Calcium Pyrophosphate Dehydrate Research Articles

Synovial Membrane Is a Major Producer of Extracellular Inorganic Pyrophosphate in Response to Hypoxia.

Calcium pyrophosphate dehydrate (CPPD) crystals are found in the synovial fluid of patients with articular chondrocalcinosis or sometimes with osteoarthritis. In inflammatory conditions, the synovial membrane (SM) is subjected to transient hypoxia, especially during movement. CPPD formation is supported by an increase in extracellular inorganic pyrophosphate (ePPi) levels, which are mainly controlled by the transporter Ank and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We demonstrated previously that transforming growth factor (TGF)-β1 increased ePPi production by inducing Ank and Enpp1 expression in chondrocytes. As the TGF-β1 level raises in synovial fluid under hypoxic conditions, we investigated whether hypoxia may transform SM as a major source of ePPi production. Synovial fibroblasts and SM explants were exposed to 10 ng/mL of TGF-β1 in normoxic or hypoxic (5% O2) culture conditions. Ank and Enpp1 expression were assessed by quantitative PCR, Western blot and immunohistochemistry. ePPi was quantified in culture supernatants. RNA silencing was used to define the respective roles of Ank and Enpp1 in TGF-β1-induced ePPi generation. The molecular mechanisms involved in hypoxia were investigated using an Ank promoter reporter plasmid for transactivation studies, as well as gene overexpression and RNA silencing, the respective role of hypoxia-induced factor (HIF)-1 and HIF-2. Our results showed that TGF-β1 increased Ank, Enpp1, and therefore ePPi production in synovial fibroblasts and SM explants. Ank was the major contributor in ePPi production compared to ENPP1. Hypoxia increased ePPi levels on its own and enhanced the stimulating effect of TGF-β1. Hypoxic conditions enhanced Ank promoter transactivation in an HIF-1-dependent/HIF-2-independent fashion. We demonstrated that under hypoxia, SM is an important contributor to ePPi production in the joint through the induction of Enpp1 and Ank. These findings are of interest as a rationale for the beneficial effect of anti-inflammatory drugs on SM in crystal depositions.

Sequential presentation of CPPD in shoulder and elbow: A case report

Calcific tendinitis is a self-limiting condition characterized by the deposition of calcium crystals into the tendons, most commonly affecting the Shoulder joint. Calcium hydroxyapatite crystals are often seen, but calcium pyrophosphate dehydrate (CPPD) is a rare variant of crystal deposition in tendons. Calcific deposits at triceps insertion are not a common presentation of calcific tendinitis. A 35-year male patient presented with acute onset elbow pain and swelling with CPPD crystal deposition and calcific tendinitis of the triceps tendon. The patient had a previous history of calcific tendinitis of the shoulder, which was treated with arthroscopy. The patient underwent ultrasound-guided needling for calcific tendinitis of triceps and lavage, followed by physiotherapy. He had excellent results with full return to functions on follow-up.

Síndrome de la apófisis odontoides coronada, una manifestación inusual de dolor cervical. Presentación de un caso

The calcium pyrophosphate dehydrate (CPPD) or hydroxyapatite (HA) crystal deposition disease can appear in any joint and the accumulation fo crystals in the cervical spine may be painful. Crowned dens syndrome is a rare clinical condition that involves crown-like calcification of the ligaments around the odontoid process. A 70-year-old man presented cervical pain, fever and a headache for over a week, therefore, a neurological condition was suspected. A CT scan revealed lentiform calcifications of the transverse ligament of the atlas. Steroid treatment and a non-steroidal anti-inflammatory diminished the symptoms. A proper clinical history and imaging studies avoid unnecessary procedures and makes it possible to include this entity as a differential diagnosis in acute cervical pain. Key words: Crystal deposition disease; acute cervical pain; crowned dens syndrome; Odontoid process

Model of Pathological Collagen Mineralization Based on Spine Ligament Calcification.

The aim of the study was to determine the time of mineral growth in human spine ligaments using a mathematical model. The study was based on our previous research in which the physicochemical analysis and computed microtomography measurements of deposits in ligamenta flava were performed. Hydroxyapatite-like mineral (HAP) constituted the mineral phase in ligament samples, in two samples calcium pyrophosphate dehydrate (CPPD) was confirmed. The micro-damage of collagen fibrils in the soft tissue is the crystallization center. The growth of the mineral nucleus is a result of the calcium ions deposition on the nucleus surface. Considering the calcium ions, the main component of HAP, it is possible to describe the grain growth using a diffusion model. The model calculations showed that the growth time of CPPD grains was ca. a month to 6 years, and for HAP grains >4 years for the young and >5.5 years for the elderly patients. The growth time of minerals with a radius >400 μm was relatively short and impossible to identify by medical imaging techniques. The change of growth rate was the largest for HAP deposits. The mineral growth time can provide valuable information for understanding the calcification mechanism, may be helpful in future experiments, as well as useful in estimating the time of calcification appearance.

Calcium Pyrophosphate Dihydrate Crystal Deposition Disease Involving the Ligamentum Flavum of the Cervical Spine with Intense Enhancement on MRI: A Case Report

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is characterized by chondrocalcinosis, which mainly affects the knees, wrists, pelvis, and rarely, the spine. According to previous reports, CPPD crystal deposits display heterogeneous enhancement on MRI. When combined with inflammation of the surrounding soft tissue, strong enhancement by CPPD crystal deposition may appear similar to imaging features of other conditions such as infectious spondylitis. In these conditions, CT plays an important role in differential diagnosis. Here, we present a case of CPPD crystal deposition disease in the ligamentum flavum of the cervical spine that showed intense enhancement on MRI.

Crowned dens syndrome, yet another rheumatic disease imposter.

Crowned dens syndrome (CDS) is defined as acute cervical or occipital pain due to a local inflammatory reaction related to calcifications in the ligaments surrounding the odontoid process. Virtually, all previous descriptions of CDS have related to calcium pyrophosphate dehydrate (CPPD) arthropathy. We prospectively identified a total of twenty-four consecutive inpatients with Crowned dens syndrome from January 2016 to December 2017 in our institution. All patients (age range 54 to 87 years, 67% females) presented with acute onset pain in the upper neck and/or occiput accompanied with extreme neck stiffness. Most patients (79%) had elevated inflammatory markers. Four patients underwent temporal artery biopsy, which was negative for arteritis in all cases, and one was subjected to lumbar puncture, which was non-contributory. Seventeen patients (71%) had known rheumatic disease on presentation: 10 patients had the diagnosis of calcium pyrophosphate dehydrate arthropathy, 3 patients had ankylosing spondylitis, 2 patients had rheumatoid arthritis, 1 patient had Behcet's disease, and 1 suffered from Familial Mediterranean Fever. In 4 more patients, crowned dens syndrome was the presenting symptom of calcium pyrophosphate dehydrate disease. All patients were treated with glucocorticoids as 0.5 mg/kg prednisone plus colchicine 0.5 mg bid resulting in dramatic improvement in both clinical (head/neck pain alleviated and cervical spinal mobility regained) and laboratory measures. Crowned dens syndrome should be considered, and craniocervical junction imaged in the context of acute cervical or occipital pain with stiffness and elevated inflammation markers not only in patients previously diagnosed with calcium pyrophosphate dehydrate arthropathy but also in diverse clinical settings.Key Points• This report highlights that crowned dens syndrome should be considered in various clinical setting besides calcium pyrophosphate dehydrate (CPPD) arthropathy.• Vigilance to this syndrome allows rapid treatment and may spare the patient unnecessary invasive procedures (i.e., temporal artery biopsy or lumbar puncture).

Chondrocalcinosis: idiopathic or manifestation of rare metabolic diseases?

Calcification in hyaline and fibrocartilage is caused by the deposition of calcium pyrophosphate dehydrate, commonly referred to as chondrocalcinosis. Clinically, this can lead to arthritis symptoms similar to agout attack -"pseudogout". Nonetheless, also chronic or asymptomatic disease courses are possible. The prevalence of chondrocalcinosis increases with age. The diagnostic workup of degenerative joint disease, therefore, often reveals calcifications of articular cartilage as harmless incidental findings. However, particularly in patients younger than 60years of age, chondrocalcinosis can be the symptom of an underlying metabolic disease. This review article highlights these rare diseases and presents unusual manifestations of chondrocalcinosis.

Intra-Articular Cartilage Calcification Associated with Type II Pro-Collagen Accumulation in Chondrocytes and Abnormal Fibrils in the Extra Cellular Matrix (ECM): Case Report

Objective: The purpose of this case-study was to perform morphological and molecular analysis of articular cartilage biopsies from the femoral condyle of a 33 year old woman with intra-articular calcification in the right knee joint and compare the findings with those of normal cartilage. Methods: Femural condyle cartilage biopsies were used for Light Microscopy (LM), Transmission Electron Microscopy (TEM), explant culturing and DNA mutation analysis of the COL2A1 gene. Results: X-ray of the affected knee joint showed intra-articular calcifications on the femur condyle, tibia and meniscus. Pathological LM and TEM examination of cartilage biopsies revealed calcified islands morphologically identical to calcium pyro-phosphate dehydrate (CPPD) and hydroxyapatite (HA)-like crystals. In addition, chondrocytes showed accumulation of pro-collagen molecules. With explant culturing and immunochemistry, it was confirmed that matrix calcification correlated with high intracellular matrix accumulation and expression of type X collagen. The induction of hypertrophy in chondrocytes was further associated with matrix vesicle (MV) release and a prominent calcification zone. Surprisingly, TEM showed crystal development on thick abnormal type II collagen fibrils suggesting that these ECM components might nucleate and contribute to calcification. Conclusions: We suggest that intra-articular calcification may be associated with type II pro-collagen accumulation in chondrocytes. In particular, we hypothesize that matrix accumulation may induce hypertrophy and type X collagen expression in cartilage cells and release of MV’s into the ECM, which together with thick abnormal type II collagen hetero-fibrils, are responsible for crystal deposition in the ECM.

Physicochemical characterization of mineral deposits in human ligamenta flava.

The aim of our study was the detailed characterization of calcium deposits in ligamenta flava. The use of microcomputed tomography allowed extending the routine medical investigations to characterize mineral grains in the microscopic scale. A possible connection between spinal stenosis and ligament mineralization was investigated. The studies were carried out on 24 surgically removed ligamentum flavum samples divided into control and stenosis groups. Physicochemical characterization of the inorganic material was performed using X-ray fluorescence, X-ray diffraction, and Fourier transform infrared spectroscopy. The minerals were present in 14 of 24 ligament samples, both in stenosis and control groups. The inorganic substance constitutes on average ~0.1% of the sample volume. The minerals are scattered in the soft tissue matrix without any regular pattern. It was confirmed that minerals possess an internal structure and consist of the organic material and small inorganic grains mixture. The physicochemical analyses show that the predominant crystalline phase was hydroxyapatite (HAP). In the stenosis group calcium pyrophosphate dehydrate (CPPD) was identified. Both structures were never present in a single sample. Two different crystal structures suggest two independent processes of mineralization. The formation of CPPD may be treated as a more intense process since CPPD minerals are characterized by bigger values of the structural parameters and higher density than HAP deposits. The formation of HAP minerals is a soft tissue degeneration process that begins, in some cases, at early age or may not occur at all. Various density and volume of mineral grains indicate that the mineralization process does not occur in a constant environment and proceeds with various speeds. The formation of minerals in ligamenta flava is not directly associated with diagnosed spinal canal stenosis.

Crystal arthritides - gout and calcium pyrophosphate arthritis : Part1: Epidemiology and pathophysiology.

Gout and calcium pyrophosphate deposition disease (CPPD, pseudogout) are still the most frequent inflammatory arthritides in multimorbid elderly patients. Gout and CPPD are different diseases and based on different pathophysiological principles. Gout is closely associated with the metabolic syndrome and is an independent risk factor for cardiovascular mortality. The prevalence of asymptomatic hyperuricemia is estimated to be 10-20% of adults in industrial nations and prevalence is strongly associated with age. More than 7% of persons aged over 65years suffer from clinically manifest gout. The underlying pathophysiological principle is an imbalance between the formation and elimination of uric acid. The degradation of the purine bases adenine and guanosine to uric acid is catalysed by xanthine oxidase and genetic polymorphisms and mutations play an important role in absorption and excretion processes. Furthermore, carrier proteins, such as URAT-1 or OAT-4 also have an influence on these processes. An imbalance of the physiological processes results in the solubility product being exceeded, which in consequence leads to crystallization of urate. This induces acascade of massive inflammatory reactions at the molecular and cellular level with the activation of cytokines. The inflammatory process can be stopped by neutrophil extracellular traps (NETs) that modulate aggregation and degradation of chemokines and cytokines and partitioning of crystallized urate against immune cells. Calcium pyrophosphate dehydrate (CPP) crystals are formed in the cartilage and CPP deposition can be found in 30% of people aged over 80years. Inorganic pyrophosphate (PPi) is synthesized in chondrocytes and plays an important part in the formation of calcium pyrophosphate crystals. The degradation is catalyzed by inorganic pyrophosphatases. If there is dysregulation of this homeostasis more PPi is produced, which ultimately contributes to the formation of the CPP crystals.

Crystal-induced arthritis after arthroplasty: 7 cases

ObjectivesTo describe the occurrence in prosthetic joints of crystal-induced arthritis (CIA) defined as the deposition within the synovial membrane and/or joint cavity of calcium pyrophosphate dehydrate (CPPD) (chondrocalcinosis), sodium urate (gout), or hydroxyapatite. MethodsWe retrospectively reviewed the 7 cases of prosthetic-joint CIA seen between 1993 and 2013 at a medical-surgical center specialized in the management of osteoarticular infections. ResultsThe 4 females and 3 males ranged in age from 67 to 79 years. Acute CIA occurred at the knee in 6 patients (5 with total knee arthroplasty and 1 with unicompartmental knee arthroplasty) and at the hip in 1 patient (with total hip arthroplasty). Time from arthroplasty to CIA varied from 7 days to 9 years. An abrupt onset was a consistent feature, with pain, complete loss of function, and local evidence of inflammation. A single patient had a fever and 6 patients had laboratory evidence of systemic inflammation. Joint aspiration showed hemarthrosis in 3 patients and inflammatory joint fluid with 20,000 to 79,000neutrophils/mm3 in 6 patients. Joint fluid cultures were negative in 6 patients. CPPD crystals were evidenced in 5 patients, including 1 who also had hydroxyapatite crystals detected by electron microscopy after alizarin red staining. Monosodium urate crystals were found in 1 patient. The remaining patient had both CPPD crystals and positive cultures for Campylobacter fetus. In 5 patients, treatment with colchicine or a nonsteroidal antiinflammatory drug ensured prompt control of the symptoms and systemic inflammation. The patient with total hip arthroplasty underwent joint aspiration for hemarthrosis. In 1 patient, an intraarticular injection of triamcinolone hexacetonide improved the symptoms and systemic inflammation. The patient with Campylobacter fetus infection was treated with antibiotics, excision of the abscess, and synovectomy. ConclusionCIA may occur after arthroplasty, within synovial membrane remains or neosynovium developed around the prosthetic joint. CIA is a manifestation of a metabolic disease that persists and can reactivate after surgery. Routine testing for crystals is rarely performed in patients with sterile arthritis of a prosthetic joint, and crystals are difficult to detect in joints with hemarthrosis; consequently, the frequency of prosthetic-joint CIA may be underestimated. Although rare, CIA should be considered routinely when symptoms suggesting septic arthritis develop in a prosthetic joint, in order to avoid unnecessary prolonged antibiotic therapy and, in some cases, surgery. The treatment is usually simple.

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

To investigate whether mechanical stress induces mineral deposits that contribute to matrix degradation at the onset of osteoarthritis (OA) in temporomandibular joint (TMJ) cartilage. 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. 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. 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.

Imaging Approach to Temporomandibular Joint Disorders.

Internal derangement is the most common temporomandibular joint disorder. Degenerative osteoarthritis and trauma are next in frequency. Less common pathology includes rheumatoid arthritis, synovial chondromatosis, calcium pyrophosphate dehydrate deposition disease, pigmented villonodular synovitis, tumors, infection, and osteonecrosis. We provide a systematic approach to facilitate interpretation based on major anatomic structures: disc-attachments, joint space, condyle, and lateral pterygoid muscle. Relevant graphic anatomy and state of the art imaging are discussed in correlation with current clinical and therapeutic highlights of pathologic entities affecting the joint.

Chondrocalcinosis related to familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Calcium pyrophosphate dehydrate (CPPD) crystal deposition disease (also known as chondrocalcinosis, CC) is a rare metabolic arthropathy mostly seen in elderly patients. Chondrocalcinosis may be associated with metabolic diseases such as hypomagnesemia when it occurs in young people. We report here a case with hypomagnesemia due to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) who developed CC during clinical follow-up. To our best knowledge this is the first case of a young patient with CPPD associated with FHHNC.

Retro-Odontoid Calcium Pyrophosphate Dehydrate Deposition: Surgical Management and Review of the Literature

Study Design Case report and review of the literature. Objective A retro-odontoid mass is a rare cause of cervical compression and myelopathy. The differential diagnosis includes the following: metastatic disease, primary tumor, collagen disorder, or inflammatory disease. Calcium pyrophosphate dihydrate (CPPD) deposition has been referred to as “crowned dens syndrome” when there are periodontoideal calcifications. There are only a few reported cases where CPPD presents as a cystic retro-odontoid mass in the atlanto-dens interval. In previous descriptions of surgical intervention, transoral resection of the mass is associated with significant morbidity and usually requires stabilization. The objective of this article is to report a case of an unusual presentation of CPPD disease of C1/C2, where we used a novel, minimally invasive surgical technique for decompression without fusion. Patients and Methods An 83-year-old female patient presented with progressive cervical myelopathy over a 3-month period. Computed tomography and magnetic resonance imaging demonstrated a cystic odontoid mass with a separate retro-odontoid compressive mass. A novel, minimally invasive transoral aspiration was performed. Histologic confirmation of CPPD was obtained. Results Postop imaging showed satisfactory decompression, which was maintained at the 6-month follow-up. This correlated with clinical improvement postop and 6-month follow-up. Conclusion CPPD in the atlanto-dens interval may present as a cystic retro-odontoideal mass and should be included in the differential. We used a transoral minimally invasive approach to aspirate the cyst. This novel technique avoided the need for a stabilization procedure or morbid transoral resection and provided excellent results immediately and at 6 months.

Calcium crystals detected by scanning electronic microscopy in synovial fluid of patients with early knee osteoarthritis. relationships with infiammation and disease severity

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S392 characterized by pain and/ or stiffness of knee and/ or hip. They were included at the first visit or within 6 months of the first visit to the general practitioner for these symptoms. Study centers comprise ten general and university hospitals located in urbanized and semiurbanized regions in the Netherlands. A special programwas developed to minimize loss to follow up, comprising newsletters, website and organizing symposia to present the results and progress of CHECK. An overview of measures that are included in the study can be found at our website www.check-research.com. Results: After 7 years a total of 105 (10%) participants had dropped out. Reasons included loss of interest (21%), comorbidity that complicated participating of CHECK too much (18%), death (12%), contact lost (11%), costs incurred for the study (5%), and other reasons (33%). Dropouts did not differ significantly from other participants in baseline characteristics. Over 7 years follow-up clinical characteristics including pain, stiffness and function of disease-specific (WOMAC) and the subscales of generic self-report questionnaire (SF36) on average did not change significantly, although at least half of the patients experienced radiographic progression. Scoring of 5-year follow up is complete: at this point, 50 % of the participants progressed by at least one Kellgren and Lawrence grade in the knee, and 25% in the hip. Preliminary analyses suggest the existence of several clinical and radiological phenotypes. Conclusions: CHECK is a valuable source of information of early symptomatic OA with a low loss to follow-up and a multidisciplinary approach that allows the collections of high-quality data on clinical, radiological and biochemical variables. 697 CALCIUM CRYSTALS DETECTED BY SCANNING ELECTRONIC MICROSCOPY IN SYNOVIAL FLUID OF PATIENTS WITH EARLY KNEE OSTEOARTHRITIS. RELATIONSHIPS WITH INFIAMMATION AND DISEASE SEVERITY R. Ramonda y, P. Frallonardo y, L. Peruzzo z, L. Tauro x, A. Scanu y, M. Lorenzin y, A. Ortolan y, P. Galozzi y, F. Oliviero y, L. Punzi y. yRheumatology Unit, Univ. of Padova, Padova, Italy; z Inst. for GeoSci.s and Earth Resources IGG-CNR, Padova, Italy; xDept. of GeoSci.s, Univ. of Padova, Padova, Italy Purpose: The presence of calcium crystals (CC) in synovial fluid (SF) of osteoarthritis (OA) is a well known and frequent feature. However, their role in the pathogenesis of OA is still unclear andmatter of discussion, in particular as regard the local inflammation. The objective of the study was to evaluate the presence of the most common CC, calcium pyrophosphate (dehydrate) (CPP) and basic calcium phosphate (BCP), in SF of the symptomatic knee OA (KOA, particularly in early disease stage (<1year) and to investigate their association with local infiammation, disease activityand severity. We performed an ultrasensitive analysis of SF crystals using the scanning electron microscopy (SEM) and the routinary method by compensated polarized ligth microscopy (CPLM) and alizarin red staining. Methods: Seventy-four (48 F, mean age 64.85 9.33 yrs, range 50-89 yrs) consecutive outpatients attending theRheumatology Unit, University of Padova with symptomatic KOA (according to the American College of Rheumatology criteria) underwent knee arthrocentesis. After optical and CPLM, the SF was analysed by SEM. Total white blood cell (WBC) count was performed and a cut-off of total WBC was established

Huge tophaceous pseudogout associated with tenosynovial chondromatosis arising from flexor digitorum tendon sheaths of the foot: a case report

Synovial chondromatosis (SC) is a benign proliferative process of synovial tissue creating multiple cartilaginous nodules in joints. It most commonly occurs in the large joints of the knee, hip, and shoulder, uncommonly in the small joints of the hand and foot, and only rarely in the tenosynovial membrane of tendon sheath, termed tenosynovial chondromatosis (TC). Unlike SC, TC predisposes to the foot or hand. The rarity and unfamiliarity of imagers with TC, as well as the variability of its histologic features often lead to an erroneous diagnosis of extraskeletal chondroma or even chondrosarcoma as in the present case. Calcium pyrophosphate dehydrate (CPPD) crystals are usually deposited in the articular cartilage or periarticular structures such as synovium and capsule, and rarely in other soft tissue structures including bursa, tendon, subcutaneous tissue, and dura mater. CPPD crystals may also be deposited in extraskeletal chondroma and SC. We present an exceptionally rare case of huge tophaceous pseudogout associated with TC that is considered to arise from the flexor digitorum longus tendon sheaths of the foot, initially mistaken for a chondrosarcoma.

Pseudogout-Associated Inflammatory Calcium Pyrophosphate Dihydrate Microcrystals Induce Formation of Neutrophil Extracellular Traps

Pseudogout is an autoinflammatory condition triggered by calcium pyrophosphate dehydrate (CPPD) crystal deposition in the joints. The innate immune system is irritated by and responds to the presence of the crystals with an inflammatory response. The synovial fluid contains activated inflammatory macrophages and neutrophil granulocytes. Several details of crystal-induced macrophage activation were recently uncovered, but very little is known about interactions of CPPD crystals with neutrophils. In this study, we show that human neutrophils engulf CPPD crystals and form large amounts of neutrophil extracellular traps (NETs) in vitro. Released extracellular DNA binds myeloperoxidase and citrullinated histone H4. CPPD crystal-stimulated neutrophils and their nuclear DNA undergo morphological changes characteristic for NET formation. The ERK/MEK signaling pathway, heat shock protein 90, PI3K, and an intact cytoskeleton are required for CPPD-induced NET formation. Blocking crystal-activated respiratory burst has, however, no effect on NETs. Human neutrophils release IL-1β and IL-8 in response to CPPD crystals, and blocking CXCR2, the main IL-8R, diminishes NET formation. Proinflammatory cytokines, TNF-α, GM-CSF, and IL-1β, increase NET release by the crystals. Enhanced bacterial killing by CPPD-induced NETs demonstrates their ability to cause cellular damage. Our work documents and provides details about extracellular trap release in human neutrophils activated by CPPD microcrystals. We suggest that crystal-triggered NET formation can be a novel contributor to inflammatory conditions observed in CPPD crystal-driven synovitis.

Acute Lumbar Spinal Pseudogout Attack After Instrumented Surgery

A case report. An elderly patient presented with an acute lumbar spinal pseudogout attack after lumbar instrumented surgery. Although gout and pseudogout are common diseases causing inflammatory arthropathy in peripheral joints, involvement of the spine is uncommon. Here, we report a patient experiencing an acute lumbar spinal pseudogout attack after lumbar instrumented surgery. The patient was treated for lumbar spondylolisthesis at L4 and L5 level and afterward complained of lower back and bilateral leg pain. Conservative treatment was not effective for the patient; therefore, we preformed posterior transforaminal lumbar interbody fusion surgery. The postoperative course was uneventful; however, he experienced lower back pain 4 weeks after surgery. Magnetic resonance image showed changes in signal intensities of vertebra and fluid accumulation in posterior back muscles. A biopsy was performed, but the culture was negative for infection. Calcium pyrophosphate dehydrate was detected in the fluid. Thus, conservative therapy without antibiotics was performed, and the patient's symptoms disappeared within 2 weeks. Here, we reported the first case of acute lumbar spinal pseudogout attack after lumbar instrumented surgery. We recommend considering pseudogout before and after surgery.

Crowned dens syndrome

Introduction Microcrystalline deposition in peri-odontoid articular structures is mainly responsible for acute or chronic cervical pain and is known as “crowned dens syndrome”.Materials and methods We described two cases of acute cervical pain associated with onset of fever and peripheral acute monoarthritis. Cervical computed tomography (CT) scan showed linear calcification of the retrodens ligament and calcium pyrophosphate dehydrate (CPPD) crystals were found in synovial fluid of inflamed joints. Both patients were treated with anti-inflammatory drugs and colchicine.Discussion Calcium depositions around the odontoid process of the axis can be occasionally detected by radiological studies. They are frequently asymptomatic but sometimes can be associated with severe neurological abnormalities, fever and acute neck pain. CPPD crystals are usually deposited in joints and bursae but occasionally can disrupt these anatomical confines and deposit in periarticular tissues, sometimes forming large masses confused with tumours.Conclusions Acute onset of cervical neck pain associated with elevation of inflammatory indicators and/or signs of cervical myelopathy should suggest CT scans searching for microcrystal depositions in the peryodonthoid tissue. Differential diagnosis of fever of unknown origin (FUO) should include crowned dens syndrome specially in the elderly after exclusion of several endocrine or metabolic disorders, infection diseases (meningitis), arthritis (psoriatic arthritis and ankylosing spondylitis) and tumours (chordoma, meningioma, osteoblastoma).