Improvement in Refractory Bone Pain with Infliximab in an Adolescent with Camurati-Engelmann Disease
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Camurati-Engelmann disease (CED) is a rare autosomal dominant sclerosing bone disorder due to pathogenic gain-of-function variants in TGFB1 that leads to increased osteoblastic activity, inflammation and hyperostosis of the long bones, skull and parts of the spine. The disease is associated with chronic bone pain and acute pain crises with variable response to treatment with steroids and/or losartan. Treatment with tumor necrosis factor (TNF) inhibitors has been reported in 3 patients with CED with or without concomitant inflammatory bowel disease, with variable response. We present a 17-year-old male with infantile-onset, severe CED and chronic, profound bone pain refractory to multiple treatments but responsive to infliximab, a TNF-α inhibitor.
Case Presentation
The patient presented at age 2 years with facial swelling and a history of irritability and refusal to walk since age 10 months, improved on prednisone. Exam showed facial swelling in the temporal area, low muscle bulk and wide-based waddling gait.
Diagnostic Workup
X-rays showed increased sclerosis of the diaphyses and regions of the skull. A clinical and radiographic diagnosis of CED was made. Subsequent molecular sequence analysis of TGFB1 demonstrated a variant of uncertain significance, c.512A>G (p.Tyr171Cys), that was ultimately reclassified as likely pathogenic.
Treatment and Management
Clinical course was complicated by severe cranial sclerosis causing increased intracranial pressure, requiring craniectomy, and by profound chronic lower extremity bone pain refractory to treatment with prednisolone, losartan, analgesics, bisphosphonate trial and tibial fenestration and reaming. Attempts to wean prednisolone triggered acute pain exacerbations. Moreover, complications of long-term steroid treatment occurred including hypertension, Cushingoid appearance, gastritis and multiple compression fractures of the spine. Due to inability to wean steroids and daily pain 10 out of 10 in severity, treatment with infliximab intravenous infusion was started at 5 mg/kg at 0, 2, 6 weeks and every 8 weeks thereafter.
Outcome and Follow-Up
Beginning after the third infusion, the patient reported decreased pain frequency and severity with some pain-free days. Seven months after treatment initiation, the patient reported little to no pain for one week after infusions, followed by recurrence of pain after one week. Infliximab frequency was increased to every 6 weeks. Compared with a study done just prior to treatment initiation, nuclear bone scan with methylene diphosphonate (MDP) after 3 months of treatment showed decreased MDP activity along the skull vertex and mandible, increased activity of the frontal bones, and essentially no change in baseline patchy increased activity in the long bones. Erythrocyte sedimentation rate and C-reactive protein level trends were similar before and after the addition of infliximab. Due to ongoing fluctuating pain, another attempt to wean prednisolone has not yet been made.
Discussion
This case highlights the difficulty in management of bone pain in individuals with CED and adds evidence for potential efficacy of TNF-α inhibitors. Although a complex relationship between TGF-β and TNF-α is well-described, the mechanism of pain improvement in CED from TNF-α inhibitors is not defined. Bone scan results in our patient suggest that infliximab did not decrease osteoblastic activity in the long bones, similarly to a previously reported patient. Other potential mechanisms should be explored, such as possible decreases in TGF-β activity or localized inflammation.
Conclusion
Given the burden of disease and its treatments on individuals with CED, studies on additional therapies and their mechanisms are needed urgently.
Camurati-Engelmann disease (CED) is a rare autosomal dominant sclerosing bone disorder due to pathogenic gain-of-function variants in TGFB1 that leads to increased osteoblastic activity, inflammation and hyperostosis of the long bones, skull and parts of the spine. The disease is associated with chronic bone pain and acute pain crises with variable response to treatment with steroids and/or losartan. Treatment with tumor necrosis factor (TNF) inhibitors has been reported in 3 patients with CED with or without concomitant inflammatory bowel disease, with variable response. We present a 17-year-old male with infantile-onset, severe CED and chronic, profound bone pain refractory to multiple treatments but responsive to infliximab, a TNF-α inhibitor.
Case Presentation
The patient presented at age 2 years with facial swelling and a history of irritability and refusal to walk since age 10 months, improved on prednisone. Exam showed facial swelling in the temporal area, low muscle bulk and wide-based waddling gait.
Diagnostic Workup
X-rays showed increased sclerosis of the diaphyses and regions of the skull. A clinical and radiographic diagnosis of CED was made. Subsequent molecular sequence analysis of TGFB1 demonstrated a variant of uncertain significance, c.512A>G (p.Tyr171Cys), that was ultimately reclassified as likely pathogenic.
Treatment and Management
Clinical course was complicated by severe cranial sclerosis causing increased intracranial pressure, requiring craniectomy, and by profound chronic lower extremity bone pain refractory to treatment with prednisolone, losartan, analgesics, bisphosphonate trial and tibial fenestration and reaming. Attempts to wean prednisolone triggered acute pain exacerbations. Moreover, complications of long-term steroid treatment occurred including hypertension, Cushingoid appearance, gastritis and multiple compression fractures of the spine. Due to inability to wean steroids and daily pain 10 out of 10 in severity, treatment with infliximab intravenous infusion was started at 5 mg/kg at 0, 2, 6 weeks and every 8 weeks thereafter.
Outcome and Follow-Up
Beginning after the third infusion, the patient reported decreased pain frequency and severity with some pain-free days. Seven months after treatment initiation, the patient reported little to no pain for one week after infusions, followed by recurrence of pain after one week. Infliximab frequency was increased to every 6 weeks. Compared with a study done just prior to treatment initiation, nuclear bone scan with methylene diphosphonate (MDP) after 3 months of treatment showed decreased MDP activity along the skull vertex and mandible, increased activity of the frontal bones, and essentially no change in baseline patchy increased activity in the long bones. Erythrocyte sedimentation rate and C-reactive protein level trends were similar before and after the addition of infliximab. Due to ongoing fluctuating pain, another attempt to wean prednisolone has not yet been made.
Discussion
This case highlights the difficulty in management of bone pain in individuals with CED and adds evidence for potential efficacy of TNF-α inhibitors. Although a complex relationship between TGF-β and TNF-α is well-described, the mechanism of pain improvement in CED from TNF-α inhibitors is not defined. Bone scan results in our patient suggest that infliximab did not decrease osteoblastic activity in the long bones, similarly to a previously reported patient. Other potential mechanisms should be explored, such as possible decreases in TGF-β activity or localized inflammation.
Conclusion
Given the burden of disease and its treatments on individuals with CED, studies on additional therapies and their mechanisms are needed urgently.