**6. Calcium Pyrophosphate Dihydrate Deposition (CPPD)**

The most widely applied and accepted imaging modality for the diagnosis of CPPD remains radiography [25], where linear or flake-like calcifications in typical localizations (e.g., the hyaline cartilage of the knee, or the triangular fibrocartilage of the wrist) may be demonstrated. Nevertheless, CPPD imaging has seen a steady advance in cross-sectional imaging techniques in recent years. Already embedded in the 2015 EULAR recommendations for the diagnosis of CPPD [25], ultrasonography has gained increased attention in recent years. This has been facilitated by the establishment and preliminary validation of ultrasonographic criteria for CPPD by the dedicated Outcome Measures in Rheumatology (OMERACT) taskforce [42,43]. A major strength of ultrasonography in CPPD imaging is its capacity to visualize inflammation by demonstration of synovitis using a power Doppler [35]. Computed tomography (CT) has long been established as an imaging tool in CPPD manifestations at the axial skeleton, especially the atlanto-axial joint (crowned dens syndrome) [44], but recent studies have applied it to the wrist [45] and knee [46], thus putting a new focus on crystal depositions, not only in cartilage but also in ligaments. The use of DECT in the diagnosis of CPPD remains controversial. Although in vitro and in vivo studies show an encouragingly high capacity for differentiation between different calcium species [47–49], evidence of added diagnostic value of DECT vs. conventional CT remains sparse [50,51]. However, DECT may be a valuable tool for strengthening the understanding of the development of specific patterns of arthropathy in CPPD as it can be used to non-invasively detect tissue remodeling [52]. To date, evidence of the usefulness of MRI in CPPD imaging is sparse. In spinal imaging, MRI may be useful for assessing acute inflammation when CPP deposition is established using alternative imaging, such as CT [53]. Imaging examples from different modalities are given in Figure 3.

**Figure 3.** Multimodality imaging in Calcium Pyrophosphate Dihydrate Deposition (CPPD). (**Left**): Crowned dens syndrome with flake-like calcifications in the CT image (arrowhead) and concurring bone marrow edema on MRI (arrowhead). (**Right**): CPPD of the wrist, showing calcifications of the luno-triquetral ligament on radiography and additional calcifications of the scapho-lunate ligament on CT (arrowhead).

### **7. BCP and Mixed Crystal Disease**

Basic calcium deposition (BCP) comprises a heterogeneous spectrum of conditions associated with a number of different calcium containing crystal species, the most common of which is hydroxy-apatite deposition disease (HADD) [54]. In terms of imaging characteristics, BCP may be distinguished from CPP crystal deposition, both by localization and calcification morphology. While HADD typically manifests as circumscribed calcific deposits inside of tendons, especially at the tendons of the rotator cuff [55], CPP crystals are typically found in ligaments and hyaline or fibrocartilage as ill defined, flake-like depositions [56]. An example of a symptomatic BCP deposit is provided in Figure 4. The most commonly applied imaging modality is radiography, which is usually sufficient for visualizing these depositions. Identification of calcium deposition on MRI imaging can be challenging, but three-dimensional imaging allows for the direct visualization of invasion of the deposit into the bursa or bone. The size of the calcific deposit does not correspond with the intensity of symptoms [57]. Symptom onset is typically observed when resorption of the calcification commences [58]. In this phase, macrophages invade [59] and, as a result, local edema, redness, swelling, and tenderness may be observed. This can be accompanied by intense pain and decreased range of motion. During this phase, calcium crystals may enter the subacromial-subdeltoid bursa [55].

A special subtype of BCP is the Milwaukee (shoulder/knee) syndrome [60]. This rare arthropathy exhibits a rapidly progressive joint destruction, often affects older women, and is connected with rotator cuff tears [61]. Synovial fluid aspiration yields a mixture of calcium crystals (predominantly hydroxy-apatite) and sero-hematic synovial fluid with low leucocyte counts [62].

**Figure 4.** BCP deposition. (**Left**): White arrowheads indicate calcific deposition on radiography. (**Right**): Axial and 3D reconstructions of the same shoulder with better visualization of the depositions.

#### **8. Adult-Onset Still's Disease (AOSD)**

Still's disease is a rare systemic auto-inflammatory disease that often poses a diagnostic challenge to clinicians. Among the clinical features of the disease are arthralgia and arthritis, which typically concur with classical fever spikes. Joint involvement is considered a common manifestation and may be observed in at least two-thirds of affected patients. It may present at any joint, including the axial skeleton [63]. Biopsy of the synovium typically reveals non-specific synovitis [64] and synovial fluid analysis shows high cellularity with neutrophil predominance [65]. Although the arthritis is non-destructive in the majority of patients, approximately 30% of patients may develop erosions. In these patients, bilateral destruction of the carpus, with subsequent carpal ankylosis in the absence of erosive changes at the metacarpophalangeal and proximal interphalangeal joints, may be a valuable imaging feature for the distinction from rheumatoid arthritis [64]. Additionally, destructive arthritis of the distal interphalangeal joints in younger patients may be observed [66].

#### **9. SAPHO and CRMO**

The syndromes synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO)/chronic recurrent multifocal osteomyelitis (CRMO) are considered related diseases, characterized mainly by neutrophilic inflammation, skin eruptions, and osteitis with bone hypertrophy [67]. Alternatively, the diseases are sometimes termed chronic non-bacterial osteomyelitis (CNO) [68]. The distribution of disease involvement differs in children and adults [69]. While the former typically presents with lesions in the long tubular bones and less frequently the spine and clavicles [70,71], the latter usually presents with involvement of the anterior chest wall, spine, and pelvis [72]. As many affected patients are children or adolescents, MRI is widely applied in the imaging of this disease family and may reliably depict osteitis in commonly affected sites [73]. An imaging example is supplied in Figure 5. However, radiography, and especially CT, are superior in the detection of hyperostosis and osteosclerosis, which are both well-established imaging characteristics of SAPHO/CRMO [74]. In adults with primary manifestations at the axial skeleton, differentiation from axial spondyloarthritis (axSpA) can be challenging; however, a valuable diagnostic clue is that generally sclerosis is more pronounced in patients with SAPHO/CRMO [69]. This imaging feature represents an interesting pathophysiological bridge towards the related axSpA spectrum. The predominantly auto-immune (e.g., B- and T-cell mediated) inflammation of the entheses in axSpA and psoriatic arthritis [75] shares many characteristics with the predominantly neutrophilic osteitis of SAPHO/CRMO [76].

**Figure 5.** MRI in CRMO. Coronal T2 weighted with fat saturation images of a whole-body MRI in a 12 year old boy with chronic recurrent multifocal osteomyelitis (CRMO). There is evidence of bilateral bone marrow edema in the distal femur, distal/proximal tibia and talus, triradiate cartilage, and unilateral BME on the right distal radius (indicated by arrowheads. In the case of bilateral lesions, only one side was annotated).
