Abstract
Background
Chronic recurrent multifocal osteomyelitis (CRMO) is a sporadic form of autoinflammatory bone disorders (ABDs) presenting with sterile chronic and/or recurrent and multiple sites of bone involvement. We aimed to describe our 10-year cohort of CRMO patients and analyze the characteristics and treatment approaches.
Methods
We retrospectively analyzed the data on patients with bone diseases at Children’s Medical Center, Tehran University of Medical Sciences, Iran in the previous 10 years. The criteria for inclusion of patients as CNO/CRMO were mono-, oligo- or multifocal inflammatory bone lesions (osteomyelitis, osteitis, osteosclerosis) by imaging techniques; duration of complaints for > 6 weeks; and onset before 18 years of age.
Results
Thirty-nine patients were enrolled. Diagnosis of five patients were found compatible with monogenic ABDs. There were four sites of bone involvement per patient. The most common sites were vertebrae, pelvis, and tibia. Eight patients (23%) had dermatologic manifestations, including three psoriasis cases and one palmar pustulosis. All patients received NSAIDs, and 85% received it as first-line. Treatment was escalated to methotrexate or prednisolone when response was suboptimal. Out of 17 patients primarily treated only with NSAIDs, 47% remitted. In general, 84% of our patients are in remission: 36% without medication and 48% with medication.
Conclusion
Our CRMO patients showed an acceptable remission response to the current treatment regimen. Results of bone scintigraphy in suspected CRMO patients should be interpreted cautiously as an adjunct to clinical investigations. Special attention should be paid to extraosseous manifestations in suspected CRMO patients to avoid overlooking monogenic ABDs.
Clinical trial number
Not applicable.
Keywords: Chronic recurrent multifocal osteomyelitis, CRMO, Autoinflammatory, Autoinflammatory bone disorders
Background
Chronic recurrent multifocal osteomyelitis (CRMO) is a sporadic form of autoinflammatory bone disorders (ABDs) presenting with sterile chronic and/or recurrent and multiple sites of bone involvement. Chronic nonbacterial osteomyelitis (CNO) is a broader terminology implying the spectrum of sterile bone inflammation irrespective of chronicity and distribution, i.e., it can present as unifocal and non-recurrent [1–3]. There are multiple hypotheses on pathophysiological mechanisms that drive CNO/CRMO; however, the following three seem to be the most convincing: imbalanced cytokine expression, increased inflammasome activation, and enhanced osteoclast differentiation [4–7].
The precise definition of CRMO has varied a lot since the first time it was defined by Giedion et al. [8] and is still inconsistent. Moreover, the borders between this condition and monogenic ABDs such as synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, Majeed syndrome, deficiency of the interleukin-1 receptor antagonist (DIRA), and pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), the diseases also described in CNO spectrum, are not sharply depicted [2].
CNO/CRMO is more common in children and adolescents and is more frequently reported in females [1, 9, 10]. It usually manifests with focal bone pain at the affected site(s). The pain can be intermittent or persistent for years. Epiphyses and metaphysis of long bones are the most affected sites, and the lesions can be found most frequently in the femur, tibia, and pelvis. Spine involvement is reported in up to one third of the patients [1, 9–11].
Different imaging modalities can be used to detect lytic or sclerotic bone lesions or periosteal reactions typically seen in CRMO; however, whole body magnetic resonance imaging (MRI) is introduced as the gold standard imaging, since it is able to find multifocal involvement of the disease, detect early disease findings such as bony edema or altered diffusion capacity, demonstrate soft tissue involvement, and exclude other diagnoses without endangering children with hazardous radiation [2, 12, 13].
The first-line treatment for CNO/CRMO remains empiric and starts with nonsteroidal anti-inflammatory drugs (NSAIDs) [1, 14, 15]. More clinical trials need to be conducted to enrich the consensus; nevertheless, we can refer to Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans as the best strategy. According to CARRA, CNO refractory to NSAIDs and/or with spinal lesions can be treated either by nonbiologic disease-modifying anti-rheumatic drugs (DMARDs), tumor necrosis factor (TNF) inhibitors with or without methotrexate (MTX), or bisphosphonates [16].
Once considered a very rare autoinflammatory disorder (AID), the prevalence of CRMO has increased in the previous years, presumably due to the improved understanding of the disease and increased availability of whole-body MRI [17, 18]. It should also be noted that in spite of the proposed diagnostic criteria [9, 19], CRMO is still a diagnosis of exclusion [20]. Therefore, acknowledging the differences between case presentations is of utmost importance. Case reports from the different regions of the world can be very beneficial for that matter. Hence, we are presenting here a series of 39 patients with the first impression of CRMO, among which five were later diagnosed with a monogenic ABD. To our knowledge, this is one of the largest longitudinal cohorts with an extensive follow-up of CRMO patients from our region and offers unique insights into diagnostic challenges and therapeutic responses in a resource-limited setting where whole-body MRI is not available.
Methods
Study design and setting
We retrospectively analyzed the data on patients with complaints of bone diseases who were referred to our rheumatology clinic or admitted at our rheumatology ward at Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran in the previous 10 years.
Inclusion and exclusion criteria
The criteria for the inclusion of patients as CNO/CRMO in our cohort were:
Mono-, oligo- or multifocal inflammatory bone lesions (osteomyelitis, osteitis, osteosclerosis) by imaging techniques.
Duration of complaints for more than 6 weeks.
Onset before 18 years of age.
The diagnosis of CRMO in our patients matched both Jansson and Bristol criteria [9, 19]. The exclusion criteria were the diagnosis of mimickers of CNO/CRMO, such as infections, malignancy, hypophosphatasia, or other autoinflammatory diseases of bone such as Majeed’s syndrome, PAPA, and DIRA. In all patients, a comprehensive clinical, laboratory, and imaging work-up was performed to exclude other inflammatory, infectious, or malignant causes of bone lesions. Bone biopsy was performed in most cases to rule out malignancy and/or to help with the diagnosis of CRMO.
Data collection
Detailed demographic and clinical data were collected anonymously. The clinical characteristics included the bones or joints involved, types of organ involvement, and types of skin presentations. Inflammatory markers including WBC, ESR, and CRP, and fluorescent antinuclear antibody test (FANA) were gathered.
Treatment and outcome assessment
The type of treatment, response to the treatment in terms of remission, partial response, and no response, time to reach remission, and duration of follow-up were reported.
Definitions of treatment response
We reviewed the literature to find the most appropriate definitions for treatment response [21–23], and came up with the following:
Remission
Clinically inactive disease in terms of absence of pain, normalization of inflammatory markers, and, when available, the absence of osteitis detected by imaging, for at least six consecutive months.
Remission on medication
Patient is in remission while still on treatment.
Remission without medication
Patient is in remission while the medication had been stopped for more than six months.
Partial response
Persistence of some clinical manifestations or perturbation of laboratory examinations and imaging.
No response
Absence of improvement of disease activity.
Statistical analysis
All statistical analyses were conducted using IBM SPSS Statistics (version 27.0). Descriptive statistics were computed to summarize the dataset. Descriptive statistics were used to summarize demographic, clinical, laboratory, treatment, and outcome variables. Categorical variables were presented as frequencies and percentages, and continuous variables were summarized using means and standard deviations, or medians and interquartile ranges, as appropriate, based on the data distribution.
To assess the correlations between treatment response and other variables, we used Spearman’s correlation test. A p-value of less than 0.05 was considered indicative of potential statistical relevance.
Ethical considerations
The study adhered to the principles of the Declaration of Helsinki. The study protocol was approved by the ethical subcommittee of Tehran University of Medical Sciences.
Results
Patient enrollment and diagnosis refinement
We enrolled 39 patients with the criteria. It is worth noting that during our search we found two patients initially treated with CRMO with negative workup results for malignancy who were diagnosed with leukemia and lymphoma after years. Following the investigations, diagnosis of five patients were found compatible with other diseases, namely interleukin (IL)17-receptor antagonist (RA) deficiency, NOD-like receptor protein (NLRP)1 mutation, MAJEED syndrome, SAPHO, and DIRA.
Demographic and clinical characteristics
Out of 34 CRMO patients, 50% were girls. The age of onset varied between five months to 12 years, and the median was five years and a half. The interval for diagnosis was between one month to nine years, and the median was three months. At the presentation, 97% reported bone pain, 27% arthralgia, and 27% fever. Nine patients (27%) had arthritis (one polyarticular, four oligoarticular, and four monoarticular), and knee was the most common site (Figs. 1 and 2).
Fig. 1.
Sites of involvement in a CRMO patient. STIR MRI and bone scan images of a patient with limping and left thigh and hip pain. MRI shows abnormal signal in right femoral proximal metaphysis, right intertrochanteric, left acetabulum and ischium. Bone scan shows hyperactive lytic lesion in left acetabular roof, and focal increased uptake in right lesser trochanter
Fig. 2.
Sites of involvement in CNO/CRMO patients. Right: bones; left: joints. Percentages out of bone and joint sites are given separately
Bone involvement
The primary imaging modalities included X-ray, computed tumoral (CT) scan, and MRI. When CRMO was suspected, bone scintigraphy was done to investigate other sites of involvement.
In total, there were 133 sites of bone involvement, i.e., four sites per patient. The most common sites were vertebrae, pelvis, and tibia (Fig. 2). Symmetric lesions were found in 27% of the patients. Three patients (1%) had unifocal involvement. The recurrences of episodes were between one to five times, with a median of two times.
Extraosseous and dermatologic manifestations
Eight patients (23%) had dermatologic manifestations, with three psoriasis cases and one palmar pustulosis. One of the patients has a suspicious granulomatous ulcerative lesion inside the nasal cavity extending to outside and on the nose, which necessitated extensive work-up and has been reported [24]. Other extra-skeletal manifestations included parotiditis, 6th nerve palsy, and chronic serous otitis.
Laboratory findings
Normal WBC counts were found in 32% of the patients. CRP and ESR were high in 71% and 85% of the patients, respectively.
Treatment and response
Please refer to the Methods section for response definitions.
All patients received NSAIDs, and 85% received it as first-line. Prednisolone short course therapy was initiated for two patients as the first treatment, but both patients needed to be treated with next-step treatments after a few months. combination therapy with MTX and prednisolone was initiated for two patients with debilitating symptoms and spinal involvement. Treatment was escalated to methotrexate or prednisolone when response was suboptimal. Out of 17 patients primarily treated only with NSAIDs, 47% remitted. There were eight patients for whom MTX plus NSAIDs were started as the primary treatment. One of them responded to this treatment and has been in remission for two years. Out of the seven remaining, three of them had to be escalated to a third line treatment. We believe this is since these patients had either spinal involvement or a more severe presentation that needed more intensive therapy in the beginning. Anakinra, etanercept, and adalimumab were used as second line in three resistant cases which then responded partially to treatments, and adalimumab was initiated as third line in one other resistant case, which is now on remission with medication.
In general, 84% of our patients are in remission: 36% without medication and 48% with medication. The time interval between therapy initiation and patient remission was less than or equal to 6 months for seven patients (25% of those on remission and 21% in general) and more than two years for seven patients (25% and 21%, respectively). By running Spearman’s correlation test in SPSS 27, we could not find an association between treatment response and the number of sites involved (P value = 0.6).
We have been following the patients between five months to 11 years, with a median of 3.5 years.
Patients’ characteristics are summarized in Table 1 and treatment lines are illustrated in Fig. 3.
Table 1.
Patients’ characteristics
| CRMO patients’ characteristics (N = 34) | |
| Age of onset, months, median (range) | 66 (5-144) |
| Age of diagnosis, year, median (range) | 85 (8-162) |
| Gender, female, n (%) | 17 (50%) |
| Fever, n (%) | 9 (27%) |
| Bone pain, n (%) | 33 (97%) |
| Arthralgia, n (%) | 9 (27%) |
| Arthritis, n (%) | 9 (27%) |
| Extraosseous manifestations, n (%) | 11 (32%) |
| Dermatologic manifestations, n (%) | 8 (23%) |
| Laboratory evaluations | |
| Elevated white blood cell count, n/total cases (%) | 23/34 (68%) |
| Elevated ESR, n/total cases (%) | 29/34 (85%) |
| Elevated CRP, n/total cases (%) | 24/34 (71%) |
| Elevated FANA, n/total cases (%) | 1/16 (1%) |
CRMO: chronic recurrent multifocal osteomyelitis; ESR: estimated sedimentation rate, CRP: C-reactive protein, FANA: fluorescent antinuclear antibody
Fig. 3.
Treatment distribution across different lines of therapy. The numbers represent total number of patients
Discussion
In this study, we present a cohort of 34 pediatric CRMO patients followed for up to 11 years. There is a high remission rate of 84%, with 36% of patients achieving remission without medication. The most involved bones were the vertebrae, pelvis, and tibia, and nearly a quarter of the patients had dermatologic manifestations, including psoriasis and palmar pustulosis. Our findings highlight the diagnostic complexity of CRMO, as five patients were ultimately diagnosed with alternative autoinflammatory diseases, and two initially misdiagnosed patients were later found to have malignancies. To our knowledge, this is one of the most extensive longitudinal cohorts of CRMO patients from our region and offers unique insights into diagnostic challenges and therapeutic responses in a resource-limited setting where whole-body MRI is not routinely available. These findings underscore the need for a comprehensive clinical approach and emphasize on the fact that CRMO is a diagnosis of exclusion [25].
Inflammatory markers of estimated sedimentation rate (ESR) and C-reactive protein (CRP) are usually mild-moderately increased in the setting of CNO/CRMO, while white blood cell (WBC) count is usually normal [1, 10, 14]. This was echoed in our findings. Very high levels of ESR and/or CRP might be suggestive of another diagnosis such an infection or malignancy [26]. Although serum markers and cytokine levels have been found characteristic in CRMO patients in some studies, further investigations are required to demonstrate their efficacy in diagnosis [20, 27].
CRMO is one of the most challenging diagnoses in our rheumatologic patients, as it is mostly a diagnosis of exclusion, needs extensive workup, and might yield a new diagnosis in a couple of years. Many patients are investigated or treated with other impressions for long before a diagnosis of CRMO is made [28]. It is also crucial not to overlook life threatening diagnoses, such as malignancies or ABDs, when considering a diagnosis of CRMO.
Skin manifestations are helpful in diagnosis of CRMO [29]. There were three presentations of psoriasis and one palmar pustulosis in our patients. These two manifestations are among the major criteria in Jansson criteria [9]. On the other hand, presence of skin involvement mandates more meticulous investigations for a probable ABD, such as SAPHO or DIRA, which are the diagnoses of two of our patients as well [30]. A scoring system has been recently proposed by Qiu et al. for delineating SAPHO from non-SAPHO patients, incorporating osseous manifestations (range 0–1 point), cutaneous lesions (range 0–3 points), radiological findings (range 0–4 points), and laboratory tests (range − 2 to 1 points). They set the score of 5 as the cut off with acceptable sensitivity and specificity [31].
Bone scintigraphy has been replaced in many centers by whole body MRI for diagnosis of CRMO [12, 22, 23, 32, 33]. Nevertheless, whole body MRI findings in CRMO have overlaps with other musculoskeletal diseases [34]. Since whole body MRI is not available in our country, scintigraphy is used widely for diagnosis of CRMO. Scintigraphy is a sensitive diagnostic modality; however, it does not have high specificity. We believe that the results should be interpreted considering the clinical finding, i.e., pain, tenderness, and swelling [35]. Our cases have been diagnosed and treated by expert pediatric rheumatologists with the mentioned approach. Whenever in doubt, we have used other diagnostic modalities, such as X ray, computed tomography (CT) scan, or MRI of the region. Asymptomatic regions with increased uptake might indicate non-inflammatory lesions such as brodie abscess or malignancies. Diagnosing arthritis based on scintigraphy should be done with caution, since increased uptake in growth plates of children can be interpreted as arthritis. Therefore, the label of arthritis was not assigned to our patients merely with scintigraphy findings, but when patients’ signs and symptoms confirmed it. When scintigraphy shows increased uptake without corresponding patient complaints, we recommend following up with no or minimal therapy, keeping an eye on possible emerging symptoms. In highly suspicious cases, other imaging techniques can be used to confirm.
Well-powered randomized controlled trials (RCTs) have not been performed in CRMO patients, which can be due to rarity of disease and absence of internationally agreed diagnostic criteria and outcome measures [36]. Treatment is mostly based on personal experience, retrospective case series, and the expert consensus treatment plan proposed by CARRA. NSAIDs have successfully been used as the first line therapy in many CRMO patients [35, 37, 38], and CARRA suggests non-biologic DMARDS methotrexate or sulfasalazine, TNF inhibitors with or without methotrexate, or bisphosphonates in CRMO patients who failed to respond to NSAIDs [16]. The strategy of prescribing TNF inhibitors along with methotrexate has become more favorable during the last years [39]. However, as no gold standard has been defined among these options, the choice of drugs highly depends on the accessibility and expert experience in a center. We have a high remission percentage with our current protocols, as we start with NSAIDs with or without methotrexate and move on to methotrexate as the second line. We have rarely been forced to use biologic drugs, bisphosphonates, or colchicine in our patients. In our experience, short courses of steroids help in managing disease flares. The Dutch national referral center for CNO is conducting a clinical trial on adults with resistant to treatment CRMO who receive pamidronate [40]. Some centers have reported favorable results for colchicine treatment in CRMO, but the reports are scarce [41]. We have provided an approach algorithm for CRMO based on what we learned from our cohort with an eye on what we found in the literature (Fig. 4).
Fig. 4.
Proposed approach to CRMO patients. CRMO: chronic recurrent multifocal osteomyelitis; NSAID: non-steroidal anti-inflammatory drug; MTX: methotrexate; TNF: tumor necrosis factor
Our cohort of 39 CRMO patients and five monogenic ABD patients provides invaluable information on these groups of patients in our region. We found acceptable remission rates in our CRMO patients with current treatment regimens. Unavailability of whole-body MRI might be a limitation for our precise diagnosis; on the other hand, CRMO cannot be diagnosed by MRI alone. We still consider CRMO as an exclusion diagnosis and need to carefully assemble the puzzle pieces of clinical manifestations, laboratory evaluations, and imaging, to reach the diagnosis of CRMO. Moreover, this is a study with a relatively small sample size and retrospective nature. Combining the cases with other centers and a prospective approach can yield more representative results and stronger evidence to develop standardized treatment protocols for CRMO.
Conclusions
Our cohort of CRMO patients showed an acceptable remission response to the current treatment regimen. Results of bone scintigraphy in suspected CRMO patients should be interpreted cautiously as an adjunct to clinical investigations. Special attention should be paid to extraosseous manifestations in suspected CRMO patients to avoid overlooking monogenic ABDs.
Acknowledgements
The authors gratefully acknowledge the invaluable input of Dr. Elaheh Baharvand to this research.
Abbreviations
- CRMO
Chronic recurrent multifocal osteomyelitis
- ABD
Autoinflammatory bone disorder
- CNO
Chronic non-bacterial osteomyelitis
- SAPHO
Synovitis, acne, pustulosis, hyperostosis, and osteitis
- DIRA
Deficiency of the interleukin-1 receptor antagonist
- PAPA
Pyogenic arthritis, pyoderma gangrenosum and acne
- ESR
Estimated sedimentation rate
- CRP
C-reactive protein
- WBC
White blood cell
- MRI
Magnetic resonance imaging
- NSAID
Nonsteroidal anti-inflammatory drug
- CARRA
Childhood Arthritis and Rheumatology Research Alliance
- DMARD
Disease-modifying anti-rheumatic drug
- TNF
Tumor necrosis factor
- MTX
Methotrexate
- AID
Autoinflammatory disorder
- FANA
Fluorescent antinuclear antibody test
- IL
Interleukin
- NLRP
NOD-like receptor protein
- CT
Computed tomography
- RCT
Randomized controlled trials
Author contributions
KA gathered the patients’ data, analyzed them, and wrote the manuscript. VZ presented some of the patients’ data, did conceptualization, and reviewed the article. MM, FTS, RA, and SRR each contributed to presenting some of the patients’ data and reviewed the article.
Funding
None.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
The ethical committee of Tehran University of Medical Sciences approved this study. Informed written consent was obtained from the patients or parents of patients for participating their children in this report of the patients.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Girschick H, Finetti M, Orlando F, Schalm S, Insalaco A, Ganser G, et al. The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever international registry. Rheumatology. 2018;57(7):1203–11. [DOI] [PubMed] [Google Scholar]
- 2.Hetrick R, Oliver M. Pediatric autoinflammatory bone disorders—a mini review with special focus on pathogenesis and inborn errors of immunity. Front Pead. 2023;11. [DOI] [PMC free article] [PubMed]
- 3.Kraus R, Laxer RM. Characteristics, treatment options, and outcomes of chronic non-bacterial osteomyelitis in children. Curr Treat Options Rheumatol. 2020;6:205–22. [Google Scholar]
- 4.Epsley S, Tadros S, Farid A, Kargilis D, Mehta S, Rajapakse CS. The effect of inflammation on bone. Front Physiol. 2021;11. [DOI] [PMC free article] [PubMed]
- 5.Greenhill CJ, Jones GW, Nowell MA, Newton Z, Harvey AK, Moideen AN, et al. Interleukin-10 regulates the inflammasome-driven augmentation of inflammatory arthritis and joint destruction. Arthritis Res Therapy. 2014;16:1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Cox AJ, Darbro BW, Laxer RM, Velez G, Bing X, Finer AL, et al. Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO). PLoS ONE. 2017;12(3):e0169687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hassan M, Assi H, Hassan M, Bies JJ, Prakash S, Hassan A, et al. Chronic Recurr Multifocal Osteomyelitis: Compr Literature Rev Cureus. 2023;15(8):e43118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Giedion A. Subacute and chronic symmetrical osteomyelitis. Ann Radiol Paris. 1972;15:329–42. [PubMed] [Google Scholar]
- 9.Jansson A, Renner E, Ramser J, Mayer A, Haban M, Meindl A, et al. Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology. 2007;46(1):154–60. [DOI] [PubMed] [Google Scholar]
- 10.Bhat CS, Anderson C, Harbinson A, McCann LJ, Roderick M, Finn A, et al. Chronic Non bacterial osteitis-a multicentre study. Pediatr Rheumatol. 2018;16:1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kostik MM, Kopchak OL, Maletin AS, Mushkin AY. The peculiarities and treatment outcomes of the spinal form of chronic non-bacterial osteomyelitis in children: a retrospective cohort study. Rheumatol Int. 2020;40(1):97–105. [DOI] [PubMed] [Google Scholar]
- 12.Sergi CM, Miller E, Demellawy DE, Shen F, Zhang M. Chronic recurrent multifocal osteomyelitis. A narrative and pictorial review. Front Immunol. 2022;13:959575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Hirota R, Emori M, Teramoto A. Fluorodeoxyglucose positron emission tomography evaluation of chronic recurrent multifocal osteomyelitis. Cureus. 2024;16(9):e69735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wipff J, Costantino F, Lemelle I, Pajot C, Duquesne A, Lorrot M, et al. A large National cohort of French patients with chronic recurrent multifocal osteitis. Arthritis Rheumatol. 2015;67(4):1128–37. [DOI] [PubMed] [Google Scholar]
- 15.Hu M, Zeng W, Zhang J, Yan H, Huang F, Xiong H, et al. Chronic recurrent multifocal osteomyelitis in pediatric patients: A Chinese single center observational study and literature review. Med (Baltim). 2024;103(49):e40805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Zhao Y, Wu EY, Oliver MS, Cooper AM, Basiaga ML, Vora SS, et al. Consensus treatment plans for chronic nonbacterial osteomyelitis refractory to nonsteroidal antiinflammatory drugs and/or with active spinal lesions. Arthritis Care Res. 2018;70(8):1228–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Schnabel A, Range U, Hahn G, Siepmann T, Berner R, Hedrich C. Unexpectedly high incidences of chronic non-bacterial as compared to bacterial osteomyelitis in children. Rheumatol Int. 2016;36(12):1737–45. [DOI] [PubMed] [Google Scholar]
- 18.Ramachandran S, Zhao Y, Ferguson PJ. Update on treatment responses and outcome measure development in chronic nonbacterial osteomyelitis. Curr Opin Rheumatol. 2023;35(5):255–64. [DOI] [PubMed] [Google Scholar]
- 19.Roderick M, Shah R, Rogers V, Finn A, Ramanan A. Chronic recurrent multifocal osteomyelitis (CRMO)–advancing the diagnosis. Pediatr Rheumatol. 2016;14(1):1–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Singhal S, Landes C, Shukla R, McCann LJ, Hedrich CM. Classification and management strategies for paediatric chronic nonbacterial osteomyelitis and chronic recurrent multifocal osteomyelitis. Expert Rev Clin Immunol. 2023;19(9):1101–16. [DOI] [PubMed] [Google Scholar]
- 21.Ma L, Liu H, Tang H, Zhang Z, Zou L, Yu H, et al. Clinical characteristics and outcomes of chronic nonbacterial osteomyelitis in children: a multicenter case series. Pediatr Rheumatol. 2022;20:1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Hofmann C, Holl-Wieden A, Reiser C, Beer M, Raab P, Morbach H, et al. Chronic non-bacterial osteomyelitis in children- five-year standardized follow-up of a prospective observational cohort in the pre-biological era. Pediatr Rheumatol Online J. 2025;23(1):50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kaut S, Van den Wyngaert I, Christiaens D, Wouters C, Noppe N, Herregods N, et al. Chronic nonbacterial osteomyelitis in children: a multicentre Belgian cohort of 30 children. Pediatr Rheumatol. 2022;20(1):41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Farzanefar S, Salehi Y, Abbasi M, Ziaee V. Chronic recurrent multifocal osteomyelitis: A case report. Iran J Pediatr. 2017;27(5).
- 25.Zhao Y, Oliver MS, Schnabel A, Wu EY, Wang Z, Marino A, et al. EULAR/American college of rheumatology classification criteria for pediatric chronic nonbacterial osteomyelitis. Arthritis & Rheumatology; 2025. [DOI] [PubMed]
- 26.Zhao Y, Dedeoglu F, Ferguson PJ, Lapidus SK, Laxer RM, Bradford MC et al. Physicians’ perspectives on the diagnosis and treatment of chronic nonbacterial osteomyelitis. International journal of rheumatology. 2017;2017. [DOI] [PMC free article] [PubMed]
- 27.Hofmann SR, Böttger F, Range U, Lück C, Morbach H, Girschick HJ, et al. Serum interleukin-6 and CCL11/eotaxin May be suitable biomarkers for the diagnosis of chronic nonbacterial osteomyelitis. Front Pead. 2017;5:256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Assari R, Ziaee V, Ahmadinejad Z, Vasei M, Moradinejad M-H. Caseous granuloma: tuberculosis or chronic recurrent multifocal osteomyelitis? Iran J Pediatr. 2014;24(6):770. [PMC free article] [PubMed] [Google Scholar]
- 29.Robert M, Giolito A, Reumaux H, Rossi-Semerano L, Guillemin C, Biarrotte L, et al. Extra-osseous manifestations in chronic recurrent multifocal osteomyelitis: a retrospective study. Rheumatology (Oxford). 2024;63(Si2):Si233–9. [DOI] [PubMed] [Google Scholar]
- 30.Matucci-Cerinic C, Attico A, Malattia C, Consolaro A, Rosina S, Breda L et al. Towards the definition of disease phenotypes in pediatric SAPHO syndrome: a National multicentric study. Rheumatology (Oxford). 2025. [DOI] [PubMed]
- 31.Qiu C, Li M, Wu Q, Zhou J, Liu T, Li J, et al. A statistical symptomatic evaluation on SAPHO syndrome from 56 cases of confirmed diagnosis and 352 cases of non-SAPHO involvement. Clin Rheumatol. 2024;43(5):1763–75. [DOI] [PubMed] [Google Scholar]
- 32.Korchi AM, Hanquinet S, Anooshiravani M, Merlini L. Whole-body magnetic resonance imaging: an essential tool for diagnosis and work up of non-oncological systemic diseases in children. Minerva Pediatr. 2014;66(3):169–76. [PubMed] [Google Scholar]
- 33.Falip C, Alison M, Boutry N, Job-Deslandre C, Cotten A, Azoulay R, et al. Chronic recurrent multifocal osteomyelitis (CRMO): a longitudinal case series review. Pediatr Radiol. 2013;43(3):355–75. [DOI] [PubMed] [Google Scholar]
- 34.Lanckoroński M, Gietka P, Mańczak M, Sudoł-Szopińska I. Whole-Body MRI at initial presentation of chronic recurrent multifocal osteomyelitis, juvenile idiopathic arthritis, their overlapping syndrome, and Non-Specific arthropathy. J Clin Med. 2024;13(4). [DOI] [PMC free article] [PubMed]
- 35.Girschick HJ, Krauspe R, Tschammler A, Huppertz HI. Chronic recurrent osteomyelitis with clavicular involvement in children: diagnostic value of different imaging techniques and therapy with non-steroidal anti-inflammatory drugs. Eur J Pediatr. 1998;157(1):28–33. [DOI] [PubMed] [Google Scholar]
- 36.Hedrich C, Beresford M, Dedeoglu F, Hahn G, Hofmann S, Jansson A, et al. Gathering expert consensus to inform a proposed trial in chronic nonbacterial osteomyelitis (CNO). Clin Immunol. 2023;251:109344. [DOI] [PubMed] [Google Scholar]
- 37.Catalano-Pons C, Comte A, Wipff J, Quartier P, Faye A, Gendrel D, et al. Clinical outcome in children with chronic recurrent multifocal osteomyelitis. Rheumatology (Oxford). 2008;47(9):1397–9. [DOI] [PubMed] [Google Scholar]
- 38.Schnabel A, Range U, Hahn G, Berner R, Hedrich CM. Treatment response and longterm outcomes in children with chronic nonbacterial osteomyelitis. J Rheumatol. 2017;44(7):1058–65. [DOI] [PubMed] [Google Scholar]
- 39.Beck NA, Roudnitsky E, Nuzzi LC, Padwa BL, Dedeoglu F. How have the diagnosis and treatment of chronic recurrent multifocal osteomyelitis changed over time?? J Oral Maxillofac Surg. 2023;81(2):238–47. [DOI] [PubMed] [Google Scholar]
- 40.Leerling AT, Cañete AN, Smit F, Hamdy NAT, van de Burgt A, Appelman-Dijkstra NM, et al. Pamidronate for pain in adult chronic nonbacterial osteitis: protocol of a randomized, double-blind, placebo-controlled trial. JBMR Plus. 2024;8(10):ziae114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Quintana-Ortega C, Prieto-Moreno Pfeifer A, Palomino Lozano L, Lancharro Á, Saavedra Lozano J, Villa-García ÁJ, et al. Colchicine as rescue treatment in two pediatric patients with chronic recurrent multifocal osteomyelitis (CRMO). Mod Rheumatol Case Rep. 2023;7(1):215–8. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.