Background
Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory bone disease, characterized by sterile bone lesions due to an abnormal regulation of the innate immune response resulting in osteoclast differentiation and activation, osteolysis and bone remodeling [
1,
2]. It was first described in 1972 as an unusual form of subacute and chronic symmetrical osteomyelitis [
3]. Nowadays the term chronic nonbacterial osteomyelitis is preferred [
4,
5].
Incidence rate of CNO varies 1–4 per million children from different reports [
6] and an incidence of approximately 1:1,000,000 [
7] or 2–5% of all osteomyelitis cases [
8]. However, this may be underestimated due to low awareness. The average age of onset ranges between 7 and 12 years [
4,
9] with a preference for the female gender [
9,
10]. The disease is characterized by bone inflammation. The etiopathogenesis still remains unclear. It is believed to be polygenic and multifactorial leading to an imbalanced expression of anti-inflammatory/immunomodulating (IL-10 and IL-19) and proinflammatory (IL-1β, IL-6, TNF-α, IL-20) cytokines [
2,
11,
12].
Clinical presentation and severity of CNO vary significantly from asymptomatic subjects at one end to patients with multiple recurrent lesions with significant functional impact at the other end [
13,
14]. The cardinal feature is bone pain. Onset is often insidious and patients may or may not experience concomitant systemic symptoms including low-grade fever and generalized malaise [
9,
15]. About 30% of patients had unifocal disease at diagnosis but most of them developed new lesions during the follow-up period [
16]. Only 25–40% of individuals have symmetrical bone involvement [
4]. Finally, a subset of CNO patients exhibit extra-osseous inflammatory organ involvement, including psoriasis and palmoplantar pustulosis (~ 8%), severe acne (~ 10%) and inflammatory bowel disease (~ 10%) [
13,
14,
16,
17].
The diagnosis of CNO still remains a diagnosis of exclusion and a bone biopsy is often advocated to confirm the diseases. Imaging is becoming increasingly important in the diagnosis and follow-up of these patients [
18,
19]. Inflammatory lesions in CNO may be detected by conventional radiographs with low sensitivity [
20]. Computed tomography (CT) may show lytic lesion and sclerosis at a higher sensitivity than radiograph in CNO. Its use is limited due to the high radiation dose. Bone scintigraphy and positron emission tomography (PET)-CT are sometimes used to offer a whole-body level assessment in order to identify lesions simultaneously [
21]. However, both are radiation-based techniques. Whole-body magnetic resonance imaging (WB-MRI) represents the current gold standard in the diagnosis and management of CNO patients. It allows the assessment of multiple affected sites simultaneously through typical findings of marrow edema (hypointense on T1-weighted images and hyperintense on T2-weighted images, or short tau inverse recovery [STIR] during the active phase of the disease) [
22,
23]. MRI can also demonstrate associated periosteal reaction, soft tissue inflammation and transphyseal disease. In addition, clinically asymptomatic lesions, also known as “silent” lesions, can often be detected by MRI. WB-MRI is radiation-free and well suited for surveillance and monitoring of therapeutic response; however it requires sedation in younger children.
Recently the ChRonic nonbacterial Osteomyelitis MRI Scoring (CROMRIS) was developed as a standardized evaluation tool of WB-MRI by an international group of pediatric radiologists [
24]. It includes the most commonly described characteristics seen in children with CNO from MRI, such as signal intensity, size of signal abnormality within bone marrow, and associated features on MRI. Grading of severity of the findings was discussed by 11 pediatric radiologists through monthly conference calls and a consensus meeting and an atlas was created.
Based on this tool, we developed a radiological activity index (RAI-CROMRIS) to obtain a quantitative measure of bone involvement at multiple sites in individual patients with the aim to measure the “entire radiological burden” of the disease at a whole-body level.
Discussion
Whole-body MRI (WB-MRI) is one of the mainstays in the diagnosis and management of CNO patients. It is becoming the imaging modality of choice because of its sensitivity in detecting lesions and their characteristic pattern, as well as clinically silent lesions, without ionizing radiation [
29]. However, the issue of appropriate interpretation, particularly in children growing bones, has led a number of investigators to propose standardized MRI protocols and scoring systems with the aims to improve reproducibility and inter-examiner variability and, ultimately, diagnosis and staging of the disease [
30,
31]. Some of the available scoring systems have shown merits, but also some limitations and they have not been validated. One is an MRI score system for the osteitis lesions used in patients who met the criteria for SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis syndrome). This score ranges from 0 to 2 with score 0 defined as no bone marrow edema, osteal erosions or synovitis (with or without joint effusion); score 1 defined as the presence of one of these findings; and score 2 defined as the presence of 2 or more findings. In case of more than one osteitis lesion, the lesion with the highest score was used as reference for that patient [
30,
32]. In the RINBO index, points are assigned for each of four parameters of interest: the number of radiologic active lesions clustered into 3 categories as unifocal, paucifocal [2–4 lesions] and multifocal [5 or more lesions], the diameter of the largest lesion, the presence of extra medullary involvement, the presence of spinal involvement [
33]. Differently from the previous score, the RINBO generates a total score summing the score of the lesions. The main limitation is that the measurement of the size of lesions is not reported as relative to the size of each bone, which is more appropriate, particularly, in children.
We chose to use as a basis of a global quantitative radiological assessment the CROMRIS, a standardized grading of the different features of CNO lesions, irrespective of the bone involved, recently designed by Zhao et al. [
24]. It is based on CNO features previously used to score region-specific MRI [
31], but with modifications developed, through a consensus process, by 11 pediatric experienced radiologists from 7 different centers and 2 continents (North America and Europe). These authors produced, after a literature review, a complete atlas that consists of detailed definitions and grading of signal intensity, size of signal abnormality within bone marrow and surrounding tissue, physis damage and vertebral compression for each individual bone unit. This method showed excellent reliability and agreement in each category of bones and moderate to substantial reliability and agreement in readings from individual bones [
24]. This score was designed to be easily applied in settings with non-experienced radiologists. Therefore, the CROMRIS represents an excellent standardized semi-quantitative scoring system [
24]. A total score reflecting the radiological activity of each individual patient has not been proposed. A total score taking all lesions into account is needed because the fluctuating course of CNO implies that new lesions may occur while others are vanishing. Hence, we chose to integrate scores from each bone unit in a comprehensive RAI-CROMRIS that could measure the “entire radiological burden” of the disease at a whole-body level.
Few studies with small cohorts addressed the direct correlation between radiological and clinical findings in CNO patients. A comparison of clinical and radiological findings was previously performed in small cohort without a quantitative radiological score [
34,
35]. More recently, the RINBO score was evaluated in 40 patients and found to have a fair agreement with the clinical evaluation of each bone site; however, patients’ medication and follow-up scans were not taken into account [
33]. In our study we evaluated the correlation of the RAI-CROMRIS with disease activity in 76 patients before starting treatment and in 46 patients also at two subsequent time points (6 and 12 months). We found a significant association of the RAI-CROMRIS with disease activity parameters including the PGA, presence of functional impairment and increased inflammatory markers in patients at baseline. These observations suggest that the burden of radiological activity, as measured by the RAI-CROMRIS, reflects the overall degree of clinical activity of each individual patient. Examining 46 patients with WB-MRI at baseline and at 6 and 12 months, we found a significant decrease in the RAI-CROMRIS overtime. Importantly, a correlation between the RAI-CROMRIS and the PGA was observed, not only at baseline, but also during follow up at 6 and 12 months, at times when the disease activity was significantly lower, suggesting that this score may be able to reflect minor changes in disease activity.
Several studies have shown the effectiveness of bisphosphonates as a treatment option for patients with significant disease burden, with physical limitations or active vertebral lesions or in those who have persistently active symptoms and abnormal MRI findings who have failed others treatment (NSAID, DMARDS, biologic agents) [
28,
31,
36,
37]. This is reflected by the recently developed consensus treatment plans [
28]. The patients whom we chose to treat with bisphosphonates, not only had a more severe disease (as shown by more frequent functional impairment and more frequent vertebral involvement), but also had a significantly higher baseline RAI-CROMRIS compared to patients who received other treatments. After 6 months of treatment, the improvement in disease activity was associated with a significant decrease in the RAI-CROMRIS. The decrease in the score was particularly evident for extension of bone hyperintensity, as well as for soft tissue hyperintensity. As hyperintensity is indicative of inflammatory edema, this observation is consistent with the hypothesis of an anti-inflammatory effects of targeting osteoclasts in CNO.
There is no guideline of how frequently whole-body MRI needs to be performed in CNO patients. In the CARRA consensus treatment plan, MRI is strongly recommended to objectively assess disease activity at 6 and 12 months after adjusting therapy [
28]. The timing of MRI in this work follows the consensus reached by the CARRA investigators.
There are some limitations of our study. Even if our series is large, the monocentric nature of the study, its observational design, the heterogeneity of the treatments used and the rather long time interval in which the patients were enrolled require caution in drawing definitive conclusions. Although we have used a comprehensive PGA including different variables, such as physician reported outcome, patient reported outcome and increase in acute phase markers, this is not validated. Indeed, there is not yet an internationally validated tool for measuring disease activity in CNO. It should also be noted that bone hyperintensity on STIR sequences may be present in healthy children during growth and, therefore differentiating this physiological hyperintensity from the pathological inflammatory oedema of CNO may be challenging [
38]. Bone-marrow-edema like changes in the hand skeleton are reported in healthy children aged 5–16 years in the hand skeleton [
39,
40], as well as in feet [
41] and pelvis [
38]. The low prevalence of bone hyperintensity within these sites in our cohort and the relevant change after treatment argue against over-reading. Further studies are warranted to compare the minimal changes detected in children with CNO with those from healthy children in order to identify the key difference that would be specific to active disease in CNO and to determine the minimum clinically significant difference of MRI findings by using external validation measurements [
42].
Furthermore, a potential limitation of the CROMRIS is that the parameters, except extension of hyperintensity in each bone unit, have the same scoring range, which may have diluted an important variable. Also all bone units were considered equally, though hands bones and foot bones were grouped together and assigned the same unbiased weight. Whether these issues are relevant in the evaluation of the total radiological burden of disease and its relation to clinical disease activity remains to be established. Our study provides follow-up information up to 1 year, which is informative on the short term, but longer-term follow-up is needed in a chronic relapsing disease such as CNO. Radiological follow-up studies are lacking. In the only available follow-up study WB-MRI performed more than 10 years after disease onset, revealed radiologically active lesions in more than 50% of patients even in long-term clinical remission [
35].
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