Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03433287 |
| Other study ID # |
Protokol-49657 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 1, 2015 |
| Est. completion date |
December 1, 2022 |
Study information
| Verified date |
May 2022 |
| Source |
Rigshospitalet, Denmark |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Chronic recurrent multifocal osteomyelitis (CRMO) is an immune-mediated chronic inflammatory
self- limiting disease with non-suppurative inflammation involving one or multiple bone foci.
A bacterial etiology has not yet been proven, but the investigators hypothesize that CRMO is
caused by chronic infection. Using existing knowledge of chronic infections combined with
sensitive molecular techniques, the hope is to elucidate the cause of CRMO by proving or
disproving bacteria as the underlying etiology.
In addition, a novel method, 18F-NaF-PET/MRI, will be investigated as to which it can improve
diagnosis of CRMO. The investigators hypothesize that 18F-NaF-PET/MRI will have higher
diagnostic accuracy than 99m-diphosphonate planar bone scintigraphy and SPECT/CT.
Description:
Epidemiology, clinical manifestations and prognosis Chronic recurrent multifocal
osteomyelitis (CRMO) is an immune-mediated chronic inflammatory self- limiting disease with
non-suppurative inflammation involving one or multiple bone foci. The disease occurs
primarily in children and adolescents. The estimated prevalence is 1-5/10.000 in the European
population, but since there are no studies providing precise estimates, the number of cases
can be both under- and overestimated.
The mean age of CRMO onset is 10 years. There is a female preponderance with twice as many
girls affected.
CRMO presents with bone pain with or without swelling and warmth. Some patients have a more
acute presentation with severe pain, malaise and fever. All bones except the neurocranium can
be affected. Involvement of the clavicle is classical, but the metaphyses of the long bones,
the mandible and the pelvis are also frequently affected. Vertebral involvement is seen in 4
to 30% of cases in retrospective studies.
Extra-skeletal involvement can include the skin, the eyes and the gastrointestinal tract.
Involvement of the skin may manifest as plantar pustulosis, psoriasis acne, pyoderma
gangrenosum and Sweet Syndrome. In the gastrointestinal tract, Crohn's disease or lesions
mimicking this disease have been associated with CRMO.
Previously, the prognosis of CRMO patients was considered favorable, as the disease is often
self-limiting, but newer studies have revealed that physical impairment may persist in up to
50% of patients. They typically suffer from chronic pain, bone deformities and have increased
fracture risk. Furthermore, there is evidence that CRMO may evolve into spondyloarthropathy
with clinical and radiological sacroiliitis.
Pathophysiology The pathophysiology of CRMO is largely unknown, but is regarded as an
auto-inflammatory bone disorder. Recent findings indicate that an imbalance between the
pro-inflammatory cytokines Interleukine-6 (IL-6) and Tumor Necrosis Factor α (TNF-α), and the
anti-inflammatory cytokine IL-10 may play a central role in the molecular pathology of CRMO.
High levels of IL-6 and TNF-α have been found in serum from CRMO patients. Furthermore, it
has been demonstrated that monocytes in patients with CRMO fail to produce IL-10. IL-10 is an
immunomodulatory cytokine that attenuates inflammation on multiple levels.
However, in bone biopsies from CRMO patients, the lesions resemble infectious osteomyelitis
histologically. Initially the predominating cell types are neutrophils, but in later disease
stages monocytes, macrophages, lymphocytes and plasma cells can be detected. In the final
disease stage of CRMO sclerosis and/or fibrosis can be seen. Infection with propionibacterium
acnes (P. acnes) or other commensal skin bacteria (i.e. Bartonella) have been suggested to
trigger CRMO. P. acnes may induce the toll-like receptors in the monocyte cell membrane,
resulting in mitogen-activated protein kinase (MAP kinase) activation leading to production
of pro-inflammatory cytokines. This could suggest that bacteria might be the reason for the
observed imbalance in the pro-inflammatory cytokines, but the presence of bacteria in
biopsies from CRMO lesions has only been demonstrated in single cases. However, in the
majority of reported cases the microbiological investigations were performed solely by the
use of microbiological culture and very few studies have utilized modern molecular
techniques. The methods applied in these studies are more than 10 years old and the
microbiological investigations are far more advanced today.
Discrepancy between bacteria found by culture swaps and modern molecular techniques have been
seen in chronic wounds and chronic infection in soft tissue fillers lesions. In these chronic
infections the bacteria are able to form a biofilm. The biofilm itself induces an ongoing
inflammatory reaction, as it provides a protected environment for the bacteria, in which they
may avoid the effects of antibiotics and host immune defence. Bacteria in biofilm grow in
small clusters like planktonic bacterial cells and this complicates identification of these
microorganisms in biopsy material.
Furthermore, a porcine model demonstrated chronic inflammation with formation of biofilm in
bone infected with Staphylococcus aureus. S. aureus is the most frequent cause of
osteomyelitis in children.
Diagnosis There are no validated diagnostic criteria and no diagnostic tests for CRMO. First
of all, it is important to exclude differential diagnoses as infection (mycobacterium, septic
osteomyelitis etc.), malignancies (bone tumors, metastases, leukemia or lymphoma), benign
tumors (osteoid osteoma, bone cysts, fibrosis etc.) or other auto-inflammatory disorders.
Biopsy is often needs to exclude an infections etiology or malignancy.
Bone scintigraphy using methylene diphosphonate or hydroxymethylene diphosphonate labeled
with Technetium 99m has high sensitivity in identifying symptomatic as well as asymptomatic
lesions. Monitoring disease activity during treatment or follow-up is also possible with bone
scintigraphy by evaluating the degree of tracer uptake in the lesions. Furthermore, the
technique can be useful in targeting biopsy to the most active lesion or identifying a more
easily accessible lesion than the presenting site.
Another frequently used modality to diagnose CRMO is whole-body Magnetic Resonance Imaging
(MRI). A study comparing MRI and planar bone scintigraphy found higher sensitivity of MRI in
identifying CRMO lesions. Especially lesions in the spine, pelvis and femora were better
visualized by MRI.
The functional imaging of bone scintigraphy and the morphological information from MRI can be
combined in Positron Emission tomography (PET)/MRI. PET/MRI using 18F-fluorodeoxy-glucose
(18FDG) is increasingly used clinically and in research settings in pediatric patients with
malignant disease. The PET-tracer fluoride 18-labeled sodium fluoride (18F-NaF) is a
positron-emitting bone-seeking tracer that provides higher resolution and better
signal-to-background images, compared to 99mTc-diphosphonate bone tracers. Studies of
18F-NaF-PET in pediatric patients conclude the technique is useful for investigating the
cause of bone pain in children.
There are several potential advantages of 18F-NaF-PET/ MRI. Simultaneous acquisition of PET
and MRI reduces the use of anesthesia and sedation, which is often required for younger
children. The effective radiation dose of 18F-NaF-PET is approximately 3 milliSievert (mSv),
which corresponds to the dose from a 99mTc-diphosphonate bone scintigraphy. Whole body MRI
eliminates the need for low-dose CT scan used in SPECT and therefore reduces total radiation
dose to the child.
The added value of 18F-NaF-PET/MRI in CRMO patients has not yet been investigated. The
hypothesis is that the technique has the potential of being a novel gold-standard method for
evaluating bone pathology in children, with the superior morphological images from MRI and
high resolution imaging of bone metabolism from 18F-NaF-PET.
