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This study at IRCCS Galeazzi - Sant'Ambrogio Hospital involves patients with gout, CPPD, and osteoarthritis as a control group. Patients will receive routine care with regular clinical, laboratory, and imaging assessments every six months, alongside urgent visits as needed. The study aims to understand crystal deposits in joints and blood vessels and monitor their progression over time, assessing how these deposits respond to standard treatments and if they are associated with cardiovascular complications. Data will be collected from medical records over a follow-up period of up to 10 years, offering long-term insights into disease impact and treatment effectiveness.
This is a monocentric observational longitudinal study in which patients diagnosed with gout or CPPD and disease-controls with OA will be consecutively recruited from the outpatient clinics of the Rheumatology and Orthopaedic Hip Departments of the IRCCS Galeazzi - Sant'Ambrogio Hospital.
The investigators will enroll consecutive patients with CPPD and gout and disease-controls with OA fulfilling the inclusion and exclusion criteria, from the outpatient clinics of the Rheumatology Department and Orthopaedic Hip Department of the IRCCS Galeazzi - Sant'Ambrogio Hospital, who will be seen for routine or urgent gout/CPPD/OA care following local scheduling processes, without applying any further selection criteria. All patients, in line with clinical routine practice, will undergo a standard clinical, laboratory and imaging assessment, both at baseline and during scheduled follow-up visits (every 6 months) and urgent follow-up visits, tailored to each patient's needs. The study comprises two phases. The first, aims to evaluate the extent of crystal deposition in joints and in blood vessels in patients with CPPD and gout. The second, focuses on monitoring the extension of crystals deposits, their associations with conventional therapies, and evaluating the development of cardiovascular complications in patients with CPPD and gout in comparison to disease-controls with OA. The data for the study will be retrieved from the medical records of the patients and recorded into an appositely created electronic case report form (CRF). The enrollment period will last 3 years (starting from the time of approval of the study), and the follow up period will last 10 years.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Gout | Patients affected by gout according to ACR/EULAR classification criteria | ||
| CPPD | Patients affected by gout according to ACR/EULAR classification criteria | ||
| Disease control | Patients with a diagnosis of osteoarthritis according to ACR classification criteria |
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| Measure | Description | Time Frame |
|---|---|---|
| Extent of CPP crystal deposition assessed by ultrasound over time | Calcium pyrophosphate crystal deposition (CPPD) will be assessed using the OMERACT Ultrasound Scoring System for CPPD at patient level and at joint level. Each anatomical site will be graded on a semi-quantitative scale from 0 to 3. According to the clinical scenario and the clinician decision, patients will undergo an US examination of the affected joints. Case by case the following joints will be evaluated: shoulder, elbow, wrist, hand, hip, knee, ankle, Achilles tendon, foot. The total score will be calculated as the sum of scores across all evaluated sites and normalized by the number of sites assessed per patient. The measure will be assessed longitudinally to evaluate changes in crystal deposition over time. | Baseline and every 6 months up to 10 years |
| Extent of MSU crystal deposition assessed by ultrasound over time | Assessment of the extent of monosodium urate (MSU) crystal deposition Calcium pyrophosphate crystal deposition (CPPD) will be assessed using the OMERACT Ultrasound Scoring System for Gout Lesions (double contour sign, tophi, aggregates). Each lesion will be graded on a semi-quantitative scale from 0 to 3. A total score will be calculated by summing scores across all evaluated joints. According to the clinical scenario and the clinician decision, patients will undergo an US examination of the affected joints. Case by case the following joints will be evaluated: shoulder, elbow, wrist, hand, hip, knee, ankle, Achilles tendon, foot. The total score will be calculated as the sum of scores across all evaluated sites and normalized by the number of sites assessed per patient. The measure will be assessed longitudinally to evaluate changes in crystal deposition over time. | Baseline and every 6 months up to 10 years |
| Progression of bone erosions assessed by ultrasound | Bone erosions will be assessed using the OMERACT Ultrasound Scoring System for Bone Erosions. Each site will be graded from 0 to 3 and summed across all evaluated joints to obtain a total erosion score. The measure will be assessed longitudinally to evaluate changes over time. | Baseline and every 6 months up to 10 years |
| Measure | Description | Time Frame |
|---|---|---|
| ESR | Change From Baseline in Erythrocyte Sedimentation Rate (ESR mm/h) between patients with CPPD and gout and disease-controls with OA | From baseline every 6 months up to 10 years |
| CRP | Change From Baseline in C-Reactive Protein (CRP mg/L) between CPPD and Gout patients and controls with OA |
| Measure | Description | Time Frame |
|---|---|---|
| Serum suPAR Levels Assessed by Enzyme Immunoassay | Serum soluble urokinase plasminogen activator receptor (suPAR) levels will be measured using an ELISA-based assay on blood and/or synovial fluid, whenever the patients undergo arthrocentesis for other reasons | Once during the 10 years follow up |
| Intima media thickness at ultrasound of carothid arteries |
The inclusion criteria for CPPD patients are:
The inclusion criteria for gout patients are:
The inclusion criteria for disease controls are:
The exclusion criteria for gout/CPPD patients are:
The exclusion criteria for disease controls are:
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Patients affected by gout, CPPD or osteoarthritis.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Georgios Filippou, MD | Contact | 0039 0283502707 | georgios.filippou@grupposandonato.it | |
| Silvia Sirotti, MD | Contact | 0039 0283502708 | silvia.sirotti@grupposandonato.it |
| Name | Affiliation | Role |
|---|---|---|
| Georgios Filippou, MD | Università degli Studi di Milano / IRCCS Ospedale Galeazzi-Sant'Ambrogio | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IRCCS Ospedale Galeazzi-Sant'Ambrogio | Recruiting | Milan | Milano | 20157 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28814430 | Background | Moller I, Janta I, Backhaus M, Ohrndorf S, Bong DA, Martinoli C, Filippucci E, Sconfienza LM, Terslev L, Damjanov N, Hammer HB, Sudol-Szopinska I, Grassi W, Balint P, Bruyn GAW, D'Agostino MA, Hollander D, Siddle HJ, Supp G, Schmidt WA, Iagnocco A, Koski J, Kane D, Fodor D, Bruns A, Mandl P, Kaeley GS, Micu M, Ho C, Vlad V, Chavez-Lopez M, Filippou G, Ceron CE, Nestorova R, Quintero M, Wakefield R, Carmona L, Naredo E. The 2017 EULAR standardised procedures for ultrasound imaging in rheumatology. Ann Rheum Dis. 2017 Dec;76(12):1974-1979. doi: 10.1136/annrheumdis-2017-211585. Epub 2017 Aug 16. | |
| 25520476 |
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| ID | Term |
|---|---|
| D002805 | Chondrocalcinosis |
| D006073 | Gout |
| D010003 | Osteoarthritis |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D000070657 | Crystal Arthropathies |
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CRP, ESR, full blood count, creatinine, liver function tests, uric acid, 25OH vitamin D, PTH, calcium, magnesium, lipid profile, glycemia.
| Progression of osteophites assessed by ultrasound | Osteophytes will be assessed using the OMERACT Ultrasound Scoring System for Osteophytes. Each site will be graded from 0 to 3 and summed across all evaluated joints to obtain a total osteophyte score. The measure will be assessed longitudinally to evaluate changes over time. | Baseline and every 6 months up to 10 years |
| From baseline every 6 months up to ten years |
| Synovitis Score Assessed by Global OMERACT-EULAR Synovitis Score (GLOESS) | Synovitis will be evaluated thanks to Global OMERACT-EULAR Synovitis Score (GLOESS). Ultrasound evaluation will be performed on clinically relevant joints and anatomical structures as determined by the treating physician. | Baseline and every 6 months up to 10 years |
| Tenosynovitis Score Assessed by OMERACT Ultrasound Scoring System | Tenosynovitis will be assessed using the OMERACT ultrasound scoring system on a semi-quantitative scale. Ultrasound evaluation will be performed on clinically relevant joints and anatomical structures as determined by the treating physician. | Baseline and every 6 months up to 10 years |
| Joint Effusion Score Assessed by Ultrasound | Joint effusion will be assessed using ultrasound on a semi-quantitative scale from 0 to 3. The joints to be evaluated will be selected according to the clinician's judgement | Baseline and every 6 months up to 10 years |
| Number of Tender Joints Assessed Using 68-Joint Count | The number of tender joints will be assessed using the 68-joint count method. | Baseline and every 6 months up to 10 years |
| Number of Swollen Joints Assessed Using 66-Joint Count | The number of swollen joints will be assessed using the 66-joint count method. | Baseline and every 6 months up to 10 years |
| Physician Global Assessment of Disease Activity | Disease activity will be assessed by the physician using a visual analog scale (0-100) | Baseline and every 6 months up to 10 years |
| Patient Global Assessment of Disease Activity | Scale (0-100) | Baseline and every 6 months up to 10 years |
| Patient-Reported Pain Assessed by Visual Analog Scale (VAS) | Scale (0-100) | Baseline and every 6 months up to 10 years |
| Patient-Reported Global Health Status | Scale (0-100) | Baseline and every 6 months up to 10 years |
| Functional Disability Assessed by Health Assessment Questionnaire (HAQ) | Score (0-3) for every item of the questionnaire, then the sum is calculated | From baseline every six months up to ten years |
| Cardiovascular Risk Assessed by SCORE2 and SCORE2-OP | Cardiovascular risk will be estimated using SCORE2 and SCORE2-OP algorithms, depending on patient's age. Both scores express a percentage (%) of the 10-year risk. | At baseline and if clinically indicated during follow-up up to ten years |
| Incidence of Cardiovascular Events | Occurrence of cardiovascular events recorded during follow-up (Number of events / % of patients) | During the 10 years follow up |
| Distribution of Clinical Phenotypes of CPPD and Gout | Phenotypes of calcium pyrophosphate deposition (CPPD) disease and gout will be classified according to established classification criteria (ACR/EULAR recommendations and G-CAN consensus respectively). | Baseline |
Measurment of intima-media thickness (CMIT) at ultrasound of carothid arteries performed as part of routine care will be collected to assess increased atherosclerotic risk. The European Society of Cardiology (ESC) often highlights CMIT> 0.9 as a critical threshold to determine an increased risk |
| As clinically indicated during follow-up up to ten years from baseline |
| Assessment of joint damage using X-ray, CT or MRI | On radiographs and CT, osteoarthritis severity will be evaluated based on osteophytes, joint space narrowing, and subchondral bone changes, using a semi-quantitative grading scale (e.g., Kellgren-Lawrence grade 0-4 for radiographs). On MRI, joint damage will be assessed including cartilage integrity and other structural abnormalities using appropriate semi-quantitative scoring systems (WORMS, MOAKS) | As clinically indicated during follow-up from baseline up to ten years |
| Histological and Molecular Characteristics of Joint Tissues in Patients Undergoing Arthroplasty | Biological samples (bone, cartilage, synovial membrane, ligaments/tendons, synovial fluid) collected during clinically indicated arthroplasty procedures will be analyzed using histology, immunohistochemistry, and Raman spectroscopy to assess tissue morphology, inflammatory features, and crystal deposition. | At time of surgery (as applicable) |
| Coronary stenosis at Coronary Computed Tomography Angiography (CCTA) | The presence of coronary stenosis at Coronary Computed Tomography Angiography (CCTA) will be recorded. An obstructive stenosis occupies more than 50% of the lumen. | As clinically indicated during follow up up to ten years |
| Assessment of bone mineral density at DEXA | Bone mineral density (BMD) will be measured using dual-energy X-ray absorptiometry at the lumbar spine and proximal femur. Results will be expressed in g/cm², T-scores, and Z-scores. Bone status will be classified as normal, osteopenia, or osteoporosis according to World Health Organization criteria. | As clinically indicated from baseline up to ten years follow up |
| Evaluation of CPP crystal and MSU crystal deposition at X-ray, TC or MRI | CPP and MSU crystal deposition in articular or periarticular structures at other imaging modalities (X-rays, CT scans, MRI) will be qualitatively assessed and documented as presence/absence. | As clinically indicated from baseline up to ten years follow up |
| Background |
| Hammer HB, Iagnocco A, Mathiessen A, Filippucci E, Gandjbakhch F, Kortekaas MC, Moller I, Naredo E, Wakefield RJ, Aegerter P, D'Agostino MA. Global ultrasound assessment of structural lesions in osteoarthritis: a reliability study by the OMERACT ultrasonography group on scoring cartilage and osteophytes in finger joints. Ann Rheum Dis. 2016 Feb;75(2):402-7. doi: 10.1136/annrheumdis-2014-206289. Epub 2014 Dec 17. |
| 22984169 | Background | Naredo E, D'Agostino MA, Wakefield RJ, Moller I, Balint PV, Filippucci E, Iagnocco A, Karim Z, Terslev L, Bong DA, Garrido J, Martinez-Hernandez D, Bruyn GA; OMERACT Ultrasound Task Force*. Reliability of a consensus-based ultrasound score for tenosynovitis in rheumatoid arthritis. Ann Rheum Dis. 2013 Aug;72(8):1328-34. doi: 10.1136/annrheumdis-2012-202092. Epub 2012 Sep 14. |
| 35388274 | Background | Horta-Baas G. Patient-Reported Outcomes in Rheumatoid Arthritis: A Key Consideration for Evaluating Biosimilar Uptake? Patient Relat Outcome Meas. 2022 Mar 30;13:79-95. doi: 10.2147/PROM.S256715. eCollection 2022. |
| 30770518 | Background | Duarte-Garcia A, Leung YY, Coates LC, Beaton D, Christensen R, Craig ET, de Wit M, Eder L, Fallon L, FitzGerald O, Gladman DD, Goel N, Holland R, Lindsay C, Maxwell L, Mease P, Orbai AM, Shea B, Strand V, Veale DJ, Tillett W, Ogdie A. Endorsement of the 66/68 Joint Count for the Measurement of Musculoskeletal Disease Activity: OMERACT 2018 Psoriatic Arthritis Workshop Report. J Rheumatol. 2019 Aug;46(8):996-1005. doi: 10.3899/jrheum.181089. Epub 2019 Feb 15. |
| 2242058 | Background | Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, Brown C, Cooke TD, Daniel W, Gray R, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum. 1990 Nov;33(11):1601-10. doi: 10.1002/art.1780331101. |
| 2025304 | Background | Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K, Brown C, Cooke TD, Daniel W, Feldman D, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum. 1991 May;34(5):505-14. doi: 10.1002/art.1780340502. |
| 3741515 | Background | Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986 Aug;29(8):1039-49. doi: 10.1002/art.1780290816. |
| 36122187 | Background | Sirotti S, Becce F, Sconfienza LM, Terslev L, Naredo E, Zufferey P, Pineda C, Gutierrez M, Adinolfi A, Serban T, MacCarter D, Mouterde G, Zanetti A, Scanu A, Moller I, Novo-Rivas U, Largo R, Sarzi-Puttini P, Abhishek A, Choi HK, Dalbeth N, Pascart T, Tedeschi SK, D'Agostino MA, Iagnocco A, Keen HI, Scire CA, Filippou G. Reliability and Diagnostic Accuracy of Radiography for the Diagnosis of Calcium Pyrophosphate Deposition: Performance of the Novel Definitions Developed by an International Multidisciplinary Working Group. Arthritis Rheumatol. 2023 Apr;75(4):630-638. doi: 10.1002/art.42368. Epub 2023 Jan 19. |
| 37495237 | Background | Abhishek A, Tedeschi SK, Pascart T, Latourte A, Dalbeth N, Neogi T, Fuller A, Rosenthal A, Becce F, Bardin T, Ea HK, Filippou G, Fitzgerald J, Iagnocco A, Liote F, McCarthy GM, Ramonda R, Richette P, Sivera F, Andres M, Cipolletta E, Doherty M, Pascual E, Perez-Ruiz F, So A, Jansen TL, Kohler MJ, Stamp LK, Yinh J, Adinolfi A, Arad U, Aung T, Benillouche E, Bortoluzzi A, Dau J, Maningding E, Fang MA, Figus FA, Filippucci E, Haslett J, Janssen M, Kaldas M, Kimoto M, Leamy K, Navarro GM, Sarzi-Puttini P, Scire C, Silvagni E, Sirotti S, Stack JR, Truong L, Xie C, Yokose C, Hendry AM, Terkeltaub R, Taylor WJ, Choi HK. The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease. Ann Rheum Dis. 2023 Oct;82(10):1248-1257. doi: 10.1136/ard-2023-224575. Epub 2023 Jul 26. |
| 34120185 | Background | SCORE2-OP working group and ESC Cardiovascular risk collaboration. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions. Eur Heart J. 2021 Jul 1;42(25):2455-2467. doi: 10.1093/eurheartj/ehab312. |
| 34120177 | Background | SCORE2 working group and ESC Cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J. 2021 Jul 1;42(25):2439-2454. doi: 10.1093/eurheartj/ehab309. |
| 37143665 | Background | Wang Y, Deng X, Zhang X, Geng Y, Ji L, Song Z, Zhang Z. Presence of tophi and carotid plaque were risk factors of MACE in subclinical artherosclerosis patients with gout: a longitudinal cohort study. Front Immunol. 2023 Apr 18;14:1151782. doi: 10.3389/fimmu.2023.1151782. eCollection 2023. |
| 33798500 | Background | Dalbeth N, Gosling AL, Gaffo A, Abhishek A. Gout. Lancet. 2021 May 15;397(10287):1843-1855. doi: 10.1016/S0140-6736(21)00569-9. Epub 2021 Mar 30. |
| 34523251 | Background | Bashir M, Sherman KA, Solomon DH, Rosenthal A, Tedeschi SK. Cardiovascular Disease Risk in Calcium Pyrophosphate Deposition Disease: A Nationwide Study of Veterans. Arthritis Care Res (Hoboken). 2023 Feb;75(2):277-282. doi: 10.1002/acr.24783. Epub 2022 Oct 11. |
| 35613842 | Background | Tedeschi SK, Huang W, Yoshida K, Solomon DH. Risk of cardiovascular events in patients having had acute calcium pyrophosphate crystal arthritis. Ann Rheum Dis. 2022 Aug 11;81(9):1323-1329. doi: 10.1136/annrheumdis-2022-222387. |
| 16396700 | Background | Salaffi F, De Angelis R, Grassi W; MArche Pain Prevalence; INvestigation Group (MAPPING) study. Prevalence of musculoskeletal conditions in an Italian population sample: results of a regional community-based study. I. The MAPPING study. Clin Exp Rheumatol. 2005 Nov-Dec;23(6):819-28. |
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| D012216 |
| Rheumatic Diseases |
| D011686 | Purine-Pyrimidine Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |