Chronic nonbacterial osteomyelitis in children: a multicenter case series

Design

Retrospective review

N= 19

Objective

To evaluate demographic, clinical, laboratory, imaging, histopathology characteristics, and treatment responses of pediatric chronic nonbacterial osteomyelitis (CNO) patients

Study Groups

All patients (N= 19)

Inclusion Criteria

Patients aged < 18 years, with CNO

Exclusion Criteria

Not specified

Methods

Patient data were compiled from clinical records from three tertiary centers in Chile. Treatment selection was determined per clinician discretion. Generally, nonsteroidal anti-inflammatory drugs (NSAID) were used as first-line options, followed by disease-modifying antirheumatic agents. Patients refractory to this treatment were then given tumor necrosis factor (TNF) inhibitors or bisphosphonates. 

Duration

Admitted between 2007 and 2019

Outcome Measures

Treatment response

Baseline Characteristics

All patients (N= 19)

Age, years (range)

Female

Follow-up, months

Clinical features

Number of lesions

Axial skeleton involvement

Appendicular skeleton involvement

4

36%

95% 

Initial symptoms

Bone pain

Limp

Swelling

Fever

100%

26%

11%

11%

Distribution of involvement

Upper limb

Lower limb

Axial skeleton

21%

90%

36%

Comorbidities

Any autoimmunity

Juvenile idiopathic arthritis

Uveitis

Erythema nodosum

26%

21%

5%

5%

All patients had a recurrent multifocal disease pattern. 

Results

Endpoint

All patients (N= 19)

Treatment selection

NSAIDs

Methotrexate

Corticosteroid

Sulfasalazine

Bisphosphonates

Adalimumab

Mycophenolate

18

12

7

5

5

4

1

Adverse Events

Study Author Conclusions

In conclusion, the present study describes the first series of CNO from Latin America and highlights the similarities and differences with patients from other latitudes. Increasing awareness of this condition in developing nations is of uttermost importance to decrease time to diagnosis, improve access to treatment, and reduce complications of this rare disease.

InpharmD Researcher Critique

As this study was conducted in Chile, standards of care may differ from the United States. Furthermore, due to the retrospective study design and small sample size, this study affords minimal generalizability. No details regarding adalimumab treatment regimen were provided. 

Biological therapy in refractory chronic nonbacterial osteomyelitis: A case series of 19 patients

Design

Retrospective chart review

N= 19

Objective

To describe experience with biological therapy in children with refractory chronic nonbacterial osteomyelitis (CNO)

Study Groups

All patients (N= 19)

Inclusion Criteria

Exclusion Criteria

Methods

Patient data were compiled via review of medical charts from two pediatric tertiary hospitals in Spain. 

Duration

Outcome Measures

Treatment selection, outcomes

Baseline Characteristics

All patients (N= 19)

Age range, years

Female

Symptoms

Bone pain at onset

Low-grade fever

Fever > 38 ◦C

100%

4

2

Median number of lesions

Median follow-up, months

No differences were noted for age of presentation, sex distribution, or diagnostic delay between patients who required anti-TNF therapy and those who responded to corticosteroids or pamidronate. 

Results

Endpoint

All patients (N= 19)

Therapy

Nonsteroidal anti-inflammatory drug (NSAID)

Corticosteroids

Pamidronate

Methotrexate

Tumor necrosis factor (TNF) inhibitor

Adalimumab

19

10

15

13

19

16

Treatments above may have been used in various lines of treatment. 

At last follow-up visit, 10 of 19 patients were still on biological therapy, with 8 on adalimumab. Adalimumab was withdrawn in one child after months of being asymptomatic. Overall, 18 of 19 patients remained asymptomatic.  

Adverse Events

Study Author Conclusions

This research emphasizes that anti-TNF-therapy represents an effective and safe alternative for patients with CNO refractory to conventional treatments.

InpharmD Researcher Critique

Due to the retrospective study design, limited data regarding treatment regimen is available, as well as other inherent weaknesses of retrospective case series, which include lack of proper comparisons between treatments or placebo. 

TNF-inhibitors or bisphosphonates in chronic nonbacterial osteomyelitis? - Results of an international retrospective multicenter study

Design

Retrospective international multicenter study

N= 91

Objective

To evaluate clinical and radiological treatment response to tissue necrotic factor-inhibitors (TNFi) and bisphosphonates with pamidronate in chronic nonbacterial osteomyelitis

Study Groups

Pamidronate (n= 47)

TNF-inhibitors (n= 22)

Both sequentially (n= 22)

Inclusion Criteria

Exclusion Criteria

No treatment with pamidronate and/or TNFi, uncertain diagnosis, insufficient data for treatment evaluation, parallel treatment with pamidronate and TNFi

Methods

Data were collected from patient medical records. The TNF-inhibitors were administered at standard doses for juvenile idiopathic arthritis. Pamidronate was administered at 1 mg/kg/day for 3 consecutive days, repeated after 3 and 6 months.

Duration

Outcome Measures

Primary: Clinical remission, reduction of bone lesions on magnetic resonance imaging (MRI)

Secondary: Time to treatment response, number of flares

Baseline Characteristics

TNF-inhibitors (n= 22)

Age at symptom onset, years

Age at diagnosis, years

No. of flares during follow-up

Clinical characteristics

Local inflammatory signs

Fever

Fatigue

Lymphadenopathy

Arthritis

Inflammatory bowel disease

Skin involvement

45%

14%

27%

5%

50%

18%

14%

62%

11%

0

4%

17%

4%

19%

Results

Endpoint

Pamidronate

Clinical response at 3 months

Complete remission

Partial remission

Ineffectivity

Flare

9/43 (21%)

30/43 (70%)

4/43 (9%)

0/43

21/65 (32%)

35/65 (54%)

7/65 (11%)

2/65 (3%)

Clinical response at 6 months

Complete remission

Partial remission

Ineffectivity

Flare

20/39 (51%)

15/39 (38%)

1/39 (3%)

3/39 (8%)

33/61 (54%)

20/61 (33%)

2/61 (3%)

6/61 (10%)

Clinical response at 12 months

Complete remission

Partial remission

Ineffectivity

Flare

22/34 (65%)

9/34 (26%)

1/34 (3%)

2/34 (6%)

35/51 (69%)

9/51 (17%)

2/51 (4%)

5/51 (10%)

Clinical response at 24 months

Complete remission

Partial remission

Ineffectivity

Flare

9/14 (64%)

4/14 (29%)

0

1/14 (7%)

22/35 (63%)

4/35 (11%)

3/35 (9%)

6/35 (17%)

Reduction in bone lesions

Baseline

12 months

100%

14%

100%

40%

Time to treatment response, months

6 (3-24)

3 (3-12)

Time to radiologic response, months

12 (6-12)

6 (6-12)

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

Chronic non bacterial osteitis- a multicentre study

Design

Retrospective multicenter study

N= 131

Objective

To understand the demographics, clinical features and treatment outcomes of Chronic Non-bacterial Osteitis (CNO) from three tertiary paediatric rheumatology services in the United Kingdom

Study Groups

All patients (N= 131)

Inclusion Criteria

Children < 18 years of age diagnosed as CNO

Exclusion Criteria

Not specified

Methods

Patient data were compiled via review of records from three tertiary services in United Kingdom, comprising a total of 8 pediatric centers.

Duration

Diagnosed between 2001 to 2016 or 2001 to 2017, depending on site

Outcome Measures

Treatment, response rate

Baseline Characteristics

All patients (N= 131)

Age at onset of symptoms, years (IQR)

Female

Age at diagnosis, years (IQR)

Time to diagnosis, months (IQR)

IQR, interquartile range

Results

Endpoint

Number of patients used (n= 131)

Number of patients who responded

Observed response rate

NSAIDs

Bisphosphonates

61/89 (clinical remission)

55/89 (clinical and radiological)

68.53%

61.79%

Methotrexate

Corticosteroids

80%

Adalimumab

Infliximab

Sulfasalazine

Etanercept

Mesalazine

Adverse Events

Study Author Conclusions

CNO is a chronic disease with significant disease-related sequelae in a subset of patients. The age of disease onset did not have a major impact on the severity of disease. Whole body MRI is a useful tool in detecting asymptomatic lesions. Vertebral and mandibular involvement warrants aggressive treatment. The outcome of the disease with the use of appropriate treatment is fairly good. Increased awareness of this disease amongst clinicians might hasten diagnosis and improve treatment outcomes. 

InpharmD Researcher Critique

Due to its retrospective study design, confounding variables were unaccounted for and some data were missing or could vary, including treatment regimens. Statistical comparison between adalimumab and other agents was not conducted. Proportion of patients with multifocal disease was not reported, but is likely to have affected a percentage of patients. 

A case of bone destruction caused by chronic nonbacterial osteomyelitis (CNO) successfully repaired with a tumour necrosis factor-α (TNF-α) inhibitor, adalimumab

Design

Case presentation

This case report describes a 25-year-old woman who developed right mandibular pain one year after wisdom tooth extraction, along with itchy cysts on her hands and feet that were diagnosed as pustulosis palmaris/pustular psoriasis. NSAIDs and low-dose glucocorticoids provided some relief, but not for the mandibular pain. Imaging revealed osteolytic and sclerotic changes in the right mandible, and she underwent osteotomy, but pain persisted. She was diagnosed with chronic non-bacterial osteomyelitis (CNO) based on diagnostic criteria. As the mandibular changes progressed despite NSAIDs, glucocorticoids, and surgery, she was started on the TNF-α inhibitor adalimumab for pustular psoriasis and CNO. Approximately two weeks later, her mandibular swelling and pain improved dramatically along with her pustular psoriasis, ESR normalized, and imaging showed resolution of osteolytic and sclerotic changes over two years, with no adverse events from adalimumab.

Study Author Conclusions

However, considering this osteoclast activation that arises from inflammatory pathology and the favourable clinical course, in this case, adequate control of inflammatory cytokines by TNF-a inhibitors and normalisation of bone metabolism may be important in a good therapeutic response in CNO including bone restoration.

Severe chronic non-bacterial osteomyelitis in combination with total MPO deficiency and responsiveness to TNFα inhibition

Design

Case presentation

A female patient initially developed bilateral swollen and painful thighs at age 10, which gradually resulted in advanced malnutrition over several years. She was eventually diagnosed with chronic non-bacterial osteomyelitis (CNO) at age 14. Investigations found severe malnutrition, elevated inflammatory markers, and bilateral femoral inflammation on imaging. She had a genetic diagnosis of complete myeloperoxidase (MPO) deficiency. Treatment with NSAIDs, corticosteroids, bisphosphonates, and interleukin-1 (IL-1) receptor antagonist anakinra provided no benefit, but treatment with the tumor necrosis factor-alpha (TNF-α) blocker adalimumab at a dose of 40 mg subcutaneously twice weekly resulted in rapid resolution of symptoms and normalization of markers. When adalimumab was withdrawn at age 17, symptoms returned but improved again with reintroduction of treatment, indicating the disease was TNF-α driven. Further analysis found the patient's neutrophils had normal functions except for those relying on MPO, such as neutrophil extracellular trap formation in response to PMA stimulation.

Study Author Conclusions

The patient was successfully treated with TNFα blockade resulting in instant resolution of the inflammatory symptoms disclosing that the disease was TNFα-driven. However, the treatment did not permanently abolish the underlying inflammatory condition, as the symptoms returned upon treatment withdrawal. After reintroduction of treatment the patient returned into remission.

Paradoxical keratitis and dermatitis following adalimumab treatment

Design

Case presentation

A 6-year-old girl presented for routine ophthalmic follow-up. She had a history of mild eczema and a recent diagnosis of chronic recurrent multifocal osteomyelitis, for which she had started subcutaneous adalimumab 20 mg injections every two weeks. A few days after her first adalimumab dose, her eczema significantly worsened and appeared in new locations. On follow-up exam, she was found to have bilateral symmetrical subepithelial deposits on her palpebral conjunctiva consistent with keratitis. Topical lubricants provided no improvement, but topical steroids were prescribed for 10 days along with discontinuing the adalimumab per the mother's request, as she suspected it was causing the keratitis. At the two-week follow-up, the keratopathy had resolved, and the eczema subsided after stopping the adalimumab.

Study Author Conclusions

Anti-tumor necrosis factor monoclonal antibodies are an important tool in the management of rheumatologic disease. However, paradoxical inflammation can be precipitated by their use.

Biologic therapy in refractory chronic non-bacterial osteomyelitis of childhood

Design

Case presentation 1

A 15-month-old male presented with dactylitis and was diagnosed with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome based on radiographic and histologic findings. He was treated with various medications over several years including non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, pamidronate infusions, and corticosteroid injections, which provided some improvement. At 67 months from initial diagnosis, magnetic resonance imaging (MRI) showed signal abnormalities in the feet, and infliximab therapy was started, along with continued pamidronate. Infliximab provided some pain reduction initially. At 18 months on infliximab and after stopping pamidronate, infliximab was switched to adalimumab due to increased foot pain and MRI changes, as adalimumab was administered subcutaneously. Fifteen months later, remission was maintained on adalimumab with no reported adverse effects.

Case presentation 2

A 6-year-old female presented with a 3-month history of bony pain and was diagnosed with chronic recurrent multifocal osteomyelitis (CRMO) based on bone scan and biopsy findings. She was initially treated for 3 years with corticosteroids, NSAIDs, and pamidronate with some relief. When disease activity recurred, plasma cytokine levels showed elevated IL-1ra, so she was started on anakinra with complete resolution of symptoms for 12 months. She then developed costochondritis while on anakinra, and 17 months later a psoriasis-like rash, with worsening pain despite added colchicine. Imaging showed clavicular expansion, indicating loss of efficacy of anakinra after 3 years. She was then switched to adalimumab 40 mg subcutaneously every two weeks to treat her recurrent CRMO.

Study Author Conclusions

We present our preliminary experience of using biological therapies to treat children with CRMO and SAPHO in conjunction with other immunosuppression. Further studies are needed to establish the role of these therapies in refractory CRMO and SAPHO.