamstring origin. Chondrocalcinosis is a known association of GS; however, extra-articular calcification is rare. Literature review illustrates sclerochoroidal calcification as the only reported soft tissue calcification apart from chondrocalcinosis.

Recurrent pseudogout after therapy with immune checkpoint inhibitors: a case report with immunoprofiling of synovial fluid at each flare.

BACKGROUND: Despite ground-breaking clinical success in the treatment of different cancers, immune checkpoint inhibitors can cause profound inflammatory and immune-related adverse events. Autoimmune inflammatory arthritis following immune checkpoint inhibitor treatment has been reported; however, to date, no cases of crystal arthritis following immune checkpoint inhibitors have been identified. CASE PRESENTATION: We report the first case of recurrent pseudogout, an inflammatory crystal arthritis, in a patient treated with nivolumab, a PD-1 inhibitor, for renal cell carcinoma. The patient had recurrent pseudogout flares about week to 10 days after each nivolumab infusion. After treatment with prophylactic colchicine, the patient well tolerated additional nivolumab infusions without adverse events. In parallel, we characterized immune cells of synovial fluid at each flare. Immunoprofiling of synovial fluid showed that the proportion of inflammatory IL-17-producing CD4+ T cells and amount of IL-17 were notably increased in synovial fluid with every recurrent flair, and correlated with the increase in number of synovial neutrophils, suggesting a potential role of T helper 17 (Th17) cells in neutrophil-driven inflammation during pseudogout arthritis. CONCLUSIONS: This case suggests a potential influence of Th17 cells on the neutrophil recruitment and neutrophil-driven inflammatory events leading to pseudogout induced by immune checkpoint inhibitor therapy.

Acute odontogenic infection combined with crowned dens syndrome: a case report.

BACKGROUND: Calcium pyrophosphate dihydrate crystal deposition disease is a condition in which calcium pyrophosphate dihydrate crystal is deposited in joint cartilage and ligaments. Calcium pyrophosphate dihydrate crystal deposition disease that involves calcification around the odontoid process of the second cervical vertebra is called crowned dens syndrome. Crowned dens syndrome is accompanied by fever in addition to acute and intense neck, posterior head, and temporal pain; thus, distinguishing crowned dens syndrome may be difficult in the presence of odontogenic infection. To the best of our knowledge, this is the first report describing a patient with crowned dens syndrome with coexisting odontogenic infection. CASE PRESENTATION: A 75-year-old Japanese woman was examined in the Emergency Department of this hospital due to a chief complaint of worsened buccal swelling on the left side. An odontogenic infection was considered, and she underwent her first examination. She presented with a body temperature of 37.4 °C, marked swelling and tenderness of her left lower eyelid through to her left cheek, and pain on the left temporal area. Blood tests revealed a leukocyte count of 6700/µL and a C-reactive protein level of 7.15 mg/dL. There was swelling and pain around the gingiva and acute purulent apical periodontitis of left maxillary second premolar. Cellulitis of the left cheek was diagnosed. After performing drainage of the pus, antibiotic treatment was initiated. Although her clinical symptoms improved, blood tests on day 9 of hospitalization revealed a leukocyte count of 6500/µL and a C-reactive protein level of 25.62 mg/dL, which were indicative of worsening symptoms. Computed tomography was performed to evaluate remote infection and images revealed a calcification around the odontoid process of her second cervical vertebra. When she was referred to the Orthopedic Surgery Department, pseudogout of the cervical spine was diagnosed. Subsequently, oral acetaminophen was initiated, and both her leukocyte count and C-reactive protein improved markedly. CONCLUSIONS: In the presence of persistent fever and abnormally high leukocyte and C-reactive protein indicative of an inflammatory reaction, coexistence of pseudogout should be considered. In particular, when symptoms of temporal pain are present, the possibility of pseudogout of the cervical spine must be considered in the differential diagnosis.

Pseudogout - a rare manifestation of hungry bone syndrome after focused parathyroidectomy.

Pseudogout, also known as calcium pyrophosphate deposition disease, is a rheumatological condition arising from accumulation of calcium pyrophosphate dihydrate crystals in connective tissues. We present a case of a 56-year-old Bangladeshi woman who underwent focused right inferior parathyroidectomy for primary hyperparathyroidism from a right inferior parathyroid adenoma. On the first post-operative day, she complained of left elbow painful swelling with redness and warmth. Arthrocentesis of left elbow was done due to suspicion of septic arthritis. Two weeks prior to this surgery, she had sudden bilateral knee swelling was diagnosed in her home country of bilateral knee osteoarthritis with effusion and arthrocentesis showed no crystals. Aspiration of left elbow showed calcium pyrophosphate crystals, associated with post parathyroidectomy hypocalcemia, hypomagnesemia confirming pseudogout. Her uric acid level was normal. Bilateral wrist x-rays showed triangular fibrocartilage complex chondrocalcinosis. The patient's condition improved with colchicine and naproxen, as well as calcium and magnesium replacement. Her left elbow swelling and pain resolved. Pseudogout flare is a rare but known sequelae after parathyroidectomy. Early recognition and expeditious treatment is essential.

Mineral and Bone Disorder in Chronic Kidney Disease: A Case Report from Vietnam.

We report a case of calcium pyrophosphate dihydrate deposition disease (CPDD) involving a patient on maintenance hemodialysis (MHD). The 32-year-old man presented in August 2016 with a complaint of left shoulder swelling of 8 months' duration with no trauma or fever. He was diagnosed with nephrotic syndrome in 1998, which progressed to ESRD. He commenced MHD in 2012. Examination at our hospital revealed a soft nontender swelling of the left shoulder. Blood biochemistry showed elevated serum urate, phosphate, ß2 microglobulin, and parathyroid hormone. Imaging revealed joint effusion and dense heterogenous deposition. Aspirate analysis showed urate crystals 3+, and culture yielded no growth. Following rheumatology review, the working diagnosis was periarticular tissue tuberculosis, after excluding pseudogout and amyloidosis. Following 1 month of colchicine and allopurinol, synovial fluid microscopy showed CPDD crystals. Symptoms gradually resolved over the course of 6 months. In this rare case, a diagnosis of CPDD was made with a multidisciplinary approach that included imaging and biochemical investigations.

Pseudogout of the cervical and thoracic spine mimicking infection after lumbar fusion: case report.

Pseudogout is a form of acute calcium pyrophosphate deposition (CPPD) disease that typically afflicts the elderly. CPPD commonly involves larger joints, such as the knees, wrists, shoulders, and hips, and has been known to involve the spine. The authors report the case of a 66-year-old woman with a recent history of lumbar laminectomy and fusion who presented 5 weeks postprocedure with a clinical and radiographic picture consistent with multilevel skip lesions involving the cervical and thoracic spine, thoracic discitis, and epidural abscess. Serial blood cultures and repeat biopsy samples were sterile. Subsequent wrist and ankle erythema, pain, and swelling led to synovial fluid analysis, and pseudogout was diagnosed. She was treated with an interleukin-1 inhibitor with immediate symptom relief. To the authors' knowledge, this is only the second report of spinal pseudogout presenting with a clinical and radiographic picture consistent with discitis and epidural abscess. This report is the first to report skip lesions of pseudogout occurring throughout the spine that are uniquely remote from a recent lumbar surgery.

Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.

Gitelman syndrome disclosed by calcium pyrophosphate deposition disease: early diagnosis by ultrasonographic study.

Gitelman's syndrome is a rare autosomal-recessive tubular disorder characterized by hypomagnesemia and hypocalciuria associated to hypokalemia. The clinical spectrum is wide and usually characterized by chronic fatigue, cramps, muscle weakness and paresthesiae. We describe a case of a 43 year-old male patient with early onset of knee arthritis and no other symptoms. Ultrasound revealed diffuse and confluent hyperechoic deposits in cartilage, fibrocartilage of the menisci and synovium and calcium pyrophosphate crystals were observed in the synovial fluid of the knee. The concomitant presence of hypomagnesemia, hypocalciuria and hypokalemia made clear the diagnosis of Gitelman's syndrome associated with chondrocalcinosis.

Alkaptonuria Presenting with Impressive Osteoarticular Changes and Severe Aortic Stenosis.

Alkaptonuria, or ochronosis, a rare autosomal recessive metabolic disorder, causes an excess of homogentisic acid that results in dark pigmentation, calcification, and inflammation of cartilaginous and other tissues. Cardiovascular complications are also typical of the disease. We report the case of a 78-year-old male who presented with impressive osteoarticular changes and aortic stenosis associated with alkaptonuria.

Unilateral anterior crossbite induces aberrant mineral deposition in degenerative temporomandibular cartilage in rats.

OBJECTIVE: To investigate whether mechanical stress induces mineral deposits that contribute to matrix degradation at the onset of osteoarthritis (OA) in temporomandibular joint (TMJ) cartilage. DESIGN: Female Spraguee-Dawley rats were subjected to an unilateral anterior crossbite (UAC) procedure. Histology, electron microscopy, and energy dispersive spectrometer (EDS) were used to examine cartilage matrix structures and composition of mineral deposit in the affected TMJ cartilage. Protein and/or RNA expression of phenotypic markers and mineralization modulators and matrix degradation was analyzed by immunohistochemistry and/or real-time PCR. Synthetic basic calcium phosphate (BCP) and calcium pyrophosphate dehydrate (CPPD) crystals were used to stimulate ATDC5 cells for their impact on cell differentiation and gene expression. RESULTS: Fragmented and disorganized collagen fibers, expanded fibrous spaces, and enhancement of matrix vesicle production and mineral deposition were observed in matrices surrounding hypertrophic chondrocytes in cartilage as early as 2-weeks post-UAC and exacerbated with time. The mineral deposits in TMJ cartilage at 12- and 20-weeks post-UAC had Ca/P ratios of 1.42 and 1.44, which are similar to the ratios for BCP. The expression of mineralization inhibitors, NPP1, ANK, CD73, and Matrix gla protein (MGP) was decreased from 2 to 8 weeks post-UAC, so were the chondrogenic markers, Col-2, Col-X and aggrecan. In contrast, the expression of tissue-nonspecific alkaline phosphatase (TNAP) and MMP13 was increased 4-weeks post-UAC. Treating ADTC5 cells with BCP crystals increased MMPs and ADAMTS5 expression, but reduced matrix production in a time-dependent manner. CONCLUSION: UAC induces deposition of BCP-like minerals in osteoarthritic cartilage, which can stimulate matrix degradation by promoting the expression of cartilage-degrading enzymes to facilitate OA progression.

[Gout and and calcium pyrophosphate crystal arthropathies: pathophysiology]. / Physiopathologie des arthropathies microcristallines.

Microcrystalline arthropathies are consecutive to microcrystals formation and deposition within the joint. The formation of monosodium urate crystals depends on many physico-chemical factors: the concentration of uric acid, the temperature and pH. Beyond 60 mg/L (360 µmol/L), uric acid crystallizes in tissues. Chronic hyperuricemia is a necessary condition for the occurrence of gouty arthropathy. The mechanisms of hyperuricemia and inflammatory access and their therapeutic implications are described. Chondrocalcinosis is a radiographic entity characterized by deposits of calcium pyrophosphate crystals (CPP) within the fibrocartilage or hyalin cartilage. CPP arthropathies symptomatology is polymorphic and likely resemble in primary osteoarthritis, pseudo-gout acute attacks, or chronic mono-, oligo- or polyarthritis. Its pathophysiology remains uncompletely understood, although there is growing knowledge on the place of some actors involved in the pathogenesis of chondrocalcinosis, described in the article.