[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.

Dynamic assessment of the double contour sign by ultrasonography helps to distinguish between gout and calcium pyrophosphate deposition disease.

OBJECTIVE: To test whether the double contour (DC) sign has a different dynamic behaviour in gout and calcium pyrophosphate deposition (CPPD) and whether the dynamic assessment of the DC sign increases its accuracy in gout diagnosis. METHODS: This cross-sectional analysis included patients with gout meeting the 2015 ACR/EULAR classification criteria and patients with crystal-proven diagnosis of CPPD. Hyaline cartilages were explored by ultrasound (US) to detect the DC sign (ie, abnormal hyperechoic band over the superficial margin of hyaline cartilages) and its dynamic behaviour during joint movement was evaluated ((ie, movement of the DC sign together with subchondral bone (DC sign), or in the opposite direction (pseudo DC sign)). RESULTS: Eighty-one patients with gout and 84 patients with CPPD underwent US assessment. Among them, 47 patients with gout and 9 patients with CPPD had evidence of the DC sign. During dynamic assessment, in all 47/47 patients with gout there was a DC sign. Conversely, in 7/9 (77.8%) patients with CPPD, there was a pseudo DC sign (p<0.01).The presence of DC sign during static assessment had a sensitivity, specificity and accuracy of 58.0% (95% CI 46.5% to 68.9%), 89.3% (95% CI 80.6% to 95.0%) and 73.9% (95% CI 66.5% to 80.5%) for gout, respectively. The dynamic evaluation improved the DC sign's diagnostic performance (p=0.01) as the specificity (97.6% (95% CI 91.7% to 99.7%)) and the accuracy (78.2% (95% CI 71.1% to 84.2%)) increased without loss in sensitivity. CONCLUSION: The dynamic US assessment of the DC sign may help to differentiate the DC sign due to MSU crystals from the pseudo DC sign seen in CPPD, as they move in opposite directions.

Outcomes and resource utilization in calcium pyrophosphate deposition disease patients who underwent total knee arthroplasty: a cross-sectional analysis.

This cross-sectional study aims to evaluate the predictors, outcomes, and resource utilization of total knee arthroplasty (TKA) in calcium pyrophosphate deposition disease (CPPD) patients. We used the US National Inpatient Sample database to identify CPPD and non-CPPD who underwent TKA from 2006 to 2014. Data collection included patient demographics and comorbidities. Outcomes following TKA included in-hospital mortality, complications, length of hospitalization, hospital charges, and disposition. Among the 5,564,005 patients who have undergone TKA, 11,529 (0.20%) had CPPD, with a median age of 72 years, and 53.7% were females. Compared with non-CPPD, patients with CPPD were more likely to be older (mean 72 vs 66 years; p < 0.001), male, white, and have Medicare insurance. CPPD patients were more likely to have ≥ 2 comorbidities calculated by the Charlson Comorbidity Index and discharge to an inpatient/rehabilitation facility. Regarding inpatient complications, myocardial infarction and knee reoperation were significantly more common in CPPD patients. TKA in CPPD patients was associated with significantly higher odds of increased length of stay (> 3 days) than those without CPPD (OR 1.43, 95% CI 1.37-1.49). There was no significant difference in the in-hospital mortality even after adjusting for possible confounders. CPPD patients who underwent TKA were more likely to have a longer hospital stay and discharge to a non-home setting than non-CPPD. Also, CPPD patients had a higher comorbidity burden and risk for myocardial infarction and reoperation.Key Points• This is the largest study to analyze data of CPPD patients who underwent TKA and compare them with non-CPPD patients, using a large nationwide database.• Compared to non-CPPD patients, TKA in CPPD patients is associated with a greater length of stay and disposition to a nursing/rehabilitation facility.• In-hospital complications such as myocardial infarction and reoperation were more frequently observed in CPPD patients than non-CPPD.• The results of this study should alert healthcare providers to develop strategies in order to improve outcomes of CPPD patients undergoing TKA.

Sonographic assessment of calcium pyrophosphate deposition disease at wrist. A focus on the dorsal scapho-lunate ligament.

OBJECTIVES: To investigate the diagnostic accuracy of ultrasound and conventional radiography in the evaluation of calcium pyrophosphate crystal deposits at wrist level. METHODS: Consecutive patients with a "definite" diagnosis of calcium pyrophosphate deposition disease and disease-controls were prospectively included in this cross-sectional single-centre study. Scapho-lunate ligament, triangular fibrocartilage complex, and volar recess of the radio-lunate joint were explored using ultrasound, conventional radiography and computed tomography. RESULTS: Sixty one patients and 39 disease controls were enrolled. Two-hundred wrists were evaluated using both conventional radiography and ultrasound and 26 using computed tomography. Ultrasound findings indicative of crystal deposits were found in at least one wrist in 95.1% of patients and in 15.4% of controls (P<0.001). Scapho-lunate ligament calcifications were reported in 83.6% of patients and in 5.1% of controls (P<0.001). On conventional radiography, calcifications were found in at least one wrist in 72.1% of patients and in 0% of controls (P<0.001). Using the Ryan-McCarty criteria as a gold standard, sensitivity, specificity and diagnostic accuracy were 0.72 (0.59-0.83), 1.0 (0.91-1.0) and 0.83 (0.74-0.90) for conventional radiography and 0.95 (0.86-0.99), 0.85 (0.69-0.94) and 0.91 (0.84-0.96) for ultrasound. The agreement between ultrasound and computed tomography was substantial when assessing triangular fibrocartilage complex (kappa=0.70; 0.43-0.97) and scapho-lunate ligament (kappa=0.69; 0.41-0.97), and moderate for radio-lunate joint (kappa=0.46; 0.12-0.80). CONCLUSIONS: This study supports the diagnostic accuracy of ultrasound in evaluating wrist involvement in calcium pyrophosphate deposition disease. The inclusion of the scapho-lunate ligament in a disease-oriented scanning protocol could improve the diagnostic performance of ultrasound.

Chondrocalcinosis of the Knee and the Risk of Osteoarthritis Progression: Data From the Knee and Hip Osteoarthritis Long-term Assessment Cohort.

OBJECTIVE: To assess the impact of knee chondrocalcinosis (CC) on the 5-year risk of joint replacement and disease progression in patients with knee osteoarthritis (OA). METHODS: Patients with symptomatic knee OA without previous total joint (knee or hip) replacement (TJR) were recruited from the Knee and Hip Osteoarthritis Long-term Assessment cohort. Cox proportional hazards regression and generalized estimating equation models were used to compare the time from inclusion or OA diagnosis to total knee replacement (TKR) or TJR between patients with and those without knee CC at inclusion. In patients without incident TKR, logistic regression was performed to examine the association between CC and radiographic progression (Kellgren/Lawrence [K/L] grade) or worsening of Western Ontario and McMaster Universities Arthritis Index (WOMAC) subscores for OA pain or function between years 0 and 5. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated. Analyses were adjusted for age, sex, body mass index, WOMAC subscores, and K/L grade. RESULTS: Among the 656 patients included, 93 (14.2%) had knee CC, and 91 (13.9%) underwent TKR during the follow-up. Risk of TKR was not affected by the presence of knee CC (HR 1.26 [95% CI 0.74-2.17]). Similar results were obtained for the risk of incident TJR. For patients without incident TKR, knee CC did not affect the risk of worsening of K/L grade (odds ratio [OR] 0.9 [95% CI 0.4-1.7]), WOMAC pain subscore (OR 1.1 [95% CI 0.7-1.4]), or WOMAC function subscore (OR 0.9 [95% CI 0.4-2.0]). CONCLUSION: In patients with symptomatic knee OA, the presence of knee CC did not affect the risk of arthroplasty or disease progression at 5 years.

Prevalence and incidence of non-gout crystal arthropathy in southern Sweden.

OBJECTIVE: To estimate the prevalence and incidence of non-gout crystal arthropathy in relation to socioeconomic factors in southern Sweden. METHODS: All patients (age ≥ 18 years) with at least one visit to a physician with the diagnosis of interest in the Skåne region (population of 1.3 million) in 1998-2014 were identified. Non-gout crystal arthropathy (ICD-10 codes M11.0-M11.9) was subclassified in four different groups: calcium pyrophosphate crystal deposition related arthropathy (CPPD), unspecified non-gout arthropathies, chondrocalcinosis, and hydroxyapatite crystal deposition disease. The crude and age-adjusted point prevalence on December 31, 2014, and the cumulative incidence during 2014 were calculated for all non-gout crystal arthropathies, CPPD, and other unspecified non-gout arthropathies overall and in relation to occupation, income, and level of education. RESULTS: The crude 2014 point prevalence (95% CI) and 2014 cumulative incidence (95% CI) of all non-gout crystal arthropathies were 0.23% (0.23-0.24) and 21.5 (19-25) cases/100,000 persons. Mean age (range) among all prevalent cases in 2014 was 71 (20-102) years and 56% were males. The point prevalence and cumulative incidence of CPPD were 0.09% (0.08-0.09) and 8 (7-10)/100,000 persons, respectively. The corresponding data for unspecified non-gout crystal deposition disease was 0.16% (0.16-0.17) and 15.6 (13-18)/100,000 persons, respectively. The prevalence and incidence of CPPD and unspecified non-gout crystal arthropathies were slightly higher in men and increased with age irrespective of gender. Unspecified non-gout crystal arthropathy but not CPPD was less prevalent in persons with ≥ 15 years of education, whereas there were no clear associations with occupation and income. CONCLUSION: The prevalence of all diagnosed non-gout crystal arthropathies was 0.23%, thus considerably less prevalent than gout in southern Sweden. CPPD and other unspecified non-gout crystal arthropathies are the predominant diagnoses, increasing with age and in men. With the exception for unspecified non-gout crystal arthropathies being inversely correlated to a higher level of education, no convincing association with the socioeconomic factors was found.

Review: Unmet Needs and the Path Forward in Joint Disease Associated With Calcium Pyrophosphate Crystal Deposition.

Calcium pyrophosphate (CPP) crystal deposition (CPPD) is prevalent and can be associated with synovitis and joint damage. The population of elderly persons predominantly affected by CPPD is growing rapidly. Since shortfalls exist in many aspects of CPPD, we conducted an anonymous survey of CPPD unmet needs, prioritized by experts from the Gout, Hyperuricemia and Crystal-Associated Disease Network. We provide our perspectives on the survey results, and we propose several CPPD basic and clinical translational research pathways. Chondrocyte and cartilage culture systems for generating CPP crystals in vitro and transgenic small animal CPPD models are needed to better define CPPD mechanism paradigms and help guide new therapies. CPPD recognition, clinical research, and care would be improved by international consensus on CPPD nomenclature and disease phenotype classification, better exploitation of advanced imaging, and pragmatic new point-of-care crystal analytic approaches for detecting CPP crystals. Clinical impacts of CPP crystals in osteoarthritis and in asymptomatic joints in elderly persons remain major unanswered questions that are rendered more difficult by current inability to therapeutically limit or dissolve the crystal deposits and assess the consequent clinical outcome. Going forward, CPPD clinical research studies should define clinical settings in which articular CPPD does substantial harm and should include analyses of diverse clinical phenotypes and populations. Clinical trials should identify the best therapeutic targets to limit CPP crystal deposition and associated inflammation and should include assessment of intraarticular agents. Our perspective is that such advances in basic and clinical science in CPPD are now within reach and can lead to better treatments for this disorder.

Diagnostic accuracy of musculoskeletal ultrasound and conventional radiography in the assessment of the wrist triangular fibrocartilage complex in patients with definite diagnosis of calcium pyrophosphate dihydrate deposition disease.

OBJECTIVES: To compare the diagnostic accuracy of musculoskeletal ultrasound (MSUS) and x-ray in evaluating wrist triangular fibrocartilage complex (TFCC) in patients with calcium pyrophosphate dihydrate deposition disease (CPPD) and to investigate the agreement between the extent of the calcium pyrophosphate dihydrate (CPP) crystal deposits assessed by MSUS and the radiographic findings. METHODS: We enrolled 84 patients: 36 patients with "definite" CPPD and 48 controls. The Ryan and McCarty diagnostic criteria were used. A rheumatologist performed bilateral MSUS examinations of the TFCC in all patients, assessing both the presence and absence of CCP crystals deposits and their extent (0-3; 0: absent; 1: 1-2 spots; 2: more than two spots covering <50% of the volume of the structure; 3: deposits covering >50% of the volume of the structure). A radiologist evaluated the presence/absence of x-ray calcifications at TFCC level in both groups. RESULTS: MSUS and x-ray sensitivity was 77.8% and 76.4%, respectively, whereas MSUS and x-ray specificity was 90.6% and 96.9%, respectively. Total agreement between MSUS and radiographic findings indicative of calcifications at TFCC level was 88.7%. CONCLUSIONS: This study supports the diagnostic accuracy of MSUS and x-ray in evaluating TFCC crystal deposits in patients with CPPD. Sensitivity and specificity of MSUS and x-ray resulted comparable. The highest MSUS score of the extent of the deposits correlated better with x-ray findings.

Definition and Reliability Assessment of Elementary Ultrasonographic Findings in Calcium Pyrophosphate Deposition Disease: A Study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force.

OBJECTIVE: To define the ultrasonographic characteristics of calcium pyrophosphate crystal (CPP) deposits in joints and periarticular tissues and to evaluate the intra- and interobserver reliability of expert ultrasonographers in the assessment of CPP deposition disease (CPPD) according to the new definitions. METHODS: After a systematic literature review, a Delphi survey was circulated among a group of expert ultrasonographers, who were members of the CPPD Ultrasound (US) Outcome Measures in Rheumatology (OMERACT) subtask force, to obtain definitions of the US characteristics of CPPD at the level of fibrocartilage (FC), hyaline cartilage (HC), tendon, and synovial fluid (SF). Subsequently, the reliability of US in assessing CPPD at knee and wrist levels according to the agreed definitions was tested in static images and in patients with CPPD. Cohen's κ was used for statistical analysis. RESULTS: HC and FC of the knee yielded the highest interobserver κ values among all the structures examined, in both the Web-based (0.73 for HC and 0.58 for FC) and patient-based exercises (0.55 for the HC and 0.64 for the FC). Kappa values for the other structures were lower, ranging from 0.28 in tendons to 0.50 in SF in the static exercise and from 0.09 (proximal patellar tendon) to 0.27 (triangular FC of the wrist) in the patient-based exercise. CONCLUSION: The new OMERACT definitions for the US identification of CPPD proved to be reliable at the level of the HC and FC of the knee. Further studies are needed to better define the US characteristics of CPPD and optimize the scanning technique in other anatomical sites.

The role of imaging modalities in the diagnosis, differential diagnosis and clinical assessment of peripheral joint osteoarthritis.

Peripheral joint osteoarthritis (OA) is predominantly a clinical diagnosis, though imaging may provide confirmation and aid with differential diagnosis where there is clinical doubt. Whilst radiographs (X-rays (XR)) are usually the first-line imaging modality selected, magnetic resonance imaging (MRI), ultrasound and computed tomography (CT) may all have a valuable role in assessing a person with OA, although each has its particular advantages and disadvantages. MRI is of particular use for diagnosing bone conditions that may cause a rapid increase in symptoms, such as avascular necrosis (AVN) or a subchondral insufficiency fracture (SIF), while providing concomitant soft tissue assessment. Ultrasound offers rapid assessment of peripheral joints and can easily assess for features of inflammatory arthritis. CT is faster to perform than MRI and can also image the subchondral bone, but does involve ionising radiation. Selecting the correct imaging modality, in the context of its advantages when visualising a specific joint (e.g., hand vs knee) and with clinical context in mind, will enhance the added value of imaging in clinical practice.

MR imaging assessment of inflammatory, crystalline-induced, and infectious arthritides.

The role of magnetic resonance imaging in evaluating patients with inflammatory arthritides has evolved with the recent introduction of drugs capable of modifying disease activity and natural history. In conditions like rheumatoid arthritis, active synovitis and bone marrow inflammation precede and predict bone and cartilage erosion. These imaging findings identify patients who can be treated early and aggressively to prevent future morbidity. Similarly, in gout and other crystalline disorders, specific diagnosis aided by imaging may lead to earlier medical and surgical management. Infected joints need the most rapid identification to institute immediate therapy and prevent irreversible cartilage destruction.

Ultrasound imaging for the rheumatologist. XXV. Sonographic assessment of the knee in patients with gout and calcium pyrophosphate deposition disease.

The knee is a frequent target for gout and calcium pyrophosphate dihydrate (CPPD) disease with involvement of both articular and peri-articular structures. The aims of the present study were to investigate the relationship between clinical and ultrasound (US) findings and to describe the prevalence and distribution of crystal deposits in the knee in patients with gout and CPPD disease. Thirty patients with gout and 70 patients with CPPD disease were enrolled in the study. Prior to US assessment all patients underwent a clinical examination by an expert rheumatologist who recorded the presence/absence of pain, tenderness (evocated by palpation and/or active or passive mobilisation of the knee), and knee swelling. US examinations were performed using a Logiq 9 (General Electric Medical Systems, Milwaukee, WI) equipped with a multifrequency linear probe, working at 9 MHz. Two hundred knee joints were investigated in a total of 100 patients. Fifty-one (25.5%) knee joints were found clinically involved, while at least one US finding indicative of joint inflammation was obtained in 73 (36.5%) knee joints.The most frequent US finding indicative of knee joint inflammation was joint effusion, detected in 21 (35%) out of 60 knees and in 52 (37%) out of 140 knees, in gout and CPPD disease, respectively. Ten (17%) out of 60 knees and 21 (15%) out of 140 knees were found positive for synovial hypertrophy with or without intra-articular power Doppler, in gout and CPPD disease respectively. Sonographic evidence of crystal deposition within joint cartilage (hyaline and fibrocartilage) was more frequently seen than in the soft tissue in the knee.This study demonstrated that US detected a higher number of inflamed knee joints than clinical assessment in patients with crystal related arthropathies and that the distribution of crystal deposits at joint cartilage level permitted distinction between gout and CPPD disease. Further studies are required to investigate both sensitivity and specificity of US features indicative of crystal aggregates at both tendon and entheseal level.

[The current role of ultrasound in the assessment of crystal-related arthropathies]. / Il ruolo attuale dell'ecografia nelle artropatie da microcristalli.

Over last few years, the ultrasonography (US) generated an increasing popularity among rheumatologists due to excellent potentiality and numerous applications in rheumatology. Most of the published papers focus mainly to demonstrate the utility of US in early and chronic arthritis, short-term therapy monitoring and guidance for invasive procedures. Less attention has been paid to the potential of this technique in the field of crystal-related arthropathies. By virtue of the high resolution of "new generation" equipments, minimal crystal deposits can be detected even sometime when the radiography was negative. The aim of this paper was to present the principal findings in patients with crystal-related arthropathies.

"Crystal clear"-sonographic assessment of gout and calcium pyrophosphate deposition disease.

OBJECTIVES: To date, high-resolution ultrasound (US) has not been fully exploited in the field of crystalline arthropathy. Both gout and calcium pyrophosphate deposition (CPPD) disease are significant diseases within the purview of the rheumatologist. The aim of this pictorial review was to present the principal findings in patients with crystal deposition in gout and CPPD. METHODS: US pictures were obtained from 60 consecutive patients, 34 with CPPD disease and 26 with gout, whose diagnosis was confirmed by synovial fluid analysis. The US examinations were performed using the following US systems: Diasus (Dynamic Imaging, Livingstone, UK) and Logiq 9 (General Electric Medical Systems, Milwaukee, WI). RESULTS: Pictorial evidence of the principal US findings in gout includes monosodium urate (MSU) deposition on the surface of articular cartilage, various patterns within synovial fluid ranging from completely anechoic fluid to collections filled with aggregates of variable shape and echogenicity, microdeposition within tendons, and tophus formation. In CPPD, the hallmark US features include crystal deposition within articular cartilage, calcification of fibrocartilage, together with focal crystal deposition within tendons. CONCLUSION: US is an impressive imaging modality in crystalline arthropathy. The anatomical location of the crystal deposits, clearly depictable by US, allows differentiation between MSU and CPPD aggregates.

Cost-benefit value of microscopic examination of intervertebral discs.

OBJECT: Given the virtual absence of histologically detected, clinically unsuspected disease in intervertebral disc specimens, some authors have advocated that histological examination be discontinued. However, the examination of intervertebral disc specimens remains common practice in most pathology laboratories. No cost-benefit analysis of this practice has been made; therefore, the authors' goal in this study was perform such an analysis. METHODS: Using the University of Iowa surgical pathology database, 1109 patients who had undergone a laminectomy were identified retrospectively. These cases were classified into four categories based on the patients' preoperative clinical diagnosis and final histopathological diagnosis: insignificant clinical diagnosis/insignificant pathological diagnosis (ICIP), significant clinical diagnosis/insignificant pathological diagnosis (SCIP), significant clinical diagnosis/significant pathological diagnosis (SCSP), and insignificant clinical diagnosis/significant pathological diagnosis (ICSP). A significant clinical diagnosis was defined as one other than a benign, noninfectious indication for laminectomy. A significant pathological diagnosis was a diagnosis other than degenerative changes. The cost-benefit value of performing a histological examination in cases with significant or insignificant clinical diagnoses was examined. The cases were classified as: 1068 ICIP, 17 SCIP, 21 SCSP, and three ICSP. On chart review, in all three cases of ICSP an epidural abscess was identified perioperatively and the subsequent histological diagnosis did not affect patient care. The costs per case of identifying a significant pathological diagnosis with a significant and an insignificant clinical diagnosis were $44.79 and $8811, respectively. CONCLUSIONS: Histological examination of intervertebral disc specimens is cost beneficial only if there is a significant preoperative clinical diagnosis.

Xeroradiographic techniques applied to assessment of Achilles tendon in inflammatory or metabolic diseases.

Ten patients with inflammatory disease (rheumatoid arthritis, ankylosing spondylitis, Reiter's disease) or metabolic disease (gout, pseudogout, tendinous xanthomatosis) affecting the Achilles tendons are presented and discussed. Radiological lateral views of heel were obtained with xeroradiographic techniques, which permitted the recording on the same image of details of both bone and soft tissue and the evaluation and quantification of the changes in the Achilles tendons. Xeroradiography seems to be a very suitable radiological technique for routine use in the evaluation and follow up of rheumatic diseases of the foot.