This retrospective case-observation study aimed to elucidate the demographic characteristics and clinical features of seven patients diagnosed with CRMO. CRMO has a relatively low incidence rate in China compared to bacterial osteomyelitis (8/105). However, considering China's vast population, the absolute number of cases cannot be overlooked. Previous research has indicated that the mean age of onset for CRMO is 11 years, which aligns with our observations. Our study found a male to female incidence ratio of 5:2, which deviates from previous findings in Europe and the United States but corresponds with results from other Chinese, Indian, and Japanese centers [10, 11]. These results suggest a potential correlation with geographic and ethnic genetic factors, although further validation is required in future studies.
Our study's findings revealed that the average delay in diagnosis was 8.2 months, ranging from 1.5 to 24 months, which generally agrees with the average delay of 17.3 months, ranging from 1 to 137 months, reported by the French study center. This prolonged interval between symptom onset and diagnosis could be attributed to the current lack of specific clinical and laboratory diagnostic tools for CRMO. However, as interest in the disease continues to grow, the diagnostic delay is decreasing. Studies have also demonstrated a high familial prevalence of CRMO, with up to 50% of patients experiencing concomitant inflammatory diseases such as psoriasis and inflammatory bowel disease, along with their immediate family members. Palier et al. [12] (2015) reported cases of CRMO in siblings and families. Moreover, some studies have suggested a genetic basis for CRMO associated with chromosome 18, but the hypothesis of CRMO being a hereditary disease requires further investigation due to limited available genetic evidence [13].
Patients with CRMO typically seek medical attention for unexplained bone pain, often accompanied by elevated local skin temperature and soft tissue swelling. Some may also present with manifestations similar to SAPHO syndrome, such as acne or impetigo. While CRMO was once considered a specific manifestation of SAPHO syndrome in childhood, recent reports indicate that CRMO can also occur in adults, and SAPHO syndrome can occur in children. These conditions share common features such as osteitis, unifocal or multifocal lesions, osteomalacia, and pustulosis [14–15]. However, some argue that SAPHO syndrome is not a distinct disease entity but rather a constellation of symptoms that may hinder future studies [7, 16]. Despite different ages and sites of onset, both CRMO and SAPHO syndrome are often grouped together for treatment due to the lack of a gold standard treatment for CRMO [17]. In our study, most patients presented with painful swelling and elevated skin temperature, with some exhibiting scattered pustules on the plantar aspect of the foot [5, 18]. This aligns with previous findings that palmar plantar pustulosis occurs in 3%-20% of cases. Lesions can affect any bone segment, but the most common sites include the long bone diaphysis [19], especially the distal femur, proximal and distal tibia, and fibula [20]. The typical presentation of CRMO is insidious recurrent bone pain, often worse at night [21]. Misdiagnosis of CRMO as a bone tumor or bacterial inflammation is common, reaching a rate of 69% [22], which can delay clinical treatment and unnecessarily burden patients. Thus, an early and accurate diagnosis of CRMO, with a detailed differential diagnosis, is crucial for patients with unexplained bone pain, especially nocturnal exacerbations. Misdiagnosis and underdiagnosis of CRMO can lead to serious consequences such as long bone fractures, abnormal growth in children, spinal fractures, and long-term psychological disorders for patients.
In summary, although CRMO and SAPHO syndrome share some common features and are often treated together, it is important not to overlook their distinct characteristics. Early and accurate diagnosis of CRMO is essential for effective treatment and to prevent potential long-term consequences [23, 24].
In patients with CRMO, inflammatory markers are typically non-specific and may fall within normal ranges or only show slight elevations [25]. Our study of seven cases found that the leukocyte count in peripheral blood was normal in all cases, and the sedimentation and C-reactive protein levels were only slightly elevated in one case, which is consistent with previous studies, such as the data reported by Yamashita et al. [26]. Some studies have suggested that CRMO is part of the spectrum of spondyloarthropathy, so we also performed human leukocyte antigen B27 testing on all patients. However, all of our results were negative, leading us to tentatively conclude that the correlation between CRMO and spondyloarthropathy is low.
In the realm of clinical diagnostics, the (NLR and PLR are two commonly utilized and effective tests that are easily accessible. Previous research has demonstrated the value of these parameters in diagnosing inflammation, infection, and cardiovascular diseases [27]. In recent years, NLR has emerged as a novel marker of inflammation, often used in conjunction with other inflammatory markers to identify inflammation in various clinical settings. Recognizing its growing importance, we included NLR in our study and evaluated it alongside other indices. Specifically, we assessed the NLR and PLR of our study participants, revealing that 85.71% of patients exhibited an increasing trend in platelet levels, ranging from 304 to 397. Meanwhile, 42.86% of patients demonstrated a characteristic decrease in neutrophil percentage paired with an increase in lymphocyte percentage, indicating a decreasing NLR. In fact, the final results showed a decreased NLR, with an NLR ratio range of 0.77–2.04. While previous studies have suggested a correlation between NLR indicators and autoimmune diseases such as psoriasis and rheumatoid arthritis [28], our results differed from those findings. Specifically, we found that the NLR indicators decreased in all three of our study participants. We attribute this difference to our small sample size. Additionally, we observed varying degrees of elevation in platelet indicators in all patients, which also deviated from results observed in studies conducted by other centers. It should be noted that previous analyses and investigations of the aforementioned indicators in the context of CRMO series in other research centers have not been reviewed.
Previous studies have suggested that osteolytic manifestations are common in the early stages of CRMO, while sclerotic manifestations are more frequently seen in the late stages of the disease. The reparative process is dynamic and akin to periosteal reaction [29]. To detect the location and distribution of lesions and to rule out other differential diagnoses, MRI is the preferred diagnostic tool, and in our study, all patients underwent MRI, which has high sensitivity and can better assess disease progression and treatment outcomes.
To exclude bone tumors, bacterial infections, and Langerhans cell hyperplasia, bone aspiration pathology biopsies were performed on patients. However, the results indicated a manifestation of chronic osteomyelitis, and all bacterial cultures were negative. Bjorksten et al. [30] have reported that bone histopathology in CRMO lesions is usually characterized by non-specific osteitis, with features such as osteolysis and predominance of neutrophil granulocyte and mononuclear macrophage invasion in the initial bone histopathology of the lesion. Similarly, our observations revealed that the interstitial space of bone trabeculae was filled with neutrophils, macrophages, and lymphocytes, in line with the findings of Majeed et al. [31].
Currently, NSAIDs remain the first-line treatment for CRMO due to the absence of specific treatment options. In our study, six out of seven patients experienced significant pain relief after receiving NSAID treatment, consistent with a large French study where NSAIDs were effective in 73% of patients [32]. However, effective symptom relief does not necessarily equate to complete recovery, as demonstrated in a study by Roderick et al., where NSAID treatment did not significantly improve symptoms, possibly due to the lack of uniform efficacy evaluation criteria and inter-individual variability [33]. One patient in our study showed gradual pain relief after receiving biologic therapies and adalimumab injection, which is in line with the findings of Borzutzky et al., who reported a symptom relief rate of 91% with TNF-α inhibitors compared to 57% with NSAIDs [34]. Another patient in our study experienced a recurrence of symptoms 27 months after hospital discharge, and treatment with adalimumab injection resulted in symptom improvement, consistent with the better efficacy of TNF-α blockade demonstrated in previous studies. TNF-α blockers such as infliximab, etanercept, and adalimumab may restore the balance between pro- and anti-inflammatory cytokines and have fewer adverse effects [35, 36]. Other second-line therapeutic agents for CRMO include glucocorticoids, bisphosphonates, antirheumatic drugs such as methotrexate and lutuximab, and additional TNF-α blockers. However, due to the lack of clear diagnostic criteria for CRMO, more randomized controlled clinical trials are needed to better guide clinical treatment decisions.
Despite the valuable insights gained from our research, we acknowledge several limitations that may affect the validity and generalizability of our findings. Firstly, our small sample size drawn from a single study center and incomplete patient data due to the inability of some patients to provide critical information or the incompleteness of medical records may have impacted our conclusions. Furthermore, our study lacked a sufficient follow-up period to assess the long-term status of patients and the reliability and effectiveness of treatments. Additionally, as we did not conduct genetic testing, we were unable to explore the genetic basis and etiology of CRMO in-depth. Future studies could consider incorporating genetic testing data in their samples to better comprehend the pathogenesis of CRMO and to provide more effective prevention and treatment measures. Lastly, our reliance on subjective symptom relief as a measure of treatment efficacy may have missed asymptomatic lesions due to the lack of mandatory radiological follow-up [34].