Chronic Nonbacterial Osteomyelitis Research Articles

Whole-Body Diffusion-Weighted Imaging in Chronic Recurrent Multifocal Osteomyelitis in Children.

ObjectiveChronic recurrent multifocal osteomyelitis/ chronic non-bacterial osteomyelitis (CRMO/ CNO) is a rare auto-inflammatory disease and typically manifests in terms of musculoskeletal pain. Because of a high frequency of musculoskeletal disorders in children/ adolescents, it can be quite challenging to distinguish CRMO/ CNO from nonspecific musculosketetal pain or from malignancies. The purpose of this study was to evaluate the visibility of CRMO lesions in a whole-body diffusion-weighted imaging (WB-DWI) technique and its potential clinical value to better characterize MR-visible lesions.Material and MethodsWhole-body imaging at 3T was performed in 16 patients (average: 13 years) with confirmed CRMO. The protocol included 2D Short Tau Inversion Recovery (STIR) imaging in coronal and axial orientation as well as diffusion-weighted imaging in axial orientation. Visibility of lesions in DWI and STIR was evaluated by two readers in consensus. The apparent diffusion coefficient (ADC) was measured for every lesion and corresponding reference locations.ResultsA total of 33 lesions (on average 2 per patient) visible in STIR and DWI images (b = 800 s/mm2 and ADC maps) were included, predominantly located in the long bones. With a mean value of 1283 mm2/s in lesions, the ADC was significantly higher than in corresponding reference regions (782 mm2/s). By calculating the ratio (lesion to reference), 82% of all lesions showed a relative signal increase of 10% or higher and 76% (25 lesions) showed a signal increase of more than 15%. The median relative signal increase was 69%.ConclusionThis study shows that WB-DWI can be reliably performed in children at 3T and predominantly, the ADC values were substantially elevated in CRMO lesions. WB-DWI in conjunction with clinical data is seen as a promising technique to distinguish benign inflammatory processes (in terms of increased ADC values) from particular malignancies.

Choosing the right treatment for patients with a severe course of chronic non-bacterial osteomyelitis (CNO) - pamidronate or TNF-α blockade?

Chronic non-bacterial osteomyelitis (CNO) is an inflammatory, non-infectious disorder of the skeletal system with unknown aetiology. Therapeutic options are NSAIDs, steroids and DMARDs (MTX or sulfasalazine). However, a considerable number of patients have a severe disease course and bisphosphonates or TNF-α blockade might be a therapeutic option. We performed a multicentre, retrospective chart review of all patients diagnosed with CNO in two paediatric rheumatology centres in the last 10 years and treated with pamidronate and/or TNF-α blockade. 17 patients were treated with pamidronate and/or TNF-α blockade. Out of these 17 patients, 10 were treated with pamidronate alone and showed clinical improvement. Three of the 17 patients were initially treated with TNF-α blockade; two had a positive response, one patient stopped therapy due to minor side effects. Two or one patients were initially treated with pamidonate or TNF-α blockade, respectively, but did not show clinical improvement. Interestingly, switching from pamidronate to TNF-α blockade or vice versa was associated with clinical improvement in these patients. One patient was treated with a combination therapy using pamidronate and TNF-α blockade and showed a good clinical response. Pamidronate and TNF-α blockade showed a good response in therapy refractory CNO patients. Severe adverse effects were not observed. However, some patients seem to benefit from one of the two therapeutic options in particular. Future studies are needed aiming to identify clinical and/or radiological parameters that might guide the decision to the appropriate treatment in an individual patient.

Serum biomarkers for the diagnosis of chronic recurrent multifocal osteomyelitis (CRMO)

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder mostly affecting children and adolescents. Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of CNO. It is characterized by recurring episodes of bone inflammation that can last for years and may cause chronic pain, pathological fractures, and disability. Despite recent advances in targeting disease mechanisms, the exact pathophysiology of CNO/CRMO remains unknown. Diagnosis of CNO can be challenging, because symptoms tend to be mild and highly variable, and is further complicated by the absence of widely accepted diagnostic criteria and disease biomarkers.

Comparison of different treatment approaches in chronic non-bacterial osteomyelitis.

Chronic non-bacterial osteomyelitis (CNO) is a heterogenous group of immune-mediated inflammatory bone diseases, which often co-exist with other rheumatic diseases. There are no approved treatments for CNO, except non-steroid anti-inflammatory drugs (NSAID). The efficacy of methotrexate (MTX), sulfasalazine, pamidronate (PAM), anti-IL1 and TNFα-inhibitors was shown in different reports, but there are some concerns about safety of pamidronate due to long-term accumulation and persistation in bone. The aim of our study was to compare the efficacy of non-randomized different treatment approaches in pediatric patient cohort with CNO.

Juvenile chronic non-bacterial osteomyelitis (CNO): Long term course of disease and response to treatment in a large institutional cohort

Chronic non-bacterial osteomyelitis (CNO) is an inflammatory disorder of the skeletal system of unknown etiology. Long-term follow-up and response to treatment data have rarely been reported. The aim of the study was to characterize the clinical, radiological, histological and laboratory data at juvenile CNO onset, and to analyze the long term treatment response.

Altered expression of IL-10 family cytokines in CRMO result in enhanced inflammasome activation

Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe presentation of the autoinflammatory bone disorder chronic nonbacterial osteomyelitis (CNO). The pathophysiology of CNO remains to be determined. We recently demonstrated reduced activation of mitogen-activated protein kinases ERK1 and 2 in monocytes from CRMO patients responsible for impaired activation of the transcription factor signaling protein (Sp-)1. This resulted in failure to express the immuno-modulatory cytokine IL-10. The IL10 gene, together with its homologues IL19 and IL20, is organized in the 145 kb spanning IL10 cytokine cluster on chromosome 1q32. In most cells, including monocytes, IL-10 cytokine family members are co-regulated in response to certain stimuli. IL-10 and IL-19 mainly have immune-modulating functions, while IL-20 acts as a pro-inflammatory cytokine contributing to inflammatory bone-loss. The NLRP3 inflammasome is a multi-protein complex forming in response to innate stimuli, subsequently mediating the cleavage and release of IL-1β. Enhanced inflammasome activation in IL-10 deficient mice was linked with bone-loss. Convincing evidence of this mechanism playing a role in CNO, however, is lacking.

Pediatric chronic non-bacterial osteomyelitis in Goteborg, Sweden

Chronic non-bacterial osteomyelitis (CNO) is today included among the autoinflammatory bone diseases. An alternative term in the literature is chronic recurrent multifocal osteomyelitis (CRMO). The etiology of the autoinflammatory bone diseases is unknown except for a few extremely rare monogenic diseases.

Cronic non-bacterial osteomyelitis (CNO) in a cohort of pediatric patients: clinical, biological and radiological response to treatment with Anakinra

Chronic nonbacterial osteomyelitis (CNO) is the most common autoinflammatory bone disorder in childhood (1). Diagnostic information is provided by TC-99 bone scintigraphy (BS) and/or whole body MRI. Non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, bisphosphonates and tumour necrosis factor inhibitors have been used until now with variable response (2).

Chronic nonbacterial osteomyelitis in children: a retrospective multicenter study.

BackgroundTo determine the clinical presentation, current treatment and outcome of children with nonbacterial inflammatory bone disease.MethodsRetrospective multicenter study of patients entered into the Swiss Pediatric Rheumatology Working Group registry with a diagnosis of chronic nonbacterial osteomyelitis (CNO) and synovitis acne pustulosis hyperostosis osteitis (SAPHO) syndrome. The charts were reviewed for informations about disease presentation, treatment, course and outcome.ResultsForty-one children (31 girls and 10 boys) from 6 pediatric hospitals in Switzerland diagnosed between 1995 and 2010 were included in the study. The diagnosis was multifocal CNO (n = 33), unifocal CNO (n = 4) and SAPHO syndrome (n = 4). Mean age at onset of CNO was 9.5 years (range 1.4–15.6) and mean follow-up time was 52 months (range 6–156 months). Most patients (n = 27) had a chronic persistent disease course (>6 months), 8 patients had a course with one or more relapses and 6 patients had only one episode of CNO. Forty nine percent had received at least one course of antibiotics. In 57 % treatment with nonsteroidal anti-inflammatory drugs (NSAID) was sufficient to control the disease. Twelve out of 16 children with NSAID failure subsequently received corticosteroids, methotrexate, TNF α inhibitors, bisphosphonates or a combination of these drugs.ConclusionsIn a multicenter cohort of 41 children 22 % started with unifocal lesion with a significant diagnostic delay. A higher proportion presented with chronic persistent disease than with a recurrent form. An osteomyelitis in the pelvic region is significantly associated with other features of juvenile spondylarthritis.

Aggressive Therapy Reduces Disease Activity without Skeletal Damage Progression in Chronic Nonbacterial Osteomyelitis.

To retrospectively assess changes in disease activity and skeletal damage in children with chronic nonbacterial osteomyelitis (CNO) after infliximab and methotrexate, with or without zoledronic acid or nonsteroidal antiinflammatory drug (NSAID) monotherapy, using a standardized magnetic resonance imaging (MRI) approach. Treatment-related changes in clinical and MRI measures from aggressive therapy and NSAID monotherapy groups (n = 9 per group) were evaluated using nonparametric methods. Pain, physical function, physician global assessment, inflammatory markers, nonvertebral inflammatory lesion number, and maximum bone edema score all improved significantly with aggressive therapy (p < 0.03), whereas only the maximum soft tissue inflammation severity decreased (p = 0.02) with NSAID monotherapy. Vertebral deformities and physeal damage did not worsen in the aggressive therapy group but 1 in the NSAID group had worsening of growth plate damage. An aggressive treatment regimen in CNO improved clinical and imaging measures of disease activity without progression of skeletal damage.

PP18. A case series of chronic non-bacterial osteomyelitis

PP18. A case series of chronic non-bacterial osteomyelitis

New discoveries in CRMO: IL-1β, the neutrophil, and the microbiome implicated in disease pathogenesis in Pstpip2-deficient mice.

Chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are autoinflammatory disorder(s) in which sterile osteomyelitis is frequently accompanied by inflammatory conditions of the joints, skin, or intestine. Patients with CRMO commonly have a personal or family history of psoriasis, inflammatory bowel disease, and inflammatory arthritis, suggesting shared disease pathogenesis. Work by our group and others has demonstrated that dysregulation of interleukin-1 (IL-1) signaling can drive sterile osteomyelitis in the two human monogenic forms of the disease. Recent work in the chronic multifocal osteomyelitis (cmo) mouse model demonstrates that the disease is IL-1-mediated, that neutrophils are critical effector cells and that both caspase-1 and caspase-8 play redundant roles in mediating the cleavage of pro-IL-1β into its biologically active form. Recent data in the cmo mouse demonstrate that dietary manipulation alters the cmo microbiome and can prevent the development of osteomyelitis. Further investigation is needed to determine the specific components of the diet that result in protection from disease and if this finding can be translated into a treatment for human CRMO.

A large national cohort of French patients with chronic recurrent multifocal osteitis.

To document more fully the characteristics of chronic recurrent multifocal osteomyelitis (CRMO) in pediatric patients, to collect data on the outcomes and management of the disease, and to define prognostic factors. One hundred seventy-eight patients were included (123 female patients and 55 male patients), with a mean ± SD age at diagnosis of 10.9 ± 2.9 years. Inclusion criteria were a diagnosis of CRMO, evidence of at least one lesion of osteitis confirmed by imaging, and development of the syndrome before age 18 years. Longitudinal clinical and imaging studies revealed that only 12 of 178 CRMO patients (7%) had unifocal lesions at the last medical visit. We were able to apply the clinical chronic nonbacterial osteomyelitis score to 110 of 178 patients (62%), which indicated that bone biopsy could have been avoided in 27 cases (25%). At the last medical visit, disease was in remission in only 73 of 171 patients (43%) (41% receiving therapy) after a mean ± SD of 47.9 ± 38.9 months; 44 of 171 patients (26%) experienced sequelae. Using cluster analysis, the CRMO cohort was separated into 3 homogeneous phenotypes (severe, mild, and intermediate). Patients with the severe phenotype had the worst prognosis. This group was entirely composed of male patients, most of whom had the multifocal form of CRMO and inflammatory syndrome. Patients with the mild phenotype had the best prognosis. This group was primarily composed of female patients with a unifocal form of CRMO and infrequent clavicle involvement and inflammatory syndrome. Patients with the intermediate phenotype had a good prognosis but greater reliance on treatment. This group primarily included female patients with multifocal lesions and inflammatory syndrome. This is the largest CRMO cohort described in the literature to date. Clinical evolution and imaging investigations confirmed the multifocal pattern of the disease. Three distinct subgroups of CRMO patients were distinguished, with very different prognoses.

Severe chronic non-bacterial osteomyelitis associated with MPO deficiency

We report a severe case of chronic non-bacterial osteomyelitis (CNO) associated with total myeloperoxidase (MPO) deficiency. Chronic non-bacterial osteomyelitis (CNO) is often considered an autoinflammatory disease. In pediatric literature CNO is often referred to as chronic recurrent multifocal ostemyelitis (CRMO). CNO is occasionally associated with extremely rare monogenic disease but in most cases the etiology is unknown. MPO deficiency is characterized by low levels of leukocyte MPO, and in some cases even total lack of the enzyme. The condition is seldom associated with pathology; severe Candida infection occurs in about 5% of cases and there is a slightly increased frequency of minor infections.

The toll-like receptor 4 agonist MRP8/14 protein complex (calprotectin) in autoinflammation: potential biomarker in chronic nonbacterial osteomyelitis – a case report

The cytoplasmic S100 proteins derived from cells of myeloid origin. Calprotectin (MRP8/14 protein complex) might be a biomarker either for autoinflammation and autoimmunopathy. Since autoinflammatory diseases might be a diagnostic challenge calprotectin may be helpful in the diagnosis of autoinflammatory diseases. Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory, noninfectious disease. CNO describes a wide spectrum from a monofocal bone lesion to the chronic recurring multifocal osteomyelitis (CRMO). Laboratory and histopathological findings are nonspecific. In some patients systemic inflammatory signs such as elevated acute phase proteins cannot be found.

Imaging of refractory chronic recurrent multifocal osteomyelitis succesfully treated with etanercept and methotrexate

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare form of chronic nonbacterial osteomyelitis of unknown etiology and, to date, there is no uniformly effective treatment for this disease. Role of magnetic resonance imaging (MRI) to detect lesions in CRMO has increased last years.

Does hyperbaric oxygen therapy truly help in the treatment of chronic recurrent multifocal osteomyelitis?

Chronic recurrent multifocal osteomyelitis (CRMO) is a non – infectious inflammatory bone disorder of yet to be determined etiopatology. However, it is considered that the imbalance between pro- and anti- inflammatory cytokines plays the main role in the disease expression. CRMO represents the most severe form of chronic nonbacterial osteomyelitis and predominantly affects children and adolescents, primary girls. The clinical presentation is variable onset of bone pain with or without fever, local soft tissue swelling or warmth with an unpredictable clinical course and spontaneous remissions. Methaphyses of long bones are the most specific affected sites. CRMO is a diagnosis of exclusion because of its clinical presentation and laboratory findings that are not disease-specific and vary between patients.

Chronic nonbacterial osteomyelitis.

Chronic nonbacterial osteomyelitis encompasses a spectrum of sterile bony inflammatory lesions that are incompletely understood and not well known in the otolaryngology community. Current research is investigating the underlying immunologic mechanisms postulated to be responsible for chronic nonbacterial osteomyelitis. Disruption in the innate balance between proinflammatory and anti-inflammatory cytokines is currently felt to be responsible, with several specific pathways identified as potential targets for treatment. Additionally, Propionibacterium sp. and other infectious organisms are now felt to be triggers of inflammation, rather than true causative agents. Nonsteroidal anti-inflammatory medications remain the first-line treatment for this condition. Additional medical therapy, such as glucocorticoids, can be indicated in refractory cases. Surgical options are available for recalcitrant situations, although the potential for recurrence after surgery remains, as the underlying mechanism has not been addressed with surgery alone.

PReS-FINAL-2233: Retrospective analysis of different treatment strategies in chronic non-bacterial osteomyelitis

Results Fever at onset, high painVAS and parental VAS scores highly correlated with risk of relapse disease course. Treatment: effectiveness of NSAID only 3/10 (30%), SSZ - 1/5 (20%), corticosteroids - 0/3 (short-term effect only), MTX - 4/7 (57.1%), pamidronate (PAM) with partial response 2/12 (16.7%) and with complete response 10/12 (83.3%). Biologics - adalimumab and etanercept were effective in 3/4 (75%) patients, who fail to NSAID, MTX, PAM and SSZ. During disease course treatment lead to decreasing sings of disease activity, such as: parental VAS (p = 0.015), pain VAS (p = 0.026), MDVAS (p = 0.026), CRP (p = 0.0008), WBC (p = 0.006), ESR (p = 0.00024), PLT (0.014). The main effectiveness belonged to PAM (p = 0.003) and biologics (p = 0.07) in decreasing of pain VAS (-100% and -80%), parental VAS (-92% and -74%) and MD VAS (-93% and -70%, respectively). We calculated the cumulative probability of survival (event of interest: CNO flare) in the entire patient sample, depending the kind of treatment (PAM, MTX and NSAID) obtained by the Kaplan-Meier method. Significant difference was proved comparing 3 therapeutical branches (p = 0.028). MTX treatment was effective (p = 0.04), as well as PAM (p = 0.01) than NSAID. Only flulike syndrome during PAM treatment was in 10/12 (83.3%). No any others side effects were reported. All patients who had flu-like syndrome on first infusion had complete response to PAM, vice verse patients, who had no such complication had only partial response to this treatment.

Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO)

Sterile bone inflammation is the hallmark of autoinflammatory bone disorders, including chronic nonbacterial osteomyelitis (CNO) with its most severe form chronic recurrent multifocal osteomyelitis (CRMO). Autoinflammatory osteopathies are the result of a dysregulated innate immune system, resulting in immune cell infiltration of the bone and subsequent osteoclast differentiation and activation. Interestingly, autoinflammatory bone disorders are associated with inflammation of the skin and/or the intestine. In several monogenic autoinflammatory bone disorders mutations in disease-causing genes have been reported. However, regardless of recent developments, the molecular pathogenesis of CNO/CRMO remains unclear.Here, we discuss the clinical presentation and molecular pathophysiology of human autoinflammatory osteopathies and animal models with special focus on CNO/CRMO. Treatment options in monogenic autoinflammatory bone disorders and CRMO will be illustrated.