[First classification criteria for diseases caused by calcium pyrophosphate deposition (CPPD)-Translation, explanation and assessment]. / Erste Klassifikationskriterien für durch Kalziumpyrophosphatablagerungen verursachte Erkrankungen ­ Übersetzung, Erläuterung und Bewertung.

AIM: For diseases caused by calcium pyrophosphate deposition (CPPD), validated classification criteria were previously lacking. In this article the recently developed and validated classification criteria are translated, explained, and assessed. METHODS: In recent years a multinational research group developed classification criteria for CPPD disease with the support by the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR), following an established method. The developed criteria were finally validated in an independent cohort. The translation and annotation of the new first classification criteria were carried out in an iterative procedure in consensus with the authors. RESULTS: The presence of a crowned dens syndrome or calcium pyrophosphate crystals in the synovial fluid in patients with pain, swelling or sensitivity of the joints (entry criterion) is sufficient for the classification as CPPD disease, where the symptoms cannot be completely explained by another rheumatic disease (exclusion criterion). If these symptoms are not present, a count of more than 56 points based on weighted criteria comprised of clinical features and the results of laboratory and imaging investigations can be included for classification as a CPPD disease. These criteria had a sensitivity of 92.2% and a specificity of 87.9% in the derivation cohorts (190 CPPD cases and 148 mimics), whereas the sensitivity was 99.2% and the specificity 92.5% in the validation cohorts (251 CPPD cases and 162 mimics). CONCLUSION: The ACR/EULAR classification criteria 2023 of a CPPD disease will facilitate clinical research in this field. The use in the clinical routine will show how practical the criteria are.

20 Years of Radiographic Imaging: Crystalline Deposits Causing Severe Arthropathy and Erosions.

Urate crystal gout arthritis and calcium pyrophosphate deposition disease (CPPD) are crystalline arthropathies seen in middle age to elderly patients, but are also seen in the active duty military population. Flares of either can be identified by acute joint pain, associated swelling, tenderness, and warmth. Definitive diagnosis involves synovial analysis from arthrocentesis. Gout and CPPD are common inflammatory joint diseases. Both arthropathies presenting themselves in the same joint are rather rare. An elderly female with a history of gout presented to the hospital with severe hip pain. She was on urate-lowering therapy at the time, and uric acid levels on admission were not significantly elevated. Radiographic imaging of her hip demonstrated periarticular cartilage calcifications. A review of radiographic imaging over the last 20 years found significant erosive arthropathy in multiple joints and radiographic evidence of chondrocalcinosis, suggesting CPPD. Synovial analysis was not obtained during this admission as the patient declined procedures due to her elderly age. Her condition improved with oral steroids. Few literatures have demonstrated that gout and CPPD are common crystal arthropathies that can occur concomitantly in the same joint. A 20-year review of imaging in an elderly female with known gout arthropathy found that she had radiographic evidence of concomitant CPPD-associated damage to many of her joints. Clinicians should be aware of the different erosive arthropathies, their corresponding imaging findings, evaluation for underlying metabolic disorders if appropriate, and the possibility that they may occur in the same joint. Early prevention can reduce joint destruction later in life.

Histone Deacetylase Inhibitors Downregulate Calcium Pyrophosphate Crystal Formation in Human Articular Chondrocytes.

Calcium pyrophosphate (CPP) deposition disease (CPPD) is a form of CPP crystal-induced arthritis. A high concentration of extracellular pyrophosphate (ePPi) in synovial fluid is positively correlated with the formation of CPP crystals, and ePPi can be upregulated by ankylosis human (ANKH) and ectonucleotide pyrophosphatase 1 (ENPP1) and downregulated by tissue non-specific alkaline phosphatase (TNAP). However, there is currently no drug that eliminates CPP crystals. We explored the effects of the histone deacetylase (HDAC) inhibitors (HDACis) trichostatin A (TSA) and vorinostat (SAHA) on CPP formation. Transforming growth factor (TGF)-ß1-treated human primary cultured articular chondrocytes (HC-a cells) were used to increase ePPi and CPP formation, which were determined by pyrophosphate assay and CPP crystal staining assay, respectively. Artificial substrates thymidine 5'-monophosphate p-nitrophenyl ester (p-NpTMP) and p-nitrophenyl phosphate (p-NPP) were used to estimate ENPP1 and TNAP activities, respectively. The HDACis TSA and SAHA significantly reduced mRNA and protein expressions of ANKH and ENPP1 but increased TNAP expression in a dose-dependent manner in HC-a cells. Further results demonstrated that TSA and SAHA decreased ENPP1 activity, increased TNAP activity, and limited levels of ePPi and CPP. As expected, both TSA and SAHA significantly increased the acetylation of histones 3 and 4 but failed to block Smad-2 phosphorylation induced by TGF-ß1. These results suggest that HDACis prevented the formation of CPP by regulating ANKH, ENPP1, and TNAP expressions and can possibly be developed as a potential drug to treat or prevent CPPD.

Effect of pathogenic crystals on the production of pro- and anti-inflammatory cytokines by different leukocyte populations.

PURPOSE: To evaluate cytokine production in vitro by different types of leukocytes stimulated with monosodium urate (MSU), calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals. MATERIAL AND METHODS: Polymorphonuclear cells (PMN), monocytes and lymphocytes, isolated from healthy volunteer blood, were stimulated for different time periods with increasing MSU, CPP or BCP crystal concentrations. IL-1ß, IL-8, IL-6, CCL2, IL-1Ra and TGFß1 were determined by ELISA. RESULTS: Exposure of PMN to different crystals resulted in a moderate IL-8 and IL-1Ra release. Stimulation of monocytes induced a significant production of all the cytokines evaluated. The highest levels of IL-1ß, IL-6, CCL2 and IL-8 were observed with MSU at 0.5 mg/ml, CPP at 0.01-0.05 mg/ml and BCP at 1 mg/ml after 18-48 h and then decreased. At the same crystal concentrations, IL-1Ra and TGFß1 increased until the end of the experiment. Treatment of lymphocytes with different crystals did not induce cytokine release. CONCLUSION: This study demonstrates that PMN, monocytes and lymphocytes from the same donor respond differently after stimulation with MSU, CPP or BCP crystals, depending on the dose and the time of exposure. Crystals induce a rapid increase of pro-inflammatory cytokines, whereas longer time is required to release high levels of anti-inflammatory cytokines.

Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1ß activation on macrophages.

OBJECTIVE: Macrophage activation by monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals mediates an interleukin (IL)-1ß-dependent inflammation during gout and pseudo-gout flare, respectively. Since metabolic reprogramming of macrophages goes along with inflammatory responses dependently on stimuli and tissue environment, we aimed to decipher the role of glycolysis and oxidative phosphorylation in the IL-1ß-induced microcrystal response. METHODS: Briefly, an in vitro study (metabolomics and real-time extracellular flux analysis) on MSU and CPP crystal-stimulated macrophages was performed to demonstrate the metabolic phenotype of macrophages. Then, the role of aerobic glycolysis in IL-1ß production was evaluated, as well in vitro as in vivo using 18F-fluorodeoxyglucose positron emission tomography imaging and glucose uptake assay, and molecular approach of glucose transporter 1 (GLUT1) inhibition. RESULTS: We observed that MSU and CPP crystals led to a metabolic rewiring toward the aerobic glycolysis pathway explained by an increase in GLUT1 plasma membrane expression and glucose uptake on macrophages. Also, neutrophils isolated from human synovial fluid during gout flare expressed GLUT1 at their plasma membrane more frequently than neutrophils isolated from bloodstream. Both glucose deprivation and treatment with either 2-deoxyglucose or GLUT1 inhibitor suppressed crystal-induced NLRP3 activation and IL-1ß production, and microcrystal inflammation in vivo. CONCLUSION: In conclusion, we demonstrated that GLUT1-mediated glucose uptake is instrumental during the inflammatory IL-1ß response induced by MSU and CPP crystals. These findings open new therapeutic paths to modulate crystal-related inflammation.

Outcome domains reported in calcium pyrophosphate deposition studies: A scoping review by the OMERACT CPPD working group.

INTRODUCTION: Although calcium pyrophosphate deposition (CPPD) is common, there are no validated outcome domains and/or measurements for CPPD studies. The aim of this work was to identify domains that have been reported in prior clinical studies in CPPD, to inform the development of a core set of domains for CPPD studies. METHODS: We performed a scoping literature review for clinical studies in CPPD, searching in Medline (via PubMed), EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases; published from January 1, 1946 to January 7, 2020. All reported outcomes and study design data were extracted and mapped to the core areas and domains as defined by the OMERACT Filter 2.1.The protocol was registered on PROSPERO (CRD: 42019137075; 09-07-2019). FINDINGS: There were 112 papers identified, comprising of 109 observational studies and three randomized controlled trials. Most studies reported clinical presentations of OA with CPPD or acute CPP crystal arthritis. Outcomes that mapped to 22 domains were identified; the most frequently reported measures mapped to the following domains/sub-domains: imaging (joint damage on imaging tests - 59 studies; joint calcification on imaging tests - 28 studies), joint pain (26 studies), response to treatment (23 studies), side effects of treatment (15 studies), inflammation in the joint fluid or blood (ESR or C-reactive protein - 12 studies; synovial fluid markers - 4 studies; other blood markers - 2 studies), overall function (14 studies), joint swelling (12 studies) and range of joint movement (10 studies). Very few studies mapped to domains related to life impact, societal/resource use or longevity. CONCLUSION: There is substantial variability in outcomes reported in CPPD studies. Outcomes that map to imaging manifestations, joint pain and response to treatment domains are most often reported.

Cartilage icing and chondrocalcinosis on knee radiographs in the differentiation between gout and calcium pyrophosphate deposition.

OBJECTIVE: To determine if findings of "cartilage icing" and chondrocalcinosis on knee radiography can differentiate between gout and calcium pyrophosphate deposition (CPPD). METHODS: IRB-approval was obtained and informed consent was waived for this retrospective study. Electronic medical records from over 2.3 million patients were searched for keywords to identify subjects with knee aspiration-proven cases of gout or CPPD. Radiographs were reviewed by two fellowship-trained musculoskeletal radiologists in randomized order, blinded to the patients' diagnoses. Images were evaluated regarding the presence or absence of cartilage icing, chondrocalcinosis, tophi, gastrocnemius tendon calcification, and joint effusion. Descriptive statistics, sensitivity, specificity, positive and negative predictive values, and accuracy were calculated. RESULTS: From 49 knee radiographic studies in 46 subjects (31 males and 15 females; mean age 66±13 years), 39% (19/49) showed gout and 61% (30/49) CPPD on aspiration. On knee radiographs, cartilage icing showed a higher sensitivity for CPPD than gout (53-67% and 26%, respectively). Chondrocalcinosis also showed a higher sensitivity for CPPD than gout (50-57% versus 5%), with 95% specificity and 94% positive predictive value for diagnosis of CPPD versus gout. Soft tissue tophus-like opacities were present in gout at the patellar tendon (5%, 1/19) and at the popliteus groove in CPPD (15%, 4/27). Gastrocnemius tendon calcification was present in 30% (8/27) of subjects with CPPD, and 5% (1/19) of gout. CONCLUSION: In subjects with joint aspiration-proven crystal disease of the knee, the radiographic finding of cartilage icing was seen in both gout and CPPD. Chondrocalcinosis (overall and hyaline cartilage) as well as gastrocnemius tendon calcification positively correlated with the diagnosis of CPPD over gout.

Calcium Pyrophosphate Dihydrate Crystals Increase the Granulocyte/Monocyte Progenitor (GMP) and Enhance Granulocyte and Monocyte Differentiation In Vivo.

Calcium pyrophosphate dihydrate (CPPD) crystals are formed locally within the joints, leading to pseudogout. Although the mobilization of local granulocytes can be observed in joints where pseudogout has manifested, the mechanism of this activity remains poorly understood. In this study, CPPD crystals were administered to mice, and the dynamics of splenic and peripheral blood myeloid cells were analyzed. As a result, levels of both granulocytes and monocytes were found to increase following CPPD crystal administration in a concentration-dependent manner, with a concomitant decrease in lymphocytes in the peripheral blood. In contrast, the levels of other cells, such as dendritic cell subsets, T-cells, and B-cells, remained unchanged in the spleen, following CPPD crystal administration. Furthermore, an increase in granulocytes/monocyte progenitors (GMPs) and a decrease in megakaryocyte/erythrocyte progenitors (MEPs) were also observed in the bone marrow. In addition, CPPD administration induced production of IL-1ß, which acts on hematopoietic stem cells and hematopoietic progenitors and promotes myeloid cell differentiation and expansion. These results suggest that CPPD crystals act as a "danger signal" to induce IL-1ß production, resulting in changes in course of hematopoietic progenitor cell differentiation and in increased granulocyte/monocyte levels, and contributing to the development of gout.

Adenine-(methoxy)-ethoxy-Pα,α-dithio-triphosphate inhibits pathologic calcium pyrophosphate deposition in osteoarthritic human chondrocytes.

Nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) inhibitors have been suggested as a potential treatment for calcium pyrophosphate dihydrate (CPPD) deposition disease. Here, we targeted the development of improved NPP1 inhibitors based on acyclic mimics of Pα,α-phosphorodithioate-substituted adenine nucleotides, 7-10. The latter were obtained in a facile two-step synthesis from adenine-(methoxy)ethanol. Among analogs 7-10, adenine-(methoxy)ethoxy-Pα,α-dithio-triphosphate, 8, was the most potent NPP1 inhibitor both with purified enzyme (IC50 0.645 µM) and in osteoarthritic human chondrocytes (IC50 0.033 µM). Furthermore, it efficaciously (10-fold vs. control) inhibited ATP-induced CPPD in human articular chondrocytes. Importantly, 8 was a highly selective NPP1 inhibitor which showed only minor inhibition of NPP3, CD39 and CD73, and did not inhibit TNAP (tissue nonspecific alkaline phosphatase) activity in human chondrocytes. Furthermore, 8 did not activate P2Y1,2,6 receptors. Analog 8 was not toxic to cultured chondrocytes at 100 µM. Therefore, 8 may be suitable for further development as a drug candidate for the treatment of CPPD arthritis and other NPP1-related diseases.

[Chondrocalcinosis: idiopathic or manifestation of rare metabolic diseases?] / Chondrokalzinose: Idiopathisch oder Manifestation seltener metabolischer Erkrankungen?

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 a gout 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 60 years 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.

Dual-energy computed tomography in calcium pyrophosphate deposition: initial clinical experience.

OBJECTIVE: To determine the dual-energy computed tomography (DECT) attenuation properties of meniscal calcifications in calcium pyrophosphate deposition (CPPD) in vivo, and assess whether DECT was able to discriminate meniscal CPP deposits from calcium hydroxyapatite (HA) in subchondral and trabecular bone. METHOD: Patients with clinical suspicion of crystal-related arthropathy (gout and/or CPPD) and knee DECT scans were retrospectively assigned to CPPD (n = 19) or control (n = 21) groups depending on the presence/absence of chondrocalcinosis on DECT. Two observers drew standardized regions of interest (ROI) in meniscal calcifications, non-calcified menisci, as well as subchondral and trabecular bone. Five DECT parameters were obtained: CT numbers (HU) at 80 and 140 kV, dual-energy index (DEI), electron density (ρe), and effective atomic number (Zeff). The four different knee structures were compared within/between patients and controls using linear mixed models, adjusting for confounders. RESULTS: Meniscal calcifications (n = 89) in CPPD patients had mean ± SD CT numbers at 80 and 140 kV of 257 ± 64 and 201 ± 48 HU, respectively; with a DEI of 0.023 ± 0.007, and ρe and Zeff of 140 ± 35 and 8.8 ± 0.3, respectively. Meniscal CPP deposits were readily distinguished from calcium HA in subchondral and trabecular bone (p ≤ 0.001), except at 80 kV separately (p = 0.74). Zeff and ρe both significantly differed between CPP deposits and calcium HA in subchondral and trabecular bone (p < 0.0001). CONCLUSION: This proof-of-concept study shows that DECT has the potential to discriminate meniscal CPP deposits from calcium HA in subchondral and trabecular bone in vivo, paving the way for the non-invasive biochemical signature assessment of intra- and juxta-articular calcium crystal deposits.

Value of serum procalcitonin for the diagnosis of bacterial septic arthritis in daily practice in rheumatology.

INTRODUCTION/OBJECTIVES: Septic arthritis is a diagnostic and therapeutic emergency because of a high morbidity and mortality. Nevertheless, the etiologic diagnosis is often difficult. The aim of our study was to determine if serum procalcitonin was a discriminatory biomarker in case of arthritis of undetermined etiology. METHOD: Patients were separated in five groups: gouty arthritis, calcium pyrophosphate deposition arthritis, osteoarthritis or post-traumatic arthritis ("mechanical" arthritis), chronic inflammatory rheumatic arthritis, and septic arthritis. Levels of serum white blood cells, C-reactive protein and procalcitonin were measured. RESULTS: Ninety-eight patients were included: 18 in the "gout" group, 26 in the "calcium pyrophosphate deposition arthritis" group, 16 in the mechanical group, 18 in the "chronic inflammatory rheumatic" group, and 20 in the "sepsis" group. The area under the receiver operating characteristic curve of white blood cells, C-reactive protein, and procalcitonin levels to diagnose a septic arthritis were 0.69 (IC95% 0.55-0.83), 0.82 (IC95% 0.73-0.91), and 0.87 (IC95% 0.76-0.98) respectively. For a cutoff of 0.5 ng/ml, procalcitonin sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio were 65%, 91%, 65%, 91%, 7.2, and 0.4, respectively. Serum C-reactive protein and procalcitonin levels were correlated, were not different in sepsis or gout groups, and were higher in non-septic arthritis with poly-arthritis than with mono-arthritis (p < 0.05). CONCLUSIONS: Serum procalcitonin is a useful biomarker in arthritis management with diagnosis performances higher than those of other biomarkers (white blood cells, C-reactive protein).Key Points• Diagnostic performances of serum procalcitonin level in septic arthritis are higher than those of serum C-reactive protein or white blood cells levels.• Serum procalcitonin levels are not different in septic arthritis or gouty arthritis.• Serum procalcitonin levels are higher in non-septic arthritis with poly-arthritis than with mono-arthritis.

Calcium pyrophosphate dihydrate crystal deposition disease and MRSA septic arthritis of the atlantoaxial joint in a patient with Tourette syndrome.

A 45-year-old male patient with Tourette syndrome presented to the emergency department with worsening neck pain and stiffness of 1-week duration. Associated symptoms included headache, hoarse voice, trismus and odynophagia. The patient was haemodynamically stable without fevers or leucocytosis. He exhibited cervical spinal and paraspinal tenderness with very limited range of motion. Erythrocyte sedimentation rate and C reactive protein were elevated, and blood cultures grew methicillin-resistant Staphylococcus aureus (MRSA). Lumbar puncture was unremarkable. CT and MRI of the neck showed calcification of the longus colli, fluid and capsular distention of C1-C2 joints, enhancement of the joint capsule and retropharyngeal oedema suggestive of septic arthritis. Fluid was aspirated from C1 to C2 joint by interventional radiology and showed calcium pyrophosphate crystals and heavy MRSA colonisation, consistent with both pseudogout and septic arthritis of the cervical vertebrae. The patient was started on a 6-week course of daptomycin and showed gradual improvements in neck pain and mobility.

Ultrashort Time to Echo Magnetic Resonance Evaluation of Calcium Pyrophosphate Crystal Deposition in Human Menisci.

OBJECTIVES: In human menisci, we aimed to investigate whether calcium pyrophosphate crystal deposition (CPPD) affects biomechanical and quantitative MR properties, and their zonal distribution. MATERIALS AND METHODS: From 9 cadaveric knees, sectioned triangular meniscus pieces were harvested. Samples were classified into "normal" or "CPPD" groups based upon visual inspection. Micro computed tomography scan verified CPPD. Using magnetic resonance imaging, ultrashort echo time (UTE) T2* and spin echo (SE) T2, quantitative values in 3 zones (red, red-white, and white) were determined. Using biomechanical test, indentation forces in the same zones were determined. Effects of CPPD and meniscal zone on indentation force and quantitative MR values were compared. RESULTS: On UTE MRI scans, CPPD-affected menisci exhibited punctate dark regions, found mostly (92%) in avascular white and red-white zones. Indentation forces were significantly higher for CPPD samples in the red-white (all P < 0.02) and white (all P < 0.004) zones but not in the vascular red zone (all P > 0.2). Similarly, UTE T2* red zone values were similar between both groups (~6.6 milliseconds, P = 0.8), whereas in the red-white and white zones, CPPD samples had significantly lower values (~5.1 milliseconds, P = 0.005 to 0.007). In contrast, SE T2 values showed no difference with CPPD (P = 0.12 to 0.16). UTE T2*, but not SE T2, correlated significantly with indentation force (R = -0.29, P = 0.009). CONCLUSIONS: Dark CPP deposits were detectable on UTE images featuring high signal intensity from surrounding meniscal tissue. Preliminary results indicate that CPP deposits were almost exclusively found in the avascular zones. Compared with normal, CPPD menisci featured higher indentation stiffness and lower UTE T2* values in the affected zones.