Is there any evidence for use of Humira (adalimumab) to treat chronic recurrent multifocal osteomyelitis (CRMO)?

Is there any evidence for use of Humira (adalimumab) to treat chronic recurrent multifocal osteomyelitis (CRMO)?

Comment by InpharmD Researcher

Several retrospective studies and case reports suggest that the anti-TNF biologic therapy adalimumab can be an effective treatment option for CRMO, particularly in cases refractory to conventional treatments such as NSAIDs, corticosteroids, and bisphosphonates. These reports describe successful management of refractory CNO/CRMO cases with adalimumab after failure of other medications, with improvement in symptoms, normalization of inflammatory markers, and radiographic resolution of bone lesions. However, not all cases were successfully treated and larger prospective controlled studies are still needed to better establish the role and efficacy of adalimumab in CRMO treatment.

Background

Many retrospective studies in recent years have included patients with chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis (CRMO) treated with adalimumab. A 2021 retrospective study investigated the dual diagnosis of inflammatory bowel disease (IBD) and CRMO in patients at a children's hospital over 10 years. Most patients were diagnosed with IBD first before later being diagnosed with CRMO. At the time of CRMO diagnosis, some patients' IBD treatment included sulfasalazine, infliximab, or adalimumab. One patient started on subcutaneous methotrexate for CRMO was also started on adalimumab due to ongoing IBD symptoms, with both diseases well controlled on weekly methotrexate and adalimumab. Another patient was started on adalimumab for treatment of both CRMO and IBD, with both conditions well controlled since. The authors conclude that biologics like adalimumab can be used for effective treatment of both conditions while reducing the medication burden of the patient. [1]

Another 2018 retrospective study observed 486 patients with CRMO from the Eurofever international registry, finding that adalimumab was used in 8 (1.6%) patients to treat their condition. Of those 8 patients treated with adalimumab, four were noted to reach remission and four had a partial response to the treatment. This suggests that adalimumab may be an effective therapeutic option for some patients with CRMO, with over half of those treated with it achieving either remission or a partial response. However, the small number of only 8 patients receiving adalimumab limited stronger conclusions about its efficacy. While other similar, small retrospective studies and case reports are available (see Tables 1-8), controlled prospective studies with larger patient cohorts would be needed to better determine the role of adalimumab treatment in CRMO. [2]

Literature Review

A search of the published medical literature revealed 8 studies investigating the researchable question:

Is there any evidence for use of Humira (adalimumab) to treat chronic recurrent multifocal osteomyelitis (CRMO)?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-8 for your response.

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)	10 (4-15)
	Female	47%
	Follow-up, months	18
	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
	All four patients treated with adalimumab had comorbid arthritis, with 75% achieving remission.
Adverse Events	N/A
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.

References:

Concha S, Hernández-Ojeda A, Contreras O, Mendez C, Talesnik E, Borzutzky A. Chronic nonbacterial osteomyelitis in children: a multicenter case series. Rheumatol Int. 2020;40(1):115-120. doi:10.1007/s00296-019-04400-x

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	Age < 18 years, diagnosed with CNO who received treatment with a biologic
Exclusion Criteria	Not specified
Methods	Patient data were compiled via review of medical charts from two pediatric tertiary hospitals in Spain.
Duration	Treated between January 2007 to April 2020
Outcome Measures	Treatment selection, outcomes
Baseline Characteristics		All patients (N= 19)
	Age range, years	2-12
	Female	15 (79%)
	Symptoms Bone pain at onset Low-grade fever Fever > 38 ◦C	100% 4 2
	Median number of lesions	3
	Median follow-up, months	67
	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	Adverse effects related to adalimumab were not reported.
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.

References:

Bustamante J, Murias S, Enriquez E, Alcobendas R, Remesal A, De Inocencio J. Biological therapy in refractory chronic nonbacterial osteomyelitis: A case series of 19 patients. Joint Bone Spine. 2021;88(2):105120. doi:10.1016/j.jbspin.2020.105120

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	Children and adolescents (<18 years) with chronic nonbacterial osteomyelitis
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	Follow-up: 4.6 ± 3.8 years
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)	Pamidronate (n= 47)
	Age at symptom onset, years	9.9	9.5
	Age at diagnosis, years	10.5	10.8
	No. of flares during follow-up	1.5	1.6
	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	TNF-inhibitors	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	TNFi: Abdominal pain, leukocytoclastic vasculitis, psoriasis. Pamidronate: Influenza-like symptoms, headaches, asymptomatic hypocalcemia.
Study Author Conclusions	Both bisphosphonates and TNFi are effective in CNO refractory to NSAIDs. TNFi may have higher efficacy with fewer flares. Demographic and clinical markers may predict failure to respond to pamidronate.
InpharmD Researcher Critique	Limitations included a retrospective design, lack of randomization, small sample size, and off-label use of treatments.

References:

Schnabel A, Nashawi M, Anderson C, et al. TNF-inhibitors or bisphosphonates in chronic nonbacterial osteomyelitis? - Results of an international retrospective multicenter study. Clin Immunol. 2022;238:109018. doi:10.1016/j.clim.2022.109018

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)	9.5 (8 to 11)
	Female	94 (71.7%)
	Age at diagnosis, years (IQR)	10.7 (8.9 to 12.7)
	Time to diagnosis, months (IQR)	12 (5 to 24)
	IQR, interquartile range
Results	Endpoint	Number of patients used (n= 131)	Number of patients who responded	Observed response rate
	NSAIDs	107 (81.6%)	53/92	57.6%
	Bisphosphonates	89 (67.93%)	61/89 (clinical remission) 55/89 (clinical and radiological)	68.53% 61.79%
	Methotrexate	18 (13.74%)	7/16	43.75%
	Corticosteroids	13 (9.92%)	8/10	80%
	Adalimumab	11 (8.39%)	10/11	90.9%
	Infliximab	8 (6.10%)	7/8	87.5%
	Sulfasalazine	3 (2.29%)	2/3	66.66%
	Etanercept	1 (0.76%)	1/1	100%
	Mesalazine	1 (0.76%)	1/1	100%
Adverse Events	N/A
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.

References:

Bhat CS, Anderson C, Harbinson A, et al. Chronic non bacterial osteitis- a multicentre study. Pediatr Rheumatol Online J. 2018;16(1):74. Published 2018 Nov 22. doi:10.1186/s12969-018-0290-5

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 report
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.

References:

Kanda R, Nakano K, Miyagawa I, Iwata S, Nakayamada S, Tanaka Y. A case of bone destruction caused by chronic non-bacterial osteomyelitis (CNO) successfully repaired with a tumour necrosis factor-α (TNF-α) inhibitor, adalimumab. Mod Rheumatol Case Rep. 2020;4(2):196-201. doi:10.1080/24725625.2020.1749360

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

References:

Sundqvist M, Christenson K, Wekell P, Björnsdottir H, Dahlstrand Rudin A, Sanchez Klose FP, Kallinich T, Welin A, Björkman L, Bylund J, Karlsson-Bengtsson A, Berg S. Severe chronic non-bacterial osteomyelitis in combination with total MPO deficiency and responsiveness to TNFα inhibition. Front Immunol. 2023 Oct 26;14:1233101. doi: 10.3389/fimmu.2023.1233101. PMID: 37954595; PMCID: PMC10637399.

Paradoxical keratitis and dermatitis following adalimumab treatment
Design	Case report
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.

References:

Ghali N, Khan AO. Paradoxical keratitis and dermatitis following adalimumab treatment. J AAPOS. Published online July 14, 2024. doi:10.1016/j.jaapos.2024.103970

Biologic therapy in refractory chronic non-bacterial osteomyelitis of childhood
Design	Case report
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.

References:

Eleftheriou D, Gerschman T, Sebire N, Woo P, Pilkington CA, Brogan PA. Biologic therapy in refractory chronic non-bacterial osteomyelitis of childhood. Rheumatology (Oxford). 2010;49(8):1505-1512. doi:10.1093/rheumatology/keq122