What clinical evidence is there to support use of Actemra in pediatric and/or adult patients with chronic non-bacterial osteomyelitis?

Comment by InpharmD Researcher

Available data assessing Actemra (tocilizumab) in pediatric and adult patients with chronic non-bacterial osteomyelitis (CNO) are limited and primarily derived from case studies and small observational investigations. Reported clinical experiences include isolated adult and pediatric cases describing improvements in pain, inflammatory markers, and imaging findings, while other reports, particularly in related autoinflammatory conditions, have shown minimal or no clinical response, and in some cases worsening, highlighting inconsistent outcomes. In general, experts note that although dysregulated cytokine signaling, including elevated interleukin (IL)-6 levels, provides a biologic rationale for IL-6 receptor blockade, there are no robust clinical trials to support its routine use in CNO. Consequently, the role of tocilizumab in CNO remains uncertain.

Search of PubMed and Google Scholar for (chronic nonbacterial osteomyelitis OR chronic recurrent multifocal osteomyelitis OR CRMO OR CNO OR sterile osteomyelitis OR SAPHO OR synovitis acne pustulosis hyperostosis osteitis) AND (tocilizumab OR Actemra OR IL-6 OR interleukin-6)

Background

A 2024 expert consensus aimed at gathering expert input to inform a proposed clinical trial in chronic nonbacterial osteomyelitis (CNO) highlights substantial advances in understanding disease pathophysiology. CNO is characterized by dysregulated cytokine signaling, with imbalanced expression of pro-inflammatory cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor), and the anti-inflammatory cytokine IL-10, along with consistent evidence of increased activation of the nucleotide-binding domain, leucine-rich repeat–containing protein 3 (NLRP3) inflammasome leading to excess IL-1 release. In the absence of randomized controlled trials (RCTs), treatment recommendations are based on clinical experience, retrospective case series, and limited prospective data supporting the efficacy and safety of naproxen and the bisphosphonate pamidronate. Expert consensus treatment plans developed by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) recommend nonsteroidal anti-inflammatory drugs (NSAIDs) and/or oral glucocorticoids for patients without vertebral involvement, while bisphosphonates, conventional disease-modifying antirheumatic drugs (DMARDs), or biologic therapies, most commonly TNF inhibitors (TNFi), are reserved for vertebral disease or treatment-refractory cases. Of note, the use of tocilizumab is not specifically addressed in this consensus. [1]

A 2024 review reported that IL-6 levels are elevated in adults and pediatric patients with CNO/chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, providing a biological rationale for IL-6 receptor blockade. Clinical evidence for tocilizumab is limited to three published reports: two adults with adult-onset CNO treated with tocilizumab (see Table 3), and one pediatric patient treated with tocilizumab in combination with methotrexate (see Table 1), with reported beneficial effects. In contrast, reported use of tocilizumab in two patients with SAPHO syndrome did not corroborate these findings (see Table 6). The review concludes that data on tocilizumab use in CNO/CRMO are limited and not conclusive, and it remains unclear what proportion of patients may benefit from IL-6 blockade. [2]

References: [1] Hedrich CM, Beresford MW, Dedeoglu F, et al. Gathering expert consensus to inform a proposed trial in chronic nonbacterial osteomyelitis (CNO). Clin Immunol. 2023;251:109344. doi:10.1016/j.clim.2023.109344
[2] Roberts E, Charras A, Hahn G, Hedrich CM. An improved understanding of pediatric chronic nonbacterial osteomyelitis pathophysiology informs current and future treatment. J Bone Miner Res. 2024;39(11):1523-1538. doi:10.1093/jbmr/zjae141
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What clinical evidence is there to support use of Actemra in pediatric and/or adult patients with chronic non-bacterial osteomyelitis?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-6 for your response.

 

Chronic nonbacterial osteomyelitis in children: a multicentre Belgian cohort of 30 children
Design

Retrospective review

N= 30
Objective To evaluate clinical characteristics, imaging findings, therapeutic approach and outcome of paediatric patients with Chronic Non-Bacterial Osteomyelitis (CNO)
Study Groups All patients (N= 30)
Inclusion Criteria Children diagnosed with CNO between January 1996 and December 2017 at two tertiary care centres in Belgium
Exclusion Criteria Not specified
Methods Retrospective review of medical records. Imaging data evaluated by blinded paediatric radiologists. NSAIDs used as first-line treatment, with second-line therapies including bisphosphonates, DMARDs, etanercept, and tocilizumab
Duration January 1996 to December 2017
Outcome Measures

Primary: Clinical characteristics, imaging findings, therapeutic approach, and outcome

Secondary: Remission rates, time to remission, long-term sequelae
Baseline Characteristics   All patients (N= 30)
Mean age at onset, years 10.3
Mean age at diagnosis, years 11.7
Female 73%
Mean diagnostic delay, months 17
Results   All patients (N= 30)
Remission achieved 87%
Mean time to remission, months 37.6
Vertebral compression fracture 23%
Leg length discrepancy 17%
Psychiatric support needed 13%
Adverse Events Not specified
Study Author Conclusions A typical pattern of bone involvement could be found on MRI. NSAIDs were effective as first-line treatment in nearly half of the patients. Second-line strategies included bisphosphonates, corticosteroids, methotrexate, etanercept, and tocilizumab. The prognosis was worse for patients with spinal involvement.
Critique The retrospective design and small sample size limit the generalizability of the findings. The lack of standardized treatment protocols and potential selection bias due to the inclusion of more severe cases are notable limitations.

 

References:
[1] Kaut S, Van den Wyngaert I, Christiaens D, et al. Chronic nonbacterial osteomyelitis in children: a multicentre Belgian cohort of 30 children. Pediatr Rheumatol Online J. 2022;20(1):41. Published 2022 Jun 13. doi:10.1186/s12969-022-00698-3

 

Treatment responses and relapse predictors in pediatric CNO: insights from a referral center
Design

Retrospective cohort study

N= 80
Objective

To evaluate the clinical features and diagnostic work-up of patients with Chronic Nonbacterial Osteomyelitis (CNO) followed at a tertiary referral center, and to contribute real-life data to the existing literature. We also aimed to compare our treatment approach to the EULAR recommendations for CNO
Study Groups All patients (n= 80)
Inclusion Criteria Patients diagnosed with chronic nonbacterial osteomyelitis (CNO) according to EULAR/ACR classification criteria at the center between 2020 and 2025 and currently under follow-up
Exclusion Criteria Patients who did not attend an outpatient clinic visit within the last 6 months, were over the age of 18, or had missing baseline clinical data regarding treatment response
Methods Demographic, clinical, laboratory, imaging, and treatment data were collected from electronic medical records. Patients were analyzed according to relapse status, treatment response, and MRI findings. 
Duration 2020 to 2025
Outcome Measures

Primary: Clinical features and diagnostic work-up of CNO patients

Secondary: Treatment responses, relapse predictors
Baseline Characteristics   All patients (n= 80)
Age at symptom onset, years  9.4 ± 4.2
Age at diagnosis, years  11.6 ± 3.4
Bone pain  79 (98.8%)
Pain lasting all day  44 (57.1%)
Morning pain  19 (24.7%)
Evening pain  14 (18.2%)
Continuous pain  40 (53.3%)
Intermittent pain  35 (46.7%)
Localized pain  24 (30%)
Widespread pain  56 (70%)
Fever  7 (9.2%)
Results Univariate and multivariate analysis of factors associated with relapse Group Comparison (Relapse - No Relapse) Test statistic (univariate) P-value (univariate) B (multivariate) P-value (multivariate) Exp(B)
Total number of involved bones 9.9 ± 4.0 vs 7.0 ± 4.4 771 (U) 0.003 0.141 0.036 1.151
CRP, mg/L 11.1 ± 20.8 vs 10.0 ± 22.0 594 (U) 0.498 -0.014 0.540 0.986
ESR, mm/hr 17.3 ± 20.2 vs 13.0 ± 14.7 606 (U) 0.400 0.021 0.475 1.021
Age, years 14.7 ± 2.7 vs 13.9 ± 4.1 569 (U) 0.716 0.043 0.615 1.044
Sacroiliac involvement 59.3% vs 47.5% 0.484 (χ²) 0.487 0.169 0.764 1.184
Skin involvement 37.0% vs 27.5% 0.310 (χ²) 0.578 0.501 0.407 1.650

CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; U: Mann–Whitney U test statistic; χ²: chi-squared test statistic; B: regression coefficient; Exp(B): odds ratio (exponentiated B).

Initial treatment with NSAIDs alone proved insufficient, achieving remission in only five cases. Conventional DMARDs were administered to most patients, yet a mere 11 reached clinical remission. Anti-TNF therapy emerged as the predominant treatment modality, effectively inducing remission, especially in cases of extensive skeletal involvement signifying relapse risk.

Etanercept was administered as the first-line biologic agent to a cohort of 52 patients, among which 35 exhibited a clinical response. Of the 14 patients who were switched to adalimumab after initial treatment with etanercept, 9 achieved a clinical response, while 8 patients demonstrated a response to other biologic agents. Currently, the distribution of treatments among the patients includes 31 on etanercept, 14 on adalimumab, 4 on secukinumab, 2 on infliximab, and 1 on tocilizumab. The remaining patients are under observation without active treatment. Notably, all 4 patients on secukinumab, the patient on tocilizumab, and the patient on canakinumab achieved remission. Furthermore, 20 patients received pamidronate therapy for three to eight doses, primarily for pain palliation and often in combination with anti-TNF therapy. Among these 20, 14 had vertebral involvement and 16 had sacroiliac involvement. Pamidronate was used without anti-TNF agents in only four patients, three of whom achieved complete clinical response.
Adverse Events Not reported
Study Author Conclusions

This study provides evidence that NSAIDs and conventional DMARDs are sufficient only for a limited number of CNO patients, and that these patients may have a milder disease phenotype. Cutaneous findings may be associated with a more aggressive course.. While anti-TNF therapies were the most commonly used agents and most associated with remission in our series, our data reflects the clinical heterogeneity of CNO and the differences in individual response to treatment. Prospective and controlled studies are needed to establish more precise treatment algorithms. 
Critique

The study provides valuable real-world data on CNO treatment responses and relapse predictors, highlighting the effectiveness of anti-TNF therapies. However, its retrospective design and single-center nature may limit generalizability. The study's reliance on patient records could affect the accuracy of clinical information, and the absence of prospective follow-up is a limitation. The high frequency of inadequate responses to first-line therapies may reflect the severe nature of the study population at a tertiary referral center.
References:
[1] Cam V, Cingoz E, Bayindir Y, et al. Treatment responses and relapse predictors in pediatric CNO: insights from a referral center. Rheumatology (Oxford). Published online December 3, 2025. doi:10.1093/rheumatology/keaf645

 

Adult-onset Chronic Recurrent Multifocal Osteomyelitis with High Intensity of Muscles Detected by Magnetic Resonance Imaging, Successfully Controlled with Tocilizumab

Design

 Case series 

Case 1

A 48-year-old man with a long history of right lower leg pain, occurring intermittently since he was 17, was admitted to the hospital. His condition evolved over the years with recurrent pain episodes, swelling, and redness, initially diagnosed as non-bacterial osteomyelitis without malignancy. Despite some improvement with no specific treatment, symptoms persisted. At age 41, he was diagnosed with suspected reactive arthritis due to fever, polyarthralgia, and elevated inflammatory markers, and was treated with prednisolone and salazosulfapyridine, resulting in partial symptomatic relief. By age 48, he was readmitted, presenting with right leg and upper arm pain, no fever, but elevated CRP and WBC, and low CK levels. Imaging revealed bilateral tibial osteosclerosis and enhancements on bone scans and MRIs, indicative of ongoing inflammation. Elevated serum IL-6 and TNF-α levels suggested autoinflammatory disease, leading to a diagnosis of chronic recurrent non-bacterial osteomyelitis (CRMO). Tocilizumab therapy, an IL-6 receptor antagonist, was initiated, leading to a significant reduction in inflammatory markers and symptoms, allowing the cessation of analgesics and tapering of prednisolone. Over eight months, MRI findings improved, though evidence of chronic or previous osteomyelitis remained. This case highlights the complexity of diagnosing and managing CRMO and the potential role of cytokine inhibitors like tocilizumab in treatment.

Case 2

A 26-year-old man with a history of epilepsy treated with levetiracetam and valproic acid presented with bilateral lower leg pain, polyarthralgia, and polyarthritis. Initially, rheumatoid arthritis was suspected due to the presentation of joint pain and synovitis indicated by MRI, though rheumatoid factor and other associated antibodies were negative. Elevated CRP levels suggested ongoing inflammation. Imaging studies showed cortical bone hypertrophy of the tibias and evidence suggestive of chronic osteomyelitis and myositis, with muscle enhancement and bone marrow edema in the MRI. A biopsy of a subcutaneous nodule on the left upper arm revealed necrotizing vasculitis. The patient was treated with methotrexate and prednisolone, but symptoms persisted with increased pain and polyarthralgia over time. Further tests ruled out conditions like dermatomyositis, polymyositis, sarcoidosis, and lymphoproliferative syndromes. Elevated serum IL-6 and TNF-α levels pointed towards an autoinflammatory process, leading to a trial of colchicine, which was ineffective. Chronic recurrent non-bacterial osteomyelitis was then suspected, and treatment with tocilizumab (TCZ) led to significant improvement. Bilateral lower leg pain was reduced, CRP levels normalized, and MRI showed decreased muscle intensity after 10 months, although some bone marrow intensity remained, indicative of chronic osteomyelitis. The patient's steroid dose was successfully tapered, and knee swelling improved with TCZ therapy. 

Study Author Conclusions

 In summary, we herein described the cases of two patients with adult-onset CRMO involving the diaphyses of the long bones and accompanied by high intensity of muscles on MRI and polyarthritis. Necrotizing vasculitis in one patient was also evident, based on a biopsy of a cutaneous nodule. In adult-onset CRMO, anti-IL-6 therapy should therefore be considered in patients with muscle inflammation not responding to NSAIDs, MTX and PSL.
References:
[1] Sato H, Wada Y, Hasegawa E, et al. Adult-onset Chronic Recurrent Multifocal Osteomyelitis with High Intensity of Muscles Detected by Magnetic Resonance Imaging, Successfully Controlled with Tocilizumab. Intern Med. 2017;56(17):2353-2360. doi:10.2169/internalmedicine.8473-16

 

Case series of psoriasis associated with tumor necrosis factor-α inhibitors in children with chronic recurrent multifocal osteomyelitis 

Design

 Case report

Case presentation #1

 A 5-year-old female patient was diagnosed with chronic recurrent multifocal osteomyelitis (CRMO) after 3 months of worsening neck pain, and was started on infliximab, methotrexate, and pamidronate. Five months after initiation, however, erythematous papules and pustule-studded annular plaques were observed across her extremities, neck, back, and scalp. Psoriasis improvement was seen once infliximab was discontinued and topical therapies administered; however, infliximab was restarted after worsening of CRMO and unresponsiveness to etanercept and canakinumab. Though ustekinumab improved conditions, it was discontinued due to myalgias. Adalimumab and tocilizumab were trialed, though were discontinued due to worsening of psoriasis for adalimumab and CRMO for tocilizumab. Finally, complete resolution of CRMO was observed with golimumab 2 mg/kg q4w, with only mild alopecia observed on her last follow-up.

Study Author Conclusions

 TNFi may cause psoriasis in children with CRMO. Discontinuation of the TNFi and topical medications are very effective in treating the psoriasis. In patients who required continuation of the TNFi for their CRMO, switching to another TNFi, offering an alternative or lower dosing regimen, or adding another biologic agent such as ustekinumab may be considered.

 

References:
[1] Campbell JA, Kodama SS, Gupta D, Zhao Y. Case series of psoriasis associated with tumor necrosis factor-α inhibitors in children with chronic recurrent multifocal osteomyelitis. JAAD Case Rep. 2018;4(8):767-771. Published 2018 Sep 14. doi:10.1016/j.jdcr.2018.06.008

 

Development of aseptic subcutaneous abscess after tocilizumab therapy in a patient with SAPHO syndrome complicated by amyloid A amyloidosis

Design

 Case report

Case presentation

 A 78-year-old male patient experienced recurrent painful swelling of the sternoclavicular joints and other osteoarticular symptoms for over a decade. The patient, diagnosed with SAPHO syndrome, presented with severe renal failure and elevated markers of inflammation, including serum amyloid A and C-reactive protein (CRP). Following the administration of tocilizumab (TCZ) (dosed at 8 mg/kg), a monoclonal antibody targeting the interleukin-6 (IL-6) receptor, significant improvements were noted in the patient's inflammatory markers and joint pain. However, approximately three weeks post-TCZ administration, the patient developed intractable chest pain and a notable subcutaneous abscess on the anterior chest wall. Further investigation into the pathophysiology of this adverse event revealed markedly elevated serum IL-6 levels and other cytokines, such as IL-8, eotaxin, and macrophage inflammatory protein 1 alpha (MIP-1a), compared to healthy controls. This cytokine profile suggested an inflammatory response exacerbated by SAPHO syndrome, raising suspicion that the aseptic abscess was linked to TCZ therapy. Despite the absence of infectious pathogens, the abscess was effectively managed with infliximab and prednisolone, leading to the resolution of symptoms. 

Study Author Conclusions

 Tocilizumab treatment in SAPHO syndrome with AA amyloidosis may induce aseptic abscesses, possibly due to exacerbation of the underlying condition. Caution is advised when using tocilizumab off-label.
References:
[1] Fujita S, Kosaka N, Mito T, Hayashi H, Morita Y. Development of aseptic subcutaneous abscess after tocilizumab therapy in a patient with SAPHO syndrome complicated by amyloid A amyloidosis. Int J Rheum Dis. 2015;18(4):476-479. doi:10.1111/1756-185X.12525

 

Failure of tocilizumab in treating two patients with refractory SAPHO syndrome: a case report

Design

  Case series

Case presentation 1

A 53-year-old woman presented with a history of palmoplantar pustulosis beginning in 2008, followed by progressive osteoarticular pain and swelling involving the sternoclavicular joints with elevated erythrocyte sedimentation rate (ESR). Imaging and biopsy findings were consistent with aseptic chronic osteomyelitis, and she was later diagnosed with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome based on recurrent axial skeletal involvement and chronic inflammatory changes. Over several years, she received nonsteroidal antiinflammatory drugs (NSAIDs), multiple disease-modifying antirheumatic drugs (DMARDs), and bisphosphonates, with only transient or partial responses and recurrent relapses of both skeletal and cutaneous disease. In 2017, with elevated ESR, IL-6, and TNF-α levels and biopsy-confirmed IL-6 and TNF-α expression in bone tissue, tocilizumab was initiated at 8 mg/kg due to prior thyroid carcinoma history. Following initiation, ESR decreased rapidly; however, her pre-existing osteoarticular and cutaneous manifestations worsened, and new painful swelling of the left wrist developed. Given limited remaining treatment options, systemic corticosteroids were initiated, despite prior avoidance due to concern for exacerbating vertebral compression, and partial clinical improvement was observed. The patient also developed transient severe neutropenia (neutrophil count 380/mL) on day 2 after tocilizumab initiation, leading to discontinuation of tocilizumab, after which the neutropenia resolved spontaneously within 10 days without evidence of infection.

Case presentation 2

A 29-year-old woman presented with progressively worsening osteoarticular pain involving the bilateral sternoclavicular joints, shoulders, and posterior neck, with associated clavicular swelling and restricted shoulder motion. Imaging demonstrated multifocal osteolytic and osteosclerotic lesions, and biopsy findings showed chronic inflammation, leading to a diagnosis of SAPHO syndrome. She initially responded to NSAIDs but experienced recurrent relapses with elevated ESR, serum IL-6, and TNF-α levels, prompting hospitalization in 2017. Based on IL-6–positive and TNF-α–negative immunohistochemistry and fertility considerations, tocilizumab was initiated at 8 mg/kg after informed consent. Joint pain and inflammatory markers normalized after the first dose; however, within one month, she developed worsening mandibular osteolysis, recurrent osteoarticular pain, new pustular rashes, and severe neutropenia, while inflammatory markers remained normal. Bisphosphonate and minocycline therapy were subsequently started, resulting in improvement in pain, skin findings, and mandibular lesions on follow-up imaging, and neutropenia resolved spontaneously without infection.

Study Author Conclusions

In our cases, tocilizumab showed a limited therapeutic effect and may have induced worsening of the patients’ osteoarticular and cutaneous manifestations and development of transient severe neutropenia in the treatment of refractory SAPHO syndrome. Therefore, we do not recommend the use of tocilizumab in patients with SAPHO syndrome regardless of IL-6 positivity in the biopsy tissue.
References:
[1] Sun XC, Liu S, Li C, et al. Failure of tocilizumab in treating two patients with refractory SAPHO syndrome: a case report. J Int Med Res. 2018;46(12):5309-5315. doi:10.1177/0300060518806105