DOI:
Original papers
DOI: 10.11152/mu-1193Clinical and ultrasound findings in patients with calcium pyrophosphate dihydrate deposition disease
Paulina Vele
1, Siao-Pin Simon
1,2, Laura Damian
2, Ioana Felea
2, Laura Muntean
1,2, Ileana Filipescu
1,2, Simona Rednic
1,21”Iuliu Haţieganu” University of Medicine and Pharmacy, 2Emergency County Hospital, Rheumatology Department, Cluj-Napoca, Romania
Received 27.08.2017 Accepted 03.12.2017 Med Ultrason
2018, Vol. 20, No 2, 159-163 Corresponding author: Paulina Vele
Rheumatology Department, 2-4 Clinicilor Street 400006, Cluj-Napoca, Romania
Phone: +40746-093655 E-mail: [email protected]
Introduction
Calcium pyrophosphate deposition (CPPD) disease is characterized by deposition of calcium pyrophosphate crystals inside the hyaline cartilage, fibrocartilage, and soft tissues [1,2]. The most common sites for CPPD are the meniscal fibrocartilage of the knee, hyaline cartilage of the femoral condyles, triangular fibrocartilage of the wrist, symphysis pubis discus, acromio-clavicular fibro- cartilage, and the hyaline cartilage of the shoulder, hip, and ankle [3,4].
The standard tool for diagnosis is synovial fluid anal- ysis with identification of calcium pyrophosphate (CPP) crystals by microscopy using compensated polarized light [5]. McCarty criteria used for a definite diagnosis of CPPD require the presence of CPP crystals in the syno- vial fluid analysis and typical radiographic calcifications [1]. The presence of a thin, parallel line with the articular surface (hyaline cartilage calcification) and/or punctate fibrocartilage calcification in knees, symphysis pubis, wrists, hips, elbows, and ankles is considered as evidence of CPPD [4,6].
Ultrasound (US) evaluation of CPPD is of great in- terest because of the high sensitivity and specificity of the method compared to conventional radiography. US was included in EULAR recommendations as an alterna- tive imaging technique in the CPPD diagnostic approach [2,7,8]. Three US patterns of CPP deposits are described:
a thin hyperechoic band, parallel to the surface on the Abstract
Aim: To evaluate the presence and distribution of calcium pyrophosphate (CPP) deposits in joints commonly affected by CPP deposition (CPPD) disease (acromio-clavicular, gleno-humeral, wrists, hips, knees, ankles, and symphysis pubis joints) using ultrasound (US). Material and methods: Thirty consecutive patients fulfilling McCarty diagnostic criteria for CPPD were consecutively enrolled in the study. The data registered using the US included the affected joints, the calcification site, and the pattern of calcification (thin hyperechoic bands, parallel to the surface of the hyaline cartilage, hyperechoic spots, and hyperechoic nodular or oval deposits). The presence of CPP crystals in knees was confirmed by polarized light microscopy examination of the synovial fluid and radiographs of the knees were performed in all patients. Results: In 30 patients, 390 joints were scanned, (13 joints in every patient). The mean±standard deviation number of joints with US CPPD evidence per patient was 2.93±1.8 (range 1-9). The knee was the most common joint involved both clinically and using US examination.
The second US pattern (with hyperechoic spots) was the most frequent. Fibrocartilage calcifications were more common than hyaline calcification. Using radiography as reference method, the sensitivity and specificity of US for diagnosis CPPD in knees was 79.31%, 95CI(66.65%-88.83%), and 14.29%, 95CI(1.78%-42.81%), respectively. Conclusions: The knee is the most frequent joint affected by CPPD. The second ultrasound pattern is the most common. CPPD affects the fibrocartilage to a greater extent than the hyaline cartilage.
Keywords: calcium pyrophosphate dihydrate; ultrasonography; radiography
inside of the hyaline cartilage; hyperechoic spots in the fibrocartilage; and hyperechoic nodular or oval deposits in bursae and articular recesses [7,9].
Due to the absence of histopathological correlations, no agreement in US evaluation in CPPD exists. It is not clear which joints should be screened, which definition should be used, and if the US changes are specific for CPPD.
The aim of this study was to systematically exam- ine by US all the joints potentially affected by CPPD in patients with CPPD following the McCarty criteria, in order to assess the presence and distribution of the CPP deposits. Our secondary aim was to correlate the clinical data with US findings.
Material and methods
This prospective study was performed in the Rheu- matology Department, Emergency Clinical County Hos- pital Cluj-Napoca, Romania, between January 2015 and January 2017. Patients who fulfilled McCarty diagnos- tic criteria for CPPD were consecutively enrolled in the study. Exclusion criteria were patients under 18 years of age, the presence of gout or/and other inflammatory rheu- matic diseases.
Clinical examination
All patients were evaluated by the same rheumatolo- gist. Data about age (years), sex, weight (kg), height (m2), body mass index (BMI), type of joint involvement (monoarticular – 1 joint, oligoarticular – 2-4 joints, pol- yarticular ≥5 joints), the form of arthritis (acute, chronic), and symptoms duration were recorded.
US examination
US examinations were performed using an Esaote My Lab25 Gold with 5-10 and 10-18 MHz linear probes by the same examiner. The US scanning technique was performed according to the standard musculoskeletal ultrasound guidelines [10,11]. In every patient 13 joints were systematically examined: the acromio-clavicular joints (longitudinal scans), the gleno-humeral joints (posterior transverse scan for posterior glenoid labrum), wrists for the triangular fibrocartilage (longitudinal scan with the wrist in pronation and slight radial deviation, on the lateral aspect of the wrist), the hips (anterior longitu- dinal and transverse scan with the hip in a neutral posi- tion for hyaline cartilage and fibrocartilage), the knees (anterior scans with the knee in maximum flexion for the hyaline cartilage and medial and lateral scans with the knee flexed at 300), the ankles (anterior and transverse scans for the hyaline cartilage) and the symphysis pubis (transverse scan for the fibrocartilage).
The protocol included searching for calcific deposits on cartilage and fibrocartilage. Frediani’s US patterns [7] were
used for detecting evidence of CPPD: pattern 1 – thin hyper- echoic bands, parallel to the surface of the hyaline cartilage;
pattern 2 – thin hyperechoic spots in fibrocartilage; and pat- tern 3 – homogeneous hyperechoic nodular or oval deposits in the fibrocartilage. (fig 1). The US registered data included the affected joint, the pattern of calcification (1, 2, or 3) and the calcification site (fibrocartilage, hyaline cartilage).
Radiographic examination
A radiologist experienced in evaluating musculoskel- etal system disorders studied the radiographic images.
Hyaline cartilage calcification and punctate fibrocartilage calcification in at least one of the joints were considered proof of CPPD. Hyaline cartilage calcification was defined as a radiodense linear, parallel with the subchondral bone, in the middle zone of the cartilage, while fibrocartilage calcification is described as more dense, punctuate [6,12].
The synovial fluid analysis was performed using po- larized light microscopy. Crystals with a parallelepipedic or rhomboid shape and weak birefringence were consid- ered as CPP crystals.
All patients included in the study gave their consent for participation, and the University Ethics Committee approved this research.
Statistical analysis was performed using Microsoft Excel. Results are presented as a mean±standard devia- tion (SD). We considered a level of p<0.05 statistically significant.
Results
Thirty patients with CPPD were included in the study.
The demographics and clinical data of the enrolled pa- tients are detailed in Table I. All patients had knee ef- fusion that was available for aspiration and for synovial fluid analysis.
Table I. General characteristics of study participants
Variable n=30
Age (years) 64.66±9.77
Height (m) 1.68±0.09
Weight (kg) 80.2±13.64
BMI (kg/m2) 28.36±4.8
Sex ratio of male: female 12:18
Tender joint count (TJC) 3.43±3.11
Swollen joint count (SJC) 1.76±1.13
Disease duration, weeks 15.53±21.87
Monoarticular disease 10 (33.3%)
Oligoarticular disease 13 (43.33%)
Polyarticular disease 7 (23.34%)
Acute arthritis 23 (76.66%)
Chronic arthritis 7 (23.34%)
Values are express as mean±standard deviation or as number of patients (%); BMI – body mass index.
A total of 390 joints were scanned, in 30 patients. US calcifications were found in 88 joints (22.56%).
Distribution of affected joints
The mean±SD number of joints with US evidence of CPPD per patient was 2.93±1.8 (range 1-9) (Table II).
The most frequent CPP deposition was found in the knee followed by the wrist. Symphysis pubis involve- ment was found in two patients and all these two patients had a mean average of 5.5 joints affected by CPPD. Data regarding the distribution of the joints with CPPD evi- dence on US are summarized in Table III.
US pattern and CPP deposits sites
The second US pattern was the most common, fol- lowed by the first and the third pattern (Table IV). In ad- dition, the second pattern was more frequent in patients with monoarticular or oligoarticular disease and in pa- tients with acute arthritis (fig 2, Table IV).
Radiographic evidence of CPPD were found in 46 (60%) knees (in 16 knees bilateral and in 14 unilateral).
All patients had at least one knee joint with radiographic CPPD proof. Using radiography as the reference meth- od, the sensitivity and specificity of US for diagnosis Table II. The mean US joint involvement per patient
Clinical forms Mean US joint involve-
ment p-value
Acute arthritis 2.78±1.56 p=0.08
Chronic arthritis 3.85±6.14
Monoarticular disease 3.12±2.07 p<0.05 Oligoarticular disease 2.38±0.96
Polyarticular disease 4.14±2.34 Values are express as mean±standard deviation
Table III. Joint distribution of CPP deposits evaluated by US Number of joints with CPPD Joints Total Bilateral Unilateral
Acromio-clavicular 7 3 1
Gleno-humeral 0 0 0
Wrist 17 7 3
Hip 3 1 1
Knee 58 28 2
Ankle 1 0 1
Symphysis pubis 2
Table IV. The US patterns and calcification sites
Variable N (%)
Pattern of calcification patients
I – thin hyperechoic band 10 (33.33)
II – hyperechoic spots 19 (63.33)
III – hyperechoic nodular or oval deposits 1 (3.34) Site of CPP deposits at all the joints joints
Fibrocartilage 62 (70.45)
Hyaline cartilage 22 (25)
Fibrocartilage and
hyaline cartilage 4 (4.55)
Site of CPP deposits at the knee joint joints
Medial meniscus 19 (32.76)
Lateral meniscus 14 (24.13)
Hyaline cartilage 21 (36.20)
Fibrocartilage and
hyaline cartilage 4 (6.89)
N = number of patients or joints (%)
Fig 1. Radiographic and ultrasonography images of calcium pyrophosphate deposition: a) Conventional radiography showing me- niscus calcifications (arrow); b) knee joint, transversal scans showing hyperechoic spots in the hyaline cartilage (arrow); c) knee joint, longitudinal scan of the medial compartment showing hyperechoic spots in the medial meniscus (arrow).
Fig 2. Ultrasonographic pattern of calcium pyrophosphate depo- sition distribution according to clinical findings (details inside the main text).
CPPD in knees was 79.31%, 95CI(66.65%-88.83%) and 14.29%, 95CI(1.78%-42.81%), respectively.
Discussions
US is a useful, inexpensive, noninvasive, quick tool for detecting even small deposits of CPPD, with high specificity and sensitivity, and without irradiation risks.
There are some studies, which evaluate CPPD by US, the most common at the knee joint, and only a few at multi- ple sites [8,9,13-17]. There is no agreement about which joints should be screened and no universal accepted ultra- sound definition for CPPD. The most used definition for CPPD are those described by Frediani et al [7]. Recently, the Outcome Measures in Rheumatology (OMERACT) defined the US characteristics of CPPD in the fibrocarti- lage, hyaline cartilage, tendon and synovial fluid (reliable in the assessment of the knee fibrocartilage and hyaline cartilage) together with intra and interobserver reliabil- ity. The new definitions included the form, the shape, lo- calization, and the behavior at dynamic scanning of the CPPD deposits [18].
To our knowledge, this is the first study which evalu- ates the 13 possible sites for CPPD using US.
The result regarding the clinical presentation, in terms of monoarthritis and oligoarthritis, also the female predominance were in agreement with other studies. The mean age in our study was lower compared with other studies [17,19,20] but higher than Ellabban et al study [16]. Regarding the presentation form, as acute or chron- ic arthritis, our results were not in agreement with Filip- pou et al results. They found the chronic arthritis form as the most common [21]. In the same study, in which they assessed the extent and distribution of CPP deposits in 2-5 metacarpophalangeal joints, wrists, knees, Achilles tendon, and plantar fascia the authors found also the knee to be the most common joint affected by CPPD [21]. The same results were obtained when conventional radiogra- phy was used as a tool of investigation in the Abhishek et al study [22].
Filippou’s et al study found the mean number of US affected joints (4.7) higher comparative with our study (2.93) probably because of different joints scanned and the multiple sites examined at the knee level. In addition, they did not find any correlation between clinical presentation and the number of involved sites by CPPD, contrary to our results. We observed that our patients who presented with an acute arthritis form or polyarticular disease had a mean US joint involvement significantly higher compar- ing with Filippou et al [21]. Another interesting finding was the frequency of the second ultrasound pattern in pa- tients with monoarticular, oligoarticular disease and in pa-
tients with acute arthritis. Ellaban et al conducted a study at multiple sites in which examined the shoulders, elbow, wrist, and knee joint by using US. Similar to our study, the knee was the most affected joint and the second US pattern (hyperechoic spots) was the most frequent [16]
but no correlation between clinical data and US findings were found. The higher frequency of knee involvement in CPPD was found also in other studies [8,13].
We found no US study to examine the symphysis pubis in CPPD patients. In our study, the prevalence of US symphysis pubis involvement was 6.66%. In a radio- graphic study of Abhishek et al the prevalence of CPPD in symphysis pubis was 3.6%. In another two computed tomography studies, the prevalence of CPPD in symphy- sis pubis was 21.1% [23], and 12.5-27.5 % [24]. Ramon- da et al found in a radiographic study a prevalence for symphysis pubis involvement, of 33.1% [19].
In agreement with other studies, we found the fibro- cartilage as the most frequent site of CPP deposits per total and also at the knee level [16,21]. With regard to medial versus lateral meniscus involvement by CPPD de- posits, we found no significant differences between two sites, similar to Filippou et al [21].
Our results demonstrated high sensitivity and low specificity for US when radiography was considered as standard. These findings are not in agreement with other studies, which found a high specificity [3,16].
Our study has some limitations. First, the study has a small number of patients. Also, we did not assess the in- tra and interobserver reliability for US and radiographic findings. The presence of CPP crystals was confirmed by microscopy only in the knee joints and we only as- sumed that in other joints the deposits are formed by CPP (this is, in fact, the main limitation of all other published studies). The lack of comparison of US with computer tomography and magnetic resonance imaging findings is another limitation of our study. Also, we did not evaluate by radiography all the joints scanned with US, especially due to the high dose of radiation need for all these sites.
Conclusions
US examination is a useful imaging technique to de- termine the distribution of CPP deposits. This is impor- tant especially because CPPD generally are present in more than one joint, not strictly related to clinical presen- tation. The knee joint and the wrist are the most common joints involved by CPPD, the hyperechoic spots is the most frequent US pattern and fibrocartilage is more fre- quently affected compared to the hyaline cartilage.
Conflict of interest: none.
References
1. McCarty DJ. Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease – nomenclature and diagnostic criteria. Ann Int Med 1977;87:240-242.
2. Zhang W, Doherty M, Bardin T, et al. European League Against Rheumatism recommendations for calcium py- rophosphate deposition. Part I: Terminology and diagnosis.
Ann Rheum Dis 2011;70:563-570.
3. Foldes K. Knee chondrocalcinosis: an ultrasonographic study of the hyaline cartilage. Clin Imaging 2002;26:194-196.
4. Steinbach LS. Calcium pyrophosphate dihydrate and cal- cium hydroxyapatite crystal deposition diseases: imaging perspectives. Radiol Clin North Am 2004;42:185-205.
5. Swan A, Amer H, Dieppe P. The value of synovial fluid as- says in the diagnosis of joint disease: a literature survey.
Ann Rheum Dis 2002;61:493-498.
6. Genant HK. Roentgenographic aspects of calcium pyroph- osphate dihydrate crystal deposition disease (pseudogout).
Arthritis Rheum 1976;19 (Suppl 3):307-328.
7. Frediani B, Filippou G, Falsetti P, et al. Diagnosis of cal- cium pyrophosphate dihydrate crystal deposition dis- ease: ultrasonographic criteria proposed. Ann Rheum Dis 2005;64:638-640.
8. Gutierrez M, Di Geso L, Salaffi F, et al. Ultrasound detec- tion of cartilage calcification at knee level in calcium py- rophosphate deposition disease. Arthritis Care Res (Hobo- ken) 2014;66:69-73.
9. Filippou G, Frediani B, Gallo A, et al. A “new” technique for the diagnosis of chondrocalcinosis of the knee: sensitiv- ity and specificity of high-frequency ultrasonography. Ann Rheum Dis 2007;66:1126-1128.
10. Backhaus M, Burmester GR, Gerber T, et al. Guidelines for musculoskeletal ultrasound in rheumatology. Ann Rheum Dis 2001;60:641-649.
11. Möller I, Janta I, Backhaus M, et al. The 2017 EULAR standardised procedures for ultrasound imaging in rheuma- tology. Ann Rheum Dis 2017;76:1974-1979.
12. Paparo F, Fabbro E, Ferrero G, et al. Imaging studies of crystalline arthritides. Reumatismo 2012;63:263-275.
13. Ruta S, Catay E, Marin J, Rosa J, García-Monaco R, Sori- ano E. Knee effusion: ultrasound as a useful tool for the de- tection of calcium pyrophosphate crystals. Clin Rheumatol 2016;35:1087-1091.
14. Grassi W, Meenagh G, Pascual E, Filippucci E. “Crystal clear” sonographic assessment of gout and calcium py- rophosphate deposition disease. Semin Arthritis Rheum 2006;36:197-202.
15. Gamon E, Combe B, Barnetche T, Mouterde G. Diagnos- tic value of ultrasound in calcium pyrophosphate deposi- tion disease: a systematic review and meta-analysis. RMD Open 2015;1:e000118.
16. Ellabban AS, Kamel SR, Omar HA, El-Sherif AM, Abdul- Magied RA. Ultrasonographic diagnosis of articular chon- drocalcinosis. Rheumatol Int 2012;32:3863-3868.
17. Louthrenoo W, Sukitawut. Calcium pyrophosphate dihy- drate crystal deposition: a clinical and laboratory analysis of 91 Thai patients. J Med Assoc Thai 1999;82:569-576.
18. Filippou G, Scirè CA, Damjanov N, et al. Definition and Reliability Assessment of Elementary Ultrasonographic Findings in Calcium Pyrophosphate Deposition Disease: A Study by the OMERACT Calcium Pyrophosphate Depo- sition Disease Ultrasound Subtask Force. J Rheumatol 2017;44:1744-1749.
19. Ramonda R, Musacchio E, Perissinotto E, et al. Preva- lence of chondrocalcinosis in Italian subjects from north- eastern Italy. The Pro. V. A. (PROgetto Veneto Anziani) study. Clin Exp Rheumatol 2009;27:981-984.
20. Rho YH, Zhu Y, Zhang Y, Reginato AM, Choi HK. Risk factors for pseudogout in the general population. Rheuma- tology 2012;51:2070-2074.
21. Filippou G, Filippucci E, Tardella M, et al. Extent and dis- tribution of CPP deposits in patients affected by calcium pyrophosphate dihydrate deposition disease: an ultrasono- graphic study. Ann Rheum Dis 2013;72:2836-1839.
22. Abhishek A, Doherty S, Maciewicz R, Muir K, Zhang W, Doherty M. Evidence of a systemic predisposition to chon- drocalcinosis and association between chondrocalcinosis and osteoarthritis at distant joints: A cross-sectional study.
Arthritis Care Res (Hoboken) 2013;65:1052-1058.
23. Patel T, Ryan L, Dubois M, et al. The prevalence of chon- drocalcinosis of the symphysis pubis on CT scan and corre- lation with calcium pyrophosphate dihydrate crystal depo- sition disease. Clin Rheumatol 2016;35:771-773.
24. Stensby JD, Lawrence DA, Patrie JT, Gaskin CM. Preva- lence of asymptomatic chondrocalcinosis in the pelvis.
Skeletal Radiol 2016;45:949-954.
