Chronic Nonbacterial Osteomyelitis: Challenges of a Rare Rheumatic Disease

Written by Dr Daire O’Leary, Dr Orla Killeen National Centre for Paediatric Rheumatology, Children’s Health Ireland at Crumlin UCD Centre for Arthritis Research, School of Medicine, UCD

Chronic nonbacterial osteomyelitis (CNO), which is also known as chronic recurrent multifocal osteomyelitis (CRMO) is a rare inflammatory bone disease (OMIM 259680). It predominantly affects children and adolescents. These children usually present with localised bone pain which may be associated with swelling or loss of function depending on the site involved. Less commonly, they may also present with pathological fracture of the affected bone. Most children are otherwise well and the onset of bone pain or swelling may be gradual. However, some are systemically unwell with fever and markedly raised inflammatory markers. In adults, similar bony inflammation is seen in Synovitis Acne Pustulosis HyperOstosis (SAPHO) syndrome; CNO and SAPHO may be represent different phenotypes of the same inflammatory process.

Challenges of a rare disease

Until recently, CNO was thought to affect 1 in a million children and adolescents. However, more recent research suggests it is as common as bacterial osteomyelitis in this age-group, affecting 1 in 100,000. Therefore, many children undergo a lengthy period of investigation and referral through primary and secondary care before reaching a diagnosis. Some of this diagnostic journey is currently unavoidable because there are no specific markers of disease which allow us to differentiate CNO from important differential diagnoses. Therefore, infectious and malignant causes of these symptoms must be excluded before CNO is considered.

Diagnostic scoring systems have been developed to try to reduce the time from symptom-onset to diagnosis. In particular, these scoring systems aim to remove the need for invasive investigations. However, these scores have not been validated outside the original study populations and therefore have not been widely adopted. Diagnosis is highly reliant on access to radiology. In most children with CNO, multifocal lesions are seen on whole body MRI. The presence of multiple lesions affecting the metaphyses of long bones or the clavicles in an otherwise systemically well child, in particular one with a chronic disease course, may mean that a bone biopsy is not required. Where the diagnosis is uncertain, bone biopsy is required to exclude infection and malignancy. Bone biopsy may be necessary if the child is systemically unwell, if a single or atypical lesion is found on whole body MRI or if there is likely to be a significant delay in obtaining a whole body MRI. Timely access to MRI is particularly challenging for children who require a general anaesthetic in order to stay still for the duration of the scan.

Once the diagnosis of CNO is made, it is very difficult to provide families with an accurate prognosis. The course of this disease is poorly understood with few studies involving long-term follow-up. There is also significant phenotypic variation both within and between published cohorts. The majority of children have multiple lesions with relapsingremitting symptoms. A minority have a single lesion and an even smaller minority have a single symptomatic episode. While most series report good outcomes for children with CNO, there are short- and long-term complications. Some of these complications depend on the site of bony inflammation – for example, scoliosis in children with vertebral involvement or limblength discrepancy in those with inflammation of the growth plate of long bones. Other complications do not appear to depend on the site of inflammation, however. Some children develop amplified pain or functional pain disorders which can have a serious impact on school attendance. There are additional phenotypic differences which complicate the prognosis. Some children have inflammatory disease affecting sites other than their bones. Children may have inflammatory arthritis which occurs at sites distant from their bony lesions. Others have skin inflammation such as psoriasis or severe acne. It remains unclear whether children with bone disease alone follow the same natural history of disease as those with inflammation elsewhere.

The phenotypic variability and unpredictable clinical course lead to further challenges developing treatment pathways. To date, there has only been a single pilot randomised controlled trial (RCT) comparing different treatment modalities for Chronic nonbacterial osteomyelitis. Many children respond symptomatically to treatment with nonsteroidal anti-inflammatories (NSAIDs). Many relapse once NSAIDs are weaned or flare despite ongoing NSAID use. After NSAIDs, a wide range of second-line treatments have been used in different case series; systemic corticosteroids, disease-modifying antirheumatic drugs (DMARDs), bisphosphonates and anti-tumour necrosis factor (anti-TNF) biologic agents. A consensus treatment plan was recently published by the Childhood Arthritis and Rheumatology Research Alliance which provides recommendations for the first 12 months of treatment in children who do not achieve remission with NSAIDs. However, in the absence of RCT’s, the choice of second-line treatment depends on family and physician preference. Variation in how treatment response and remission are defined and reported in different case series further compounds the difficulty agreeing a treatment plan.

Chronic nonbacterial osteomyelitis in the Irish population

In Ireland, over 100 children and adolescents have been diagnosed with Chronic nonbacterial osteomyelitis in the last 15 years. These children attend the National Centre for Paediatric Rheumatology in Children’s Health Ireland at Crumlin and Temple Street.

To date, we have detailed demographic, clinical, laboratory and radiologic data on over 50 of these children and adolescents. This information reveals some interesting information about Irish children and adolescents with Chronic nonbacterial osteomyelitis. A comparison of the data with other case series demonstrates the importance of providing the opportunity for Irish people to participate in rare disease research.

While there were similarities between the Irish cohort and those previously published, there were also some interesting differences. Demographic characteristics including median age of onset, time to diagnosis and a female preponderance were similar to those previously reported (Table 1). The incidence of unifocal disease was lower than that seen in most cohorts. However, all patients in the Irish study underwent at least one whole-body MRI which reduces the likelihood of asymptomatic lesions remaining undetected. The frequency at which different bones were involved is also similar to that seen in other studies (Figure 1).

Differences arose in terms of the frequency with which other inflammatory diseases were identified and the response to treatment. Overall, 40% of the Irish cohort have extraosseous manifestations of Chronic nonbacterial osteomyelitis which is more frequent than in other cohorts. In particular, cutaneous inflammation was more common; psoriasis affects just over 20% of the Irish cohort. Most other studies report psoriasis rates of less than 10%. A positive family history of arthritis, inflammatory bowel disease and psoriasis is also more common in the Irish cohort with reports of these diseases in over 2/3 of families.

Treatment response rates to NSAIDs and bisphosphonates are lower in the Irish cohort than previous publications. This led to a higher proportion of patients progressing to non-biologic and biologic DMARDs. Response and remission rates following methotrexate monotherapy were lower than those reported in other cohorts. Response and remission rates for anti-TNF agents were similar to those in other cohorts. At last follow-up, over 90% of patients were clinically improved or in remission. Overall, complications occurred in almost half the cohort. Psychosocial complications were more frequent than physical complications. Physical complications occurred exclusively in those with vertebral involvement; vertebral compression fractures or loss of vertebral height. The psychosocial complications were pain amplification syndrome (PAS) and prolonged school absenteeism. Twenty percent of children developed pain amplification syndrome. Ten percent had prolonged school absenteeism and PAS while 10% had prolonged school absenteeism without PAS. Prolonged school absenteeism in the years following diagnosis excluded absenteeism for scheduled outpatient care. Psychosocial complications were more frequently reported than in other cohorts.

It is unclear whether the presence of more extraosseous inflammation and psychosocial complications indicate a more inflammatory CNO phenotype in the Irish cohort, which in turn requires a higher rate of progression to DMARDs. However, it highlights the importance of including Irish families in research. Since March 2021, the National Centre for Paediatric Rheumatology, CHI at Crumlin, offers children with CNO and other rheumatic diseases the opportunity to participate in the paediatric rheumatology biobank, supported by the Arthritis Research Coalition (ARC). Collecting and analysing data through the biobank will help us determine if the Irish experience of rheumatic diseases mirrors that of other populations. It will help physicians decide if research from other populations will benefit the children and adolescents attending our services. In addition, it will increase opportunities for families to participate in research collaborations internationally which will be essential in understanding rare diseases such as Chronic nonbacterial osteomyelitis.

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