Chronic Nonbacterial Osteomyelitis and Chronic Recurrent Multifocal Osteomyelitis in Children

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Key points

  • Chronic nonbacterial osteomyelitis (CNO; also known as chronic recurrent multifocal osteomyelitis) is an inflammatory/autoinflammatory bone disease that primarily affects children and adolescents. It is a diagnosis of exclusion.

  • Often the diagnosis of CNO in children is delayed because of a lack of awareness and the occult nature of CNO. Prompt referral to pediatric rheumatology can help establish a diagnosis and determine appropriate treatment.

  • Imaging studies, especially MRI with short tau

Nomenclature

The disease has gone by many names, making nomenclature complicated (Box 1). It was first described as a symmetric multifocal osteomyelitis and later given the name chronic recurrent multifocal osteomyelitis (CRMO).1 However, because the disease may begin or stay unifocal, CRMO may not be an accurate term for these patients. Thus, the term CNO has been proposed as an umbrella term.

Incidence and demographics

In 2011, the annual incidence of CNO in Germany was reported to be 0.4 per 100,000 children,2 as compared with the reported incidence range of infectious osteomyelitis of 10 to 80 per 100,000 children per year.3 However, during 2004 to 2014 in a single center in Germany, of the 109 children seen for osteomyelitis, 53% were categorized as infectious and 47% as noninfectious, unexpectedly similar proportions.3 A single center in Britain reported increased patient referral for CNO after a letter

Major differences from adult chronic nonbacterial osteomyelitis (also known as synovitis, acne, pustulosis, hyperostosis, osteitis)

  • Cutaneous involvement in children is not as common as in adults.

  • Common bone sites affected are long bones in children compared with the sternum and clavicles in adults.

Delays in diagnosis are common

The median time between initial symptoms and diagnosis of CNO is 2 years.9 Forty-eight percent of children were not evaluated by a pediatric rheumatologist until at least 12 months after their first symptom occurred. The delay of diagnosis was likely related to the insidious development of pain, minimal findings on clinical examination, relatively normal laboratory studies, and lack of awareness of this condition. A patient survey study discussed delays in diagnosis for 21 patients who had a

When to consider chronic nonbacterial osteomyelitis

CNO should be considered in a child who has intermittent or persistent focal bone or joint pain of the lower extremities, clavicle, spine, and/or mandible. The pain is worse at night and may interfere with sleep, and the child usually has point tenderness of the affected site. Children with more superficially affected bones (eg, tibia, fibula, clavicle, and mandible) can also have local swelling and warmth (Fig. 1).

How chronic nonbacterial osteomyelitis presents

CNO typically presents as insidious bone pain with or without systemic features; however, it can also present as acute onset of pain. Young children may stop using an affected limb. Common features of CNO are shown in Box 2. Often there are minimal to no objective changes overlying the lesions, but point tenderness is common when the disease is active. The pain often results in reduced physical activities; school attendance may be affected, particularly if lower extremities and/or axial bones

Disease morbidity

The most common complications of CNO are fractures in affected bones (especially of the vertebrae) and deformities due to growth alterations. Kyphosis may occur in patients with multiple vertebral compression fractures. Pathologic fractures in the long bones may occur when there is accelerated bone resorption. Leg-length discrepancy may result after the growth plate is damaged by CNO (Fig. 3A) or due to bony overgrowth of the epiphysis from excess inflammation. Angulation of a joint may occur

Impact on quality of life

CNO causes a significant impact on the quality of life in affected children. School absence due to pain, fatigue, and frequent medical visits are common. Assistive devices may be needed in some children. Inability to participate in desired sports activity because of limited function is frequent. Based on a family survey, most parents reported that their child with CNO was challenged to perform daily tasks or hobbies because of pain, fatigue, and physical limitation.9 Another family survey study

Associated conditions

In a minority of patients, other coexisting conditions, including psoriasis vulgaris, palmar plantar pustulosis, and inflammatory bowel disease, may occur before, concurrently with, or after the diagnosis of CNO. Psoriasis has been reported in 2% to 17% (Fig. 4), palmar plantar pustulosis (PPP) in 3% to 20%, and inflammatory bowel disease (IBD) in 3% to 7% of patients with CNO.5, 6, 7, 8 One proposed diagnostic criterion considers the presence of one of these comorbid conditions to help support

Differential diagnosis or mimics

The differential diagnosis of CNO is broad and includes infections of the bone or joint, malignancy, benign bone lesions, metabolic bone disease, amplified pain syndromes, and nutritional deficiencies.

The common differential diagnosis of CNO includes the following

  • Leukemia

  • Lymphoma

  • Langerhans cell histiocytosis

  • Primary malignant bone disease

  • Benign bone tumor (osteoma, endo-chondroma)

  • Infectious osteomyelitis

  • Septic arthritis

  • Avascular necrosis (osteonecrosis)

  • Vitamin C deficiency (scurvy with bony

Imaging

Whole-body MRI is considered the gold standard imaging modality by experts. Patients almost always have a radiograph taken initially. However, MRI is preferred for its sensitivity and lack of radiation. Typical findings of CNO from each imaging modality are listed next.

Pathogenesis of chronic nonbacterial osteomyelitis

CNO is considered an autoinflammatory disease. Components of the innate immune system, including neutrophils, macrophages, monocytes, and associated cytokines, contribute to disease pathogenesis. Increased proinflammatory cytokines, such as TNF-α and interleukin (IL)-6, and decreased antiinflammatory cytokines, especially IL-10, were reported in children with CNO.23 IL-6 and C-C motif chemokine 11/eotaxin have been shown to sufficiently differentiate patients with CNO from healthy children and

How chronic nonbacterial osteomyelitis is treated

Nonsteroidal antiinflammatory drugs (NSAIDs) are often used as the first-line treatment of children with CNO.8, 17, 31 Naproxen at 10 mg/kg (maximum 500 mg) twice daily is the most commonly used NSAID. Other NSAIDs used for treatment are indomethacin and meloxicam. Based on the study of Beck and colleagues,8 responders have significant pain relief and a decrease in the number of bone lesions on MRI by as early as 3 months. Patients who have persistent bone pain and hyperintense signal within

Clinical monitoring

Different criteria have been reported to define clinical responses to treatments in CNO. Most of these criteria included 3 main components: pain due to CNO, inflammatory markers (ESR and CRP), and imaging findings. Effective treatments may lead to complete resolution of pain and normalized ESR and CRP, which may precede the complete resolution of lesions on MRI. A composite score, PedsCNO score, includes ESR, number of lesions on MRI, physician global assessment of disease activity,

Management of clinically asymptomatic lesions shown in MRI

Asymptomatic lesions have often been reported, and their clinical significance has not been fully elucidated.8, 14, 37 Currently, most physicians do not make clinical decisions based on asymptomatic lesions unless vertebral bodies are affected, which potentially poses a high risk of spinal fracture.

What is the prognosis for chronic nonbacterial osteomyelitis?

Long-term observational studies have reported an average 40% rate of clinical remission (defined as absence of bone pain) in children with CNO after 1 to 5 years of follow-up.5, 6, 7, 8, 34 The only long-term follow-up study done on adult patients with childhood onset of CNO showed a persistent presence of active bone lesions, defined as increased signal intensity on STIR images, in 10 of 17 patients who were available for a median of 15-year follow-up.14 Among these 10 patients, 6 had ongoing

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    Disclosure: Dr Y. Zhao received research funding from CARRA and Bristol-Myers Squibb (IM101-691_Zhao). Dr P.J. Ferguson’s work is supported by R01AR059703 from NIH/NIAMS.

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