**2. Familial Mediterranean Fever**

Familial Mediterranean fever (FMF) is an autoinflammatory autosomal recessive disorder that usually begins before the age of 20 and causes recurrent fever and serosal inflammation of the abdomen, lungs, and joints, leading to severe pain [3]. FMF is commonly seen in people of Mediterranean and Middle Eastern descent, including Jews, Armenians, Arabs, Kurds, Greeks, Turks, Iranians, and Italians. It is caused by mutations in the Mediterranean fever (MEFV) gene, the product of which, the pyrin protein, is involved in the control of inflammation [4].

Arthralgia of the large joints of lower extremities including hip, knee, or ankle joints is common. The patient often presents with severe pain in one joint. Very rarely, multiple joints are affected

simultaneously. The pattern of involvement of a large, lower extremity joint conjures a clinical resemblance to spondyloarthropathy (SpA). Indeed, the incidence of SpA in FMF patients was reported to be up to 7% of the total patient population. Moreover, up to 27% of patients with sacroiliitis had joint involvement [5] and a significantly higher frequency of M694V. Nonetheless, these patients maintained low HLA-B27 positivity [6].

Enthesitis, which is the hallmark of SpA, was also reported in FMF, mainly in the calcaneal insertion of the Achilles tendon, the plantar fascia, and/or the long plantar ligament [7]. The characteristic MRI features of this ankle enthesitis reported in SpA are insertional bone marrow edema (BME), thickening and high signal intensity of the affected tendon, and increased synovial fluid in the adjacent bursa [8]. A unique MRI feature in FMF is significant calcaneal BME along the insertion site of the long plantar tendon—an imaging example is given in Figure 1 [9]. This ankle enthesopathy of FMF patients is related to exertional leg pain that is a common debilitating symptom of FMF.

**Figure 1.** MRI in Familial Mediterranean fever (FMF). Sagittal T2 weighted with fat saturation image of an ankle of an 18 years old male with known FMF and exertional leg pain. There is characteristic enthesitis (black arrowhead) with extensive calcaneal bone marrow edema (white arrow heads) at the insertion of the long plantar tendon.

#### **3. Behçet Disease**

Behçet disease (BD) is an auto-inflammatory systemic vasculitis of unknown etiology. BD is characterized by mucocutaneous manifestations (i.e., recurrent oral and genital ulcerations), ocular manifestations (especially chronic relapsing uveitis and systemic vasculitis involving arteries and veins of all sizes), and peripheral arthritis [10]. Although BD does not follow a Mendelian inheritance, it is associated with HLA-B51/B5, and carriers are at high risk of developing BD compared to non-carriers [11].

Arthritic manifestation is one of the minor manifestations and it is usually overlooked. Joint involvement is typically non-erosive and non-deforming arthritis, seen in 50% of BD patients [12,13]. The most commonly involved joints include the knees, ankles, elbows, wrists, fingers, and toes [13,14]. Erosive forms of arthritis in BD are uncommon, and the most affected locations are the axial joint (sacroiliac), enthesis (calcaneal), and peripheral joints, such as metatarsophalangeal and interphalangeal joints of the feet [15]. Repeated attacks of synovitis in the same joint leads to a destructive arthritis resembling the radiological changes of rheumatoid arthritis. There are various variable reports on the

prevalence of sacroiliitis and enthesitis in BD. While some report high prevalence, others claim that there is only rare involvement [15–17].

The coexistence of BD and SpA, as well as the presence of clinical overlap between BD and some SpA subgroups (i.e., inflammatory bowel disease and reactive disease) suggest a potential common pathogenesis. However, this has not yet been proven.

### **4. Crystal Deposition**

In terms of prevalence, crystal-induced arthritides are the most common diseases on the autoinflammatory spectrum [18]. The establishment of their inflammatory nature dates back less than 20 years [19,20]. Since then, the capacity of both mono-sodium urate (MSU) and calcium species to activate the NLRP3 inflammasome [21], as well as the production and secretion of pro-inflammatory cytokines, has been widely accepted [22,23]. To date, the gold standard for diagnosis remains the demonstration of crystals in synovial fluid [24,25]. As joint aspiration is an invasive procedure, the need for improved diagnostic imaging is well established. Over the last few years, a number of imaging studies have greatly advanced the detection of MSU, calcium pyrophosphate (CPP), and basic calcium species (BCP). A common denominator of all crystal deposition diseases, however, is the fact that deposition on imaging should not be equated with disease. For CPP, community-based cross-sectional studies estimate the prevalence of deposition between 7.0% [26] and 8.1% [27], while estimates of symptomatic disease are well below 1% of the general population [28]. Asymptomatic hyperuricemia is estimated to affect approximately 2.6% of the general population [29], while the prevalence of symptomatic gout lies much lower, between 0.46% [28] and 1.1% [29]. Therefore, imaging of crystal deposition disease poses unique challenges, which are addressed in the following paragraphs.

#### **5. Gout**

Historically, radiography has been the main imaging modality for investigating gout [30]. However, as a radiograph is only able to reliably capture advancedstages of the disease, recent years have seen a shift towards cross-sectional imaging techniques. One of the most available, inexpensive, and non-invasive imaging techniques in point-of-care rheumatology is the ultrasound. Using ultrasounds, MSU depositions may be demonstrated in tendons, periarticular soft tissue, and articular cartilage (i.e., the double-contour sign) [31] with high sensitivity and specificity [32,33]. Longitudinal studies have also demonstrated the capacity of ultrasound to monitor diseases [34]. Additionally, ultrasounds can visualize erosions, joint effusion, and synovitis as surrogates of inflammation [35]. Dual-energy computed tomography (DECT) has become a well-established tool in gout imaging and was included in the 2018 update of the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria [24]. Its specificity and sensitivity have estimated to be 93.6% and 84.7% in a recent meta-analysis [36], yet its diagnostic accuracy may be lower in cases of recent onset gout [37,38]. Apart from establishing the diagnosis, DECT can be used as a tool for quantification of urate burden [39]. As such, it may be applied as a surveillance tool in urate lowering therapy [40]. Additionally, there is evidence that DECT may be useful to depict bone marrow edema, allowing for a more direct visualization of acute inflammation [41]. Clinical imaging examples of gout are supplied in Figure 2.

**Figure 2.** Multimodality imaging for gout. (**Left**): Virtual calcium subtraction imaging from dual-energy computed tomography. The arrowhead indicates bone marrow edema in the first metacarpal head. (**Right**): Ultrasound image of the same patient. The arrow indicates double-contour sign and arrowheads indicate synovitis on the power Doppler.
