The present study was a multicenter series of CNO patients from five medical centers in South China. Compared with previous reports, the clinical characteristics of our patients were a little different. (details in Table 4) [8, 12, 15, 17,18,19,20,21,22,23,24,25] The female advantage in China is not such obvious as European countries [8, 12, 15, 18, 22,23,24,25]. The median age at diagnosis and diagnostic delays were 9.2 years and 10.2 months, respectively. The diagnostic delay ranged from 1 to 72 months, suggesting that CNO is still sometimes not well recognized in our country. In term of clinical manifestation, bone pain is still the most frequency symptom, but the fever rate in our study, which up to 44.4%, is more higher than that in other studies [17, 18, 20, 22, 24]. This may be related to bone inflammation. The most common bones involved in our study is the long bones of the limbs, especially the lower bones. In cases of Europe and USA, the clavicle, pelvis and spine are more frequently involved [8]. The comorbidities of our patients are mainly arthritis, only one patient has acne and gastrointestinal ulcer. The gastrointestinal symptoms, palmoplantar pustulosis, psoriasis and acne are more frequently in European cases [8, 12, 20]. It is also different from other studies, our CNO patients had no family history, no HLA-B27 positivity and no ANA positivity, suggesting a different genetic background.

Table 4 Comparison between our study and previous reports

On physical examination, swelling is infrequently observed, but when the disease is active, it is a sign of specific points of bone sensitivity [9]. CNO most frequently involves the long bones, followed by the pelvic bones, the vertebral column or the shoulder girdle/clavicle [3, 26]. The bones involved tend to be symmetrical, except the clavicle. Unifocal long bone involvement needs to be distinguished from culture-negative bacterial osteomyelitis by blood bacterial culture or bone marrow [27].

Laboratory tests of CRMO are not specific. Routine inflammatory parameters (WBC, white blood cell count; CRP, C reactive protein; ESR, erythrocyte sedimentation rate) are usually normal or mildly elevated. Imaging techniques are vital for diagnosing CNO and for excluding differential diagnoses [28]. Of our patients, 94.5% were evaluated with MRI, 52.9% with X-ray, and 58.5% with CT, while 64.7% had a bone scintigraphy. Compared with X-ray and CT, MRI is the most sensitive imaging technique to determine the extent and severity of bone involvement, particularly in the early stage. They can detect bone edema even before bone erosions and sclerosis develop and help assess the inflammation of surrounding tissues [29, 30]. More recently, whole-body MRI has been reported to be useful to screen the entire skeleton for bone lesions [31]. Bone scintigraphy is also useful for this purpose. It provides a global skeletal assessment at a lower cost [32], which can show abnormal concentrations of radionuclides, indicating the site of lesions, but cannot distinguish between inflammation and bone marrow metabolic hyperplasia. The radiation is also harmful to the body.

Bone biopsies are usually performed to exclude chronic infections, malignancies, or other systemic diseases, especially in patients with unifocal lesions [33]. In the present study, 47.1% of our patients underwent a bone biopsy. The histopathological findings of CNO are nonspecific inflammatory changes. A bone biopsy followed by pathological and pathogenic examination is very helpful for differential diagnosis.

To help diagnosis, we used the clinical NBO scores provided by Annette F. Jansson et al. [16] Although the score provides a reference standard for the diagnosis of the disease, CNO continues to be a diagnosis of exclusion. Important differential diagnoses include malignancies, infections, immunodeficiency, Langerhans cell histiocytosis (LCH), and other autoinflammatory disorders [33].

Although three consensus treatment plans (CTPs) were developed for CNO patients refractory to NSAID monotherapy by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) [34], therapy protocols of CNO are not yet standardized. In general, first-line treatment is NSAIDs, which may reduce the pain and, in some cases, decrease the number of bone lesions in 3 months [35]. Second-line treatments usually includes methotrexate, corticosteroids, biologic drugs (mainly TNF-α inhibitors), and bisphosphonates depending on the severity of the disease and the presence of comorbidity and/or complications [36]. Almost all of our patients started treatment with NSAIDs but had to switch to other treatments because of partial response and relapse. Methotrexate was the second most frequent treatment, but six of these seven patients received steroids, bisphosphonates, or biologic drugs at the same time. Thus, it is difficult to assess the real impact of methotrexate. Different biologicals have been used to treat CNO, most commonly TNF-α inhibitors [25]. In our study, remission was achieved more frequently with TNF-α inhibitors, including adalimumab and etanercept. Bisphosphonates given to seven patients, resulted in remission in six patients. One patient experienced worsened bone pain after bisphosphonates, subsequently remitting on an adalimumab and bisphosphonate combination, which achieved a good result. Based on our clinical experiences, long bone lesions in diaphyses are more easily improved than those in epiphyses. It is worth noting that, spinal involvement can lead to fractures and secondary bone deformity [37]. This emphasizes the need for early diagnosis and aggressive treatment to prevent complications. Despite recent advances, there is no information on the optimal duration of treatment. Further studies about treatmnt are needed.

The long-term prognosis of CNO is generally favorable, with remission observed in 40% of patients after 1–5 years of follow-up [38]. In our study, we had a remission rate of 11.7% without medicines in a median follow-up of 16 months. The recurrence of the disease is very common. In a US cohort, a recurrence rate of 83% was observed after a follow-up of 1.8 years [21]. In our study, the recurrent rate was 17.6%. This may be related to the small sample size. It has been reported that patients can present a flare even 15 years after the onset of the disease, so it requires monitoring and long-term follow-up [38].

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