This single-center cross-sectional study described a rare autoinflammatory bone disease that was previously accepted as mild and self-limited. We diagnosed 18 patients as CNO in 4 years and over 75% of patients were treated with methotrexate and over 50% of patients needed anti-TNF treatment. Despite these potent treatments, our patients had poor quality of life.
In this study, the median age at onset of the disease was 12 years, the median delay time of diagnosis was 9 months and we observed a male (61%) predominance. In CNO, the peak onset age was 7–12 years and commonly female predominance was reported [2, 11]. The peak onset of CNO in studies from Turkey was between 9 and 10.2 years, and a male predominance was observed in 2 studies [12–14]. Likewise, two studies from India and Chile reported male predominance [15, 16].
Chronic non-bacterial osteomyelitis has no specific clinical features. Bone pain with/without swelling and redness is the main symptom and all of our patients had bone pain without swelling and redness [2, 5, 11].
The main pattern of pain in CNO is reported as alternating and insidious . Another reason for pain and limitation in CNO patients is joint involvement that is adjacent to the osteitis area. We observed joint involvement in 17 (94.4%) patients, and 13 of them had arthritis in MRI . Another study from Turkey reported 17.6% arthritis and 58.8% arthralgia . Limitations and pain in joints are observed in CNO and arthritis is reported up to 40% in studies .
Other conditions such as acne, psoriasis, palmoplantar pustulosis, and inflammatory bowel disease accompanying CNO are reported between 4–20% [2, 5, 11]. In this study, one patient had inflammatory bowel disease, and another one had acne and pustulosis as SAPHO syndrome.
Inflammatory parameters at diagnosis in CNO are commonly mildly elevated [2, 5, 11]. Moreover, high values should warn the clinician to check the diagnosis. We observed mildly elevated inflammatory markers except for 1 patient. This patient was accepted as CNO after a detailed evaluation for infection and malignancy. After increasing WB-MRI’s use to diagnose CNO, the bone and bone marrow biopsy rates decreased. However, bone and bone marrow biopsy should be performed to exclude malignancy and infection in necessary cases. In this study, bone biopsy was performed in 3 patients and bone marrow aspiration in 11 patients.
After the clinical suspicion of CNO, the painful areas should be imaged with plain radiography and MRI. The plain radiography has poor sensitivity to define bone marrow edema but it is important to exclude fracture and other bone disorders. The study in children reported 15% findings on radiography, such as lytic bone lesions, sclerosis, and hyperostosis . However, the absence of these findings does not exclude CNO and the MRI is necessary to find out CNO. If the regional MRI shows osteitis in metaphyseal regions of commonly affected sites, such as lower extremities, long bones, vertebrae, clavicles, and mandible, the diagnosis of CNO should be confirmed by the WB-MRI. In this study, 2 (11.1%) patients had findings in plain radiography. At diagnosis, all patients had MRIs and 15 (83.3%) of them had WB-MRIs. All patients had multifocal lesions and the lesion patterns in 15 (83.3%) patients were symmetric in WB-MRIs. The multifocal and recurrent forms of sterile osteomyelitis were severe forms of CNO. The unifocal lesion usually occur in the clavicle and mandible and might have milder symptoms. There was no patient with unifocal lesion and no mandibular involvement in this study. Patients with single and/or milder symptomatic lesions may have been misdiagnosed or underestimated and therefore had no chance to visit a pediatric rheumatologist.
We observed 170 lesions in 18 patients with a median of 8 lesions per child and the most affected bones were the pelvis (72.2%) and sacrum (61.1%). Açarı et al  reported lesion sites; femur (67.9%), tibia (57.1%), and pelvic bones (32.1%). Concha et al  observed lesions of 21% in the upper limb, 9% in the lower limb, and 36% in the axial skeleton, and the other studies reported sites of lesions under different titles and groups [11–16].
The new classification suggestion for CNO was offered according to the distribution of bone lesions. There were 2 main subgroups according to the presence of tibial and clavicular lesions. These two patterns were called “tibio-appendicular multi-focal pattern” and “claviculo-spinal pauci-focal pattern” . In this study, 9 patients had tibial lesions and were suitable for the tibio-appendicular multi-focal pattern, 5 patients had clavicular lesions and were suitable for the claviculo-spinal pauci-focal pattern. Nevertheless, 1 patient had lesions in both of them and 3 patients had lesions in none of them. As a result, it paused a question mark on whether the new suggested classification criteria covered all types of CNO.
As initial treatment, nonsteroidal anti-inflammatory drugs are the first choice for cases without vertebral involvement. A prospective observational pediatric study reported that 43% of patients achieved clinical remission after 6 months and 62% of patients had clinical remission after 12 months . A retrospective study observed relapse in 50% of patients treated with NSAIDs . In this study, all patients had NSAIDs as initial treatment and 2 patients were treated with only NSAIDs. There was no commonly accepted therapy algorithm for CNO, but it was suggested that, if the patients were unresponsive to NSAIDs, the therapy should change gradually to disease-modifying anti-rheumatic drugs (DMARDs: methotrexate) and/or biologic DMARDs (anti-TNF agents) and/or bisphosphonates. Moreover, some patients might need corticosteroids as bridging therapy in a short time and patients with vertebral involvement should be treated rapidly with methotrexate and/or anti-TNF agents [2, 21]. In this study, three patients had bisphosphonate treatment. Two of them had bone destruction and were given bisphosphonate in addition to an anti-TNF inhibitor to reform bone structure. Another one was partially responsive to anti-TNF inhibitor and had bisphosphonate.
In this study, we observed that the quality of CNO patients’ life was influenced negatively, although they were treated effectively. These negative effects of CNO were observed not only in physical activities but also in the social, emotional, and school life of patients. A current study showed similar worsening physical and school functioning in CNO patients by using PedsQL4.0 . Likewise, the same study reported anxiety and communication problems in CNO patients.
The main limitations of the present study were the single-center design and the small number of cases.