The present study was a multicenter series of CNO patients from five medical centers in South China. The clinical characteristics of our patients were similar to those of other studies from North America and Europe . We did see a predominance of female subjects in our study. 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. The clinical presentation and severity of CNO vary significantly between individual patients, covering a wide spectrum ranging from asymptomatic or mild inflammation to chronic recurrent multifocal bone involvement. Clinical signs of bone inflammation include localized skin redness, warmth and/or swelling, and pain. Bone pain is the main symptom, and it is often insidious in the early stage and typically occurs at night. Because of the pain, children sometimes limp. On physical examination, swelling is infrequently observed, but when the disease is active, it is a sign of specific points of bone sensitivity . All of our patients presented with bone pain, and only three of them presented with localized swelling and a limp. CNO most frequently involves the long bones (metaphyses and diaphyses), 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, which tends to be unilateral. In our study, bone lesions were typically distributed throughout the body, affecting more frequently the femur (94.5%), tibia (88.2%), fibula (41.2%), radius (35.3%), humerus (29.4%), and calcaneus (23.5%). Most of our patients had a multifocal pattern, expect for one patient who had only left clavicle involvement. It is possible that unifocal long bone involvement needs to be distinguished from culture-negative bacterial osteomyelitis by blood bacterial culture or bone marrow biopsy.
Besides bone lesions, patients with CNO may also present with fever, malaise, and weight loss, but they generally do not appear particularly ill . In the Nonbacterial Osteitis (NBO) scores, a fever does not result in bonus points. Up to 44.4% of our patients presented with a fever at the onset, a significantly higher percentage than in other studies [8, 12, 15, 17–25]. This may be related to bone inflammation. A subset of CNO patients exhibited inflammatory organ involvement, including psoriasis and palmoplantar pustulosis (~ 8%), inflammatory bowel disease (IBD) (~ 10%), severe acne (~ 10%), and ankylosing spondylitis (~ 25%) . Some patients may progress from childhood CNO to spondyloarthropathies later in life . Interestingly, none of our patients had psoriasis, IBD, pustulosis, ankylosing spondylitis, or uveitis, suggesting a different genetic background. However, 41.2% of them had arthritis in joints adjacent to areas where osteomyelitis is active.
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 . 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. X-ray examination can detect inflammatory bone lesion changes, such as radiolucent, osteolytic, or sclerotic lesions, but it is not sensitive in the early stages . MRI is the most sensitive imaging technique to determine the extent and severity of bone involvement. Particularly in the early stages of the disease, MRI techniques are highly sensitive. 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 . Bone scintigraphy is also useful for this purpose. It provides a global skeletal assessment at a lower cost , 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. In the present study, 47.1% of our patients underwent a bone biopsy. The histopathological findings of CNO are nonspecific inflammatory changes. The pathological changes in the early stages include osteolysis and neutrophil/mononuclear macrophage infiltration, while the late changes are characterized by reactive bone formation, bone sclerosis and hyperplasia, hypertrophy, and lymphocyte infiltration. 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.  The scoring criteria include seven risk factors: normal blood cell count; symmetric lesions; lesions with marginal sclerosis; normal body temperature; vertebral, clavicular, or sternal lesions; radiologically proven lesions ≥ 2; and CRP ≥ 1 mg/dl. The average score of our patients was 39 points, with a range of 30–53 points. 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 .
Although three consensus treatment plans (CTPs) were developed for CNO patients refractory to NSAID monotherapy by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) , therapy protocols of CNO are not yet standardized, and most evidence still relies on case series and case registries. First-line treatment NSAIDs, which may reduce the pain and, in some cases, decrease the number of bone lesions in 3 months . 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 . 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 . 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. Spinal involvement can lead to fractures and secondary bone deformity . One patient in our study (6.6%) had a thoracic vertebra fracture. This emphasizes the need for early diagnosis and aggressive treatment to prevent complications and long-term sequelae in CNO patients with vertebral involvement. Despite recent advances, there is no information on the optimal duration of treatment. Further studies are needed to determine whether a personalized treatment protocol could improve outcomes of CNO patients.
The long-term prognosis of CNO is generally favorable, with remission observed in 40% of patients after 1–5 years of follow-up . 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 . 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 .
In conclusion, this study is the first case series of CNO from South China to describe the features and outcomes of such an autoinflammatory bone disease. It can be accompanied by a fever and increased inflammatory indicators. The diagnosis should include clinical history, laboratory and imaging examination, and histopathological examination. Other causes of chronic bone pain should be ruled out. For treatment, NSAIDs are used as first-line drugs followed by steroids, MTX, SASP, bisphosphonates, and TNF-α inhibitors. Combination therapy with bisphosphonates and TNF-α inhibitors may be an option for refractory CNO. The limitation of this study is its small sample size. Thus, further studies including more patients from other tertiary centers are required to formulate diagnostic and treatment strategies for CNO.