Chronic Recurrent Multifocal Osteomyelitis (CRMO)
CRMO is a rare autoinflammatory bone disease that has a genetic component to disease susceptibility. It usually presents itself early in life and therefore, it is believed to be the pediatric presentation of SAPHO. The immune system wrongly attacks normal bone when there is no infection. This causes pain, redness and inflammation of the bone. It affects more the long bones.
There can be one or many sites involved (called multifocal). The affected areas tend to feel warm to the touch and difficult to move. Fever may be present with the bone inflammation. Attacks may last a few weeks or months. It is slightly seen more in girls than in boys. It primarily affects children and adolescents, but it can generally occur in all age groups. The peak onset of the disease is between 7 and 12 years of age.
The clinical signs and symptoms are nonspecific, hindering and delaying proper diagnosis.
Symptoms of presentation may range from mild unspecific bone pain, local swelling and warmth to severe pain, malaise, fevers and even fractures.
Symptoms of childhood nonbacterial osteomyelitis include:
Significant bone-related pain; particularly in the knee, ankle, wrist, back, pelvis or collarbone
Areas of pain which may be red, warm to the touch and difficult to move
Sterile (not bacterial) bone lesions resembling osteomyelitis are the hallmark of CRMO. Radiographs reveal osteolytic lesions with surrounding sclerosis (abnormal hardening of body tissue). Bacterial and fungal cultures from blood and bone biopsies are negative, and the granulocytic infiltrate seen on histology of affected lesions is nonspecific. Clinically CRMO presents itself with bone pain that is worse at night and occurs in the presence of fever. The onset is typically insidious (gradually causing harm). Swelling and warmth can occur overlying the affected areas. Laboratory investigations often reveal mild elevations in white blood cell count and erythrocyte sedimentation rate, but both of these may be normal.
Sporadic CNO covers a wide clinical spectrum from rather mild, time-limited, monofocal bone inflammation to severe chronically active or recurrent multifocal bone inflammation. These most severe presentations are referred to as chronic recurrent multifocal osteomyelitis (CRMO). All ethnicities from all geographic regions can be affected.
A strong association with other inflammatory diseases (such as inflammatory bowel diseases, palmar-plantar pustolosis, psoriasis vulgaris, Sweet syndrome, sclerosing cholangitis, arthritis, sacroiliac joint involvement, Still’s disease, Takayasu arteritis, ANCA-positive vasculitis, parenchymal lung disease and dermatomyositis) have been described.
CRMO is a diagnosis of exclusion. Many tests are often required. These include blood tests, X-rays, bone scans, MRI and often a bone biopsy.
Routine inflammatory parameters (WBC, white blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate) are usually normal or mildly elevated.
Imaging techniques are centrally important for diagnosing CNO/CRMO and excluding differential diagnoses. Particularly in early disease, magnetic resonance imaging (MRI) techniques are highly sensitive. They can detect bone edema (excess fluids in the bone marrow) even before bone erosions and sclerosis develop, and help assessing inflammation of surrounding tissues.
At the time of diagnosis, whole body imaging using MRI techniques (TIRM) should be performed to identify clinically silent lesions, particularly in the vertebral column.
MRI imaging techniques are also essential for the assessment of disease activity during follow-up, and the identification and monitoring of disease-associated sequelae, which may include fractures, inflammatory involvement and tissue damage to surrounding structures.
In unclear cases, bone biopsies are usually performed to exclude chronic infection, malignancies, or other systemic disease.
CRMO can be treated with medications. The goals for treatment are to reduce the pain, improve the ability to move and to improve the quality of life.
Most attacks of CRMO can be managed with nonsteroidal anti-inflammatory drugs (NSAIDs) such as Naproxen. NSAIDs are the first line of treatment. If NSAIDs are not effective, then these other drugs are often used:
DMARDs (methotrexate and sulfasalazine)
Cytokine blockers: TNF blockers (i.e. etanercept, infliximab, adalimumab) and IL-1 blockers (i.e. anakinra and canakinumab)
Anti-TNF treatment is needed in some patients to achieve remission. Also, sometimes methotrexate is used together with TNF together to try to avoid the potential of getting antibodies to the TNF inhibitor.
Apart from medications, physiotherapy can help keep the muscles strong and the joints moving properly.
Four genes have been identified that when mutated can cause sterile bone inflammation. Mutations in LPIN2, IL1RN, and FBLIM1 have been identified in humans with CRMO. CRMO are also IL-1 driven, but the role of IL-1 in non-syndromic cases is not clear.
- An Update on Autoinflammatory Diseases, Ginaldi et al, Curr Med Chem. 2013 Jan; 21(3): 261–269.
- CRMO by SickKids staff: https://www.aboutkidshealth.ca/Article?contentid=919&language=English
- “AB1121 Evaluation of cases diagnosed with crmo; single centre experience” by Kilic et al, BMJ Journals, Annals of the Rheumatic Diseases, Volume 77, Issue Suppl 2. https://ard.bmj.com/content/77/Suppl_2/1666.3
- “Chronic Recurrent Multifocal Osteomyelitis (CRMO): Presentation, Pathogenesis, and Treatment”, Hofmann, S.R., Kapplusch, F., Girschick, H.J. et al. Curr Osteoporos Rep (2017) 15: 542. https://doi.org/10.1007/s11914-017-0405-9