Crystal induced arthropathies-a comparative study of 40 patients with apatite rheumatism, chondrocalcinosis and primary synovial chondromatosis.

Introduction: Apatite rheumatism (AR), chondrocalcinosis (Ch-C), and primary synovial chondromatosis (prSynCh) are regarded as distinct clinical entities. The introduction of the non-staining technique by Bély and Apáthy (2013) opened a new era in the microscopic diagnosis of crystal induced diseases, allowing the analysis of MSU (monosodium urate monohydrate) HA (calcium hydroxyapatite), CPPD (calcium pyrophosphate dihydrate) crystals, cholesterol, crystalline liquid lipid droplets, and other crystals in unstained sections of conventionally proceeded (aqueous formaldehyde fixed, paraffin-embedded) tissue samples. The aim of this study was to describe the characteristic histology of crystal deposits in AR, Ch-C, and prSynCh with traditional stains and histochemical reactions comparing with unstained tissue sections according to Bély and Apáthy (2013). Patients and methods: Tissue samples of 4 with apatite rheumatism (Milwaukee syndrome), 16 with chondrocalcinosis, and 20 with clinically diagnosed primary synovial chondromatosis were analyzed. Results and conclusion: Apatite rheumatism, chondrocalcinosis, and primary synovial chondromatosis are related metabolic disorders with HA and CPPD depositions. The authors assume that AR and Ch-C are different stages of the same metabolic disorder, which differ from prSynCh in amorphous mineral production, furthermore in the production of chondroid, osteoid and/or bone. prSynCh is a defective variant of HA and CPPD induced metabolic disorders with reduced mineralization capabilities, where the deficient mineralization is replaced by chondroid and/or bone formation. The non-staining technique of Bély and Apáthy proved to be a much more effective method for the demonstration of crystals in metabolic diseases than conventional stains and histochemical reactions.

Calcified Chondroid Mesenchymal Neoplasms.

Calcified chondroid mesenchymal neoplasms (CCMN) represent a morphologic spectrum of related tumors. Historically, chondroid matrix or chondroblastoma-like features have been described in soft tissue chondroma, tenosynovial giant cell tumors (especially of the temporomandibular joint (TMJ) region), and in a subset of tophaceous pseudogout. Recently, these tumors have been found to share FN1-receptor tyrosine kinase (RTK) fusions. This review discusses the clinical, morphologic, immunohistochemical, and molecular genetic features of CCMN. The distinction from morphologic mimics is also discussed.

Identification of Common Pathogenic Pathways Involved in Hemochromatosis Arthritis and Calcium Pyrophosphate Deposition Disease: a Review.

OBJECTIVES: Arthritis is a common clinical manifestation of hereditary hemochromatosis (HH), and HH is one of a handful of conditions linked to calcium pyrophosphate deposition (CPPD) in joints. The connection between these two types of arthritis has not yet been fully elucidated. In light of new pathogenic pathways recently implicated in CPPD involving bone, we reviewed the literature on the etiology of hemochromatosis arthropathy (HHA) seeking shared pathogenic mechanisms. RESULTS: Clinical observations reinforce striking similarities between HHA and CPPD even in the absence of CPP crystals. They share a similar joint distribution, low grade synovial inflammation, and generalized bone loss. Excess iron damages chondrocytes and bone cells in vitro. While direct effects of iron on cartilage are not consistently seen in animal models of HH, there is decreased osteoblast alkaline phosphatase activity, and increased osteoclastogenesis. These abnormalities are also seen in CPPD. Joint repair processes may also be impaired in both CPPD and HHA. CONCLUSIONS: Possible shared pathogenic pathways relate more to bone and abnormal damage/repair mechanisms than direct damage to articular cartilage. While additional work is necessary to fully understand the pathogenesis of arthritis in HH and to firmly establish causal links with CPPD, this review provides some plausible hypotheses explaining the overlap of these two forms of arthritis.

Neutrophil extracellular traps release in gout and pseudogout depends on the number of crystals regardless of leukocyte count.

OBJECTIVES: Microcrystal-induced arthritis is still an unresolved paradigm for medicine. Overt inflammation may be absent even when crystals occur in SF. Recently, the production of neutrophil extracellular traps (NETs) embedding MSU crystals has been proposed as a possible mechanism of the auto-resolution of the inflammatory phase during gout. We aimed to verify and quantify the release of NETs in SFs during gout and pseudogout attacks and to compare any differences with respect to crystals and neutrophils number, and to analyse activation of necroptosis pathway in SF from crystal-induced arthritis. METHODS: SF samples were obtained by arthrocentesis from 22 patients presenting acute crystal-induced arthritis, gout or pseudogout (n = 11 each group), and from 10 patients with acute non-crystal arthritis as controls. NETosis was quantified in SF by nucleic acid stain and by quantification of human neutrophil elastase. Activation of phosphorylated MLKL was assessed by western blot. RESULTS: We observed that SF neutrophils encountering MSU and CPPD crystals during episodes of gout and pseudogout release NETs in relation to the number of crystals in SF and irrespective of neutrophil density and type of crystal. This release was accompanied by necroptosis through the activation of the MLKL pathway. CONCLUSIONS: Our findings suggest that a role of NETs in crystal-induced arthritis is to 'trap extracellular particles', including microcrystals. Embedding crystals in aggregates of NETs may be the basis of tophi and CPPD deposition, and may have implications for disease evolution rather than for spontaneous resolution of the acute attack.

Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score.

It is now well recognized that osteoarthritis (OA) synovial membrane presents inflammatory components. The aim of this work is to provide evidence that similar inflammatory mechanisms exist in synovial membrane (n = 24) obtained from three pathologies presenting altogether an inflammatory gradient: OA, chronic pyrophosphate arthropathy (CPPA) and rheumatoid arthritis (RA). Synovial biopsies were first characterized by a histological score based on synovial hyperplasia and infiltration of lymphocytes, plasma cells, polymorphonuclear and macrophages. All biopsies were also analyzed by 2D-nano-UPLC-ESI-Q-Orbitrap for protein identification and quantification. Protein levels were correlated with the histological score. Histological score was in the range of 3 to 8 for OA, 5 to 13 for CPPA and 12 to 17 for RA. Of the 4,336 proteins identified by mass spectrometry, 51 proteins were selected for their strong correlation (p < 0.001) with the histological score of which 11 proteins (DNAJB11, CALR, ERP29, GANAB, HSP90B1, HSPA1A, HSPA5, HYOU1, LMAN1, PDIA4, and TXNDC5) were involved in the endoplasmic reticulum (ER) stress. Protein levels of S100A8 and S100A9 were significantly higher in RA compared to OA (for both) or to CPPA (for S100A8 only) and also significantly correlated with the histological score. Eighteen complement component proteins were identified, but only C1QB and C1QBP were weakly correlated with the histological score. This study highlights the inflammatory gradient existing between OA, CPPA and RA synovitis either at the protein level or at the histological level. Inflamed synovitis was characterized by the overexpression of ER stress proteins.

Cartilage calcification is associated with histological degeneration of the knee joint: a highly prevalent, age-independent systemic process.

OBJECTIVES: To investigate if cartilage calcification (CC) is a systemic process, the purpose of this study was to determine the prevalence and the amount of meniscal/hyaline CC of the knee joint in the general population by high-resolution imaging (DCR) and to evaluate the association between CC with cartilage degeneration and age. METHODS: Cross-sectional DCR-study of 180 knee joints of 90 donors (42 female/48 male, mean age 62.3y). Histological hyaline (OARSI) and meniscal (Krenn) cartilage degeneration was determined of all knees. RESULTS: CC was observed in 100% of the donors (bilaterally in 98%), hyaline cartilage calcification (HCC) in 92% and meniscal calcification (MC) in 100%. CC was detected in more than three out of six distinct cartilage areas in 84.4% of all knees. The mean amount of CC correlated between both sides of donors, the different analyzed areas of the knee joint and between the various types of cartilage structures. There was more calcification in meniscal than in hyaline cartilage (factor 5.3) and in the medial than the lateral compartment (factor 1.2). HCC/MC were already detectable with only mild cartilage lesions and the amount correlated with histological cartilage degeneration, but not with age. CONCLUSIONS: The present study provides evidence that meniscal and hyaline CC occurs in a pattern that is compatible with CC being a systemically driven process and that meniscal fibrocartilage is more prone to calcification than hyaline cartilage. Furthermore, the age-independent association between the amount of CC and the grade of degeneration in both hyaline and meniscal cartilage, suggests that CC is an obligatory early event in initiating cartilage degeneration.

Fluorescence Differentiation of ATP-related Multiple Enzymatic Activities in Synovial Fluid as a Marker of Calcium Pyrophosphate Deposition Disease using Kyoto Green.

Calcium pyrophosphate deposition disease (CPPD) is a crystal induced inflammation in joints, and causes severe pain in elderly people. The accumulation of pyrophosphate (PPi) in synovial fluid (SF) results from several enzymatic reactions, especially the highly activated e-NPPs, which catalyze the conversion of ATP to PPi. This study demonstrates the detection of relative catalytic activity of 3 enzymes-ecto-nucleotide pyrophosphatase/phosphodiesterases (e-NPPs), tissue nonspecific alkaline phosphatase (TNAP), and ecto-nucleoside triphosphate diphosphohydrolases (e-NTPDases)-using a single molecular sensor called Kyoto Green. Kyoto Green exhibits excellent performance in sensing the catalytic activity of the commercial representatives of the e-NPPs, TNAP, and e-NTPDases, which are ENPP1, PPase, and apyrase, respectively, in both single-enzyme and multi-enzyme assays. Analysis of SF enzymes in 19 SF samples from human and swine revealed moderate activity of e-NPPs, high activity of e-NTPDases, and low activity of TNAP. Our newly developed method for analysis of multiple enzymatic activities using Kyoto Green in biological SF will assist improvement in accuracy of the CPPD prognosis/diagnosis, which will minimize unnecessary medical procedures.

Cervical CT-Dependent Diagnosis of Crowned Dens Syndrome in Calcium Pyrophosphate Dihydrate Crystal Deposition Disease.

PURPOSE: The purpose of this study is to assess the presence of crowned dens syndrome in patients with calcium pyrophosphate disease. We report 34 patients with crowned dens syndrome in one of the largest series from a single tertiary medical center in North America. METHODS: A retrospective chart review was conducted at the University of Kansas Medical Center from November 1, 2005-November 1, 2017. A total of 191 patients with calcium pyrophosphate disease were identified. The available cervical computed tomography scans were analyzed by a musculoskeletal radiologist for the presence of periodontoid calcifications and erosions. RESULTS: Of the 191 patients with calcium pyrophosphate disease, 57 had cervical computed tomography scans; 34 of them (34/57, 59.64%) had periodontoid calcifications. Only 12/34 patients were formally evaluated and diagnosed by rheumatologists with crowned dens syndrome. Twenty-two of 34 were either not seen by a rheumatologist or were not diagnosed with crowned dens syndrome. The median age was 78.5 years, with 73.52% over 70 years old; 24/34 (70.58%) were female; 17/34 patients (50%) were symptomatic; 28/34 (82.35%) had additional sites of chondrocalcinosis on available radiographs; 8 (28.57%) had 3 or more sites of chondrocalcinosis in typical calcium pyrophosphate disease locations. Six patients did not have any radiographs. CONCLUSION: Crowned dens syndrome is an under-recognized entity that should be considered in elderly patients with neck pain in the setting of calcium pyrophosphate disease. Our data demonstrated a high percentage (about 60%) of patients with calcium pyrophosphate disease who had cervical computed tomography findings consistent with crowned dens syndrome. This underscores the importance of performing cervical computed tomography when evaluating patients with neck pain and calcium pyrophosphate disease.

Pseudogout or pseudolymphoma? Calcium pyrophosphate deposition disease of the cervical spine: a rare presentation and literature review.

Calcium pyrophosphate deposition (CPPD) disease is a crystal arthropathy primarily affecting peripheral joints, most commonly the wrist and the knees. However, CPPD in the cervical spine is a rare entity. This report describes a case of CPPD of the cervical spine which presents with symptoms of neck pain and brachalgia. A 62-year-old woman presented with left-sided upper limb and neck pain. MRI scanning revealed a low signal abnormality within the C6 and C7 vertebrae, and the possibility of lymphoma was raised. The patient was recalled for gadolinium-enhanced scans which showed perivertebral and marrow enhancement. Fine-needle aspirate histology initially suggested a spindle cell tumour or lymphoma. However, CT-guided biopsy showed positively birefringent crystals, confirming CPPD. CPPD of the spine is a rare differential of nerve impingement in the cervical spine when MRI scanning perivertebral signal enhancement. Furthermore, CPPD of the spine can mimic malignancy.

Issues in CPPD Nomenclature and Classification.

PURPOSE OF REVIEW: This paper covers confusion and challenges in the nomenclature of calcium pyrophosphate deposition disease. Clinicians, investigators, and patients are faced with a variety of terms that are used to describe CPPD and its phenotypes, and clarity is greatly needed to help advance research and patient care. Motivation for the upcoming development of CPPD classification criteria is reviewed. RECENT FINDINGS: EULAR proposed recommended terminology for CPPD in 2011. International Classification of Diseases (ICD-9 and ICD-10) billing codes identify definite or probable CPPD with variable accuracy depending on the clinical setting and comparator group. READ diagnostic codes have been employed to identify pseudogout in UK datasets but their accuracy has not been evaluated. CPPD classification criteria will provide a system for identifying a relatively homogenous group of patients to be included in clinical studies, enabling comparison of outcomes across studies. CPPD nomenclature remains challenging for clinicians, investigators, and patients. A lay-friendly definition of CPPD, using easily accessible terminology, would be welcome. CPPD classification criteria are a necessary step in moving forward CPPD clinical research and may involve a range of clinical, laboratory, and imaging modalities.

Low-dose computed tomography as diagnostic tool in calcium pyrophosphate deposition disease arthropathy: focus on ligamentous calcifications of the wrist.

OBJECTIVES: To identify specific morphologic features of calcium pyrophosphate deposition disease (pseudogout, CPPD) manifestations of the wrist as detected using low-dose CT-scans. METHODS: In this retrospective study 46 patients with arthritis of the wrist were included. All patients underwent a low dose CT scan of both wrists on a 320-row detector in volume scan mode. Individual radiation exposure was recorded for all patients. Two blinded raters independently evaluated osteoarthritis, cysts, erosions, calcifications (cartilage and ligaments separately) and carpal misalignment in 33 specified locations. An expert rheumatologist classified the patients as CPPD positive or negative. Fisher's exact test was applied to identify differences between both groups. Receiver operating characteristics (ROC) analyses with calculations of area under the curve (AUC) were carried out for both in the literature established and newly identified imaging findings for each rater individually. RESULTS: Twenty-seven patients were classified as CPPD, 19 patients as other diagnoses. Ligamentous calcifications were significantly more prevalent in the CPPD group (p<0.05). All non-ligamentous findings revealed no difference in frequency. AUC analysis for established findings (0.675; 0.619 - rater 1; 2) vs. ligamentous calcifications (0.786 both raters) showed a markedly higher diagnostic accuracy for the latter. Effective radiation exposure was determined to be 0.019-0.095 mSv per patient. CONCLUSIONS: Calcifications of carpal ligaments are highly specific morphologic features of CPPD arthropathy. Low-dose CT is a useful tool to detect these calcifications at a radiation exposure similar to a standard radiograph.

Temporal mandibular joint chondrocalcinosis (tophaceous pseudogout) diagnosed by ultrasound-guided fine-needle aspiration.

Tophaceous pseudogout is a calcium pyrophosphate dihydrate crystal (CPPD) deposition disease that frequently affects elderly patient in the temporomandibular joint (TMJ). A diagnosis of CPPD deposition disease in the TMJ is challenging due to its mimicking of other benign and malignant entities. Surgical exploration followed by histologic examination is by far the most frequently used diagnostic modality. We present a case of an 87-year-old female who presented with a right TMJ mass. A final diagnosis of tophaceous pseudogout was made on cellular material obtained by ultrasound-guided fine-needle aspiration (US-guided FNA). Based on our case and current available literature, ultrasound-guided FNA is a reliable tool for diagnosing tophaceous pseudogout of the TMJ.

Most needle-shaped calcium pyrophosphate crystals lack birefringence.

OBJECTIVES: CPP crystals can be polymorphic (rhomboidal, parallelepiped: R/P), but some look like needles and could be taken as MSU under the bright field microscope. Birefringence of CPP crystals is weaker or absent compared with MSU crystals, but we aim to evaluate whether the grade of birefringence varies regarding the shape of the CPP crystal. METHODS: SF samples from patients with demonstrated acute CPP crystal arthritis were analysed by two observers, using a simple polarized light microscope equipped with two viewing stations. The analysis was performed simultaneously but in a blinded manner. Shape (needles or R/P) and the intensity of birefringence (absent, weak, moderate or MSU-like) were registered. χ2 trend test was used to evaluate the distribution of birefringence regarding the crystal shape. RESULTS: Two-hundred and fifty CPP crystals from 25 SF samples were analysed, well balanced between R/P and needles. The intensity of birefringence significantly differs between R/P or needles in the registries of both observers. R/P most often showed any grade of birefringence compared with needles, while no cases of MSU-like birefringence were found in acicular crystals. Both observers showed high agreement both in crystal shape and in intensity of birefringence. CONCLUSION: CPP crystals birefringence varies according to shape. Needle-shaped CPP crystals did not show strong birefringence, thus reinforcing the value of examining the samples with both ordinary and simple polarized light microscopes in differentiating them from MSU.

A Case of Tophaceous Pseudogout on 18F-FDG PET/CT Imaging.

A 53-year-old man with a 10-year history of gout was admitted to our hospital due to chronic low back pain. Initial CT examinations showed a high-density mass with bone destruction of bilateral facet joints at the L3 to L5 level. MRI findings also revealed lesion with the dural sac compression. On PET/CT, the juxta-articular mass of bilateral L3 to L5 facet joints showed abnormal FDG uptake with an SUVmax of 4.2. The possible diagnosis may be gouty tophi; however, the biopsy revealed the diagnosis of calcium pyrophosphate dihydrate deposition disease, also referred to as pseudogout.

[A muscular calcium pyrophosphate deposition pseudo-abscess: An atypical localization of chondrocalcinosis]. / Pseudo-abcès musculaire d'origine microcristalline : une localisation exceptionnelle de chondrocalcinose.

INTRODUCTION: Chondrocalcinosis results from calcium pyrophosphate crystals deposition in the joints. We report an exceptional case of aseptic psoas abscess with a deposition of calcium pyrophosphate crystals. CASE REPORT: A 92-year-old man presented to our department for an acute onset of inflammatory pain in the left hip. Computed tomography detected a coxofemoral arthritis and multiple intramuscular collections located in the iliopsoas muscle and the gluteus minimus. A sample of the fluid was obtained with a guided aspiration, and its analysis revealed an inflammatory liquid with no bacteria but numerous calcium pyrophosphate crystals. The final diagnosis was thus a muscular calcium pyrophosphate deposition pseudo-abscess, associated with a hip arthritis. CONCLUSION: Hip chondrocalcinosis is unusual, and the association with intramuscular deposition of calcium pyrophosphate crystals seems extremely rare as we found only four other published cases. A microcrystalline arthritis could have spread from the coxofemoral joint through the iliopsoas bursa and into the muscle. However, the imaging aspect with an abscess and a predominant muscular injury might suggest a mechanism of crystal formation originating directly within the muscle. The outcome was always favourable even if some patients required surgery.