ABSTRACT
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumoral overproduction of FGF-23. Due to local recurrence, we describe the long-term efficacy and safety profile of burosumab, an anti-FGF-23 monoclonal antibody, in a TIO patient after three unsuccessfully surgical attempts. INTRODUCTION: TIO is a rare paraneoplastic syndrome caused by tumoral overproduction of fibroblast growth factor 23 (FGF23), resulting in hyperphospaturia, hypophosphatemia, and osteomalacia. Surgery is the only definitive treatment, but tumor can locally recur, even after years from primary surgery. Furthermore, some tumors cannot be removed by surgery due to their location. METHODS: We describe the case of a 54-year-old woman affected by recurrent TIO who, after three unsuccessful surgical attempts of tumor removal, was treated with burosumab, an anti-FGF-23 monoclonal antibody. RESULTS: The patient was referred to our Bone Unit after experiencing several fractures in different sites, both traumatic and non-traumatic. At the time of first evaluation, at the age of 46, serum-phosphate (SP) was 1.2 mg/dL (reference range (RR) 2.5-4.5), 24-h urinary phosphate was 842 mg (RR 400-1000), and intact-FGF-23 was 117 pg/mL (RR 25-45). Imaging showed a metabolic pre-sacral lesion that firstly underwent to exploratory laparotomy. Then, patient underwent to surgical excision of tumor. After 18 months of well-being, tumor relapsed and even the subsequent surgery was not able to completely remove it. Since 2015, patient was maintained in phosphorus supplements and 1,25(OH)2vitamin D3, but SP levels never normalized. In September 2019, she was started on burosumab, initially at the dose of 0.3 mg/kg/month, progressively increased to the current 0.8 mg/kg/month, with great improvement of pain, physical performance, and normalization of SP levels. Burosumab was temporary and cautionary discontinued for COVID-19 pneumonia, with a worsening of SP. After restart of burosumab, biochemistry returned to normal. CONCLUSIONS: To our knowledge, this is the first European patient affected by TIO treated with burosumab for more than 2 years. Burosumab is a promising therapy in the medical treatment of TIO refractory or not eligible for definitive surgery, with good efficacy and safety profile.
ABSTRACT
Background: Complex regional pain syndrome type-1 (CRPS-1) is a severely disabling pain syndrome characterized by sensory and vasomotor disturbance, swelling, and functional impairment. Persistence of signs and symptoms has been observed in up to 64% of cases until 5.8 yrs after the onset of manifestations. Long-term disability, such as irreversible functional limitation, has been reported in up to 28% of cases with severe consequences on workability. No scores are validated to evaluate residual disability. Bisphosphonates have the best efficacy profile, compared with other therapeutic approaches, but data on long-term effectiveness are lacking. Objectives: To retrospectively evaluate long-term residual disability in patients with CRPS-1 of hand or foot after treatment with IV Neridronate (IVNer). To identify predictors of residual disability. To quantify disease outcomes, such as patient's subjective perception and residual pain. To assess long-term safety profile. Methods: We retrospectively collected data of patients affected by CRPS-1, treated with IVNer, referred to a tertiary Rheumatology Centre between Feb 2013 and Dec 2020. Visual analogue scale (VAS) and McGill Questionnaire (McGQ) were used for pain assessment. Disabilities of the Arm, Shoulder and Hand (DASH) and American Orthopaedic Foot and Ankle Society's (AOFAS) ankle-hindfoot scale for hand and foot involvement, respectively, were administered to explore disability through a phone survey. This kind of investigation was preferred for Covid pandemic. Results: 106 patients with definite diagnosis of CRPS-1 were included, mean age±standard deviation 55.6±13 yrs, 67% females, mean follow up duration 56.3 months (range 14-94), 46.2% with hand involvement. The mean VAS score before treatment onset was 55.8±23.4mm, while the McGQ was 12.9±6.7 in the sensory domain, 4.9±3.3 in the affective domain and 17.8±9.2 on the total score. Based on the patient's subjective perception and the proposed semi-quantitative scale, 77.4% described themselves as fully recovered (FR), 15% partially recovered (PR), and 7.6% with persistent disease (PD). Comparison between baseline and follow-up VAS shows a significant reduction (55.8±23.4 vs 15.1±26.4, p<0.00001). Pain assessment by McGQ showed a significant improvement in global score (baseline vs follow-up 17.8±9.2 vs 3.9±7.8, p<0.00001), sensory (12.9±6.7 vs 2.7±5.7, p<0.00001) and affective (4.9±3.3 vs 1.2±2.3, p<0.00001) domains. According to DASH score, 79.2% of the patients were FR, 3.8% had some difficulties, but with overall preserved use of the upper limb, and 17.0% had permanent functional disability. According to AOFAS ankle-hindfoot scale 76.4% of patients were FR, 16.0% had partial recovery, and 7.6% had severe functional impairment. Percentages of DASH and AOFAS scores showed a complete accordance with patients' subjective perception (Figure 1a and b). The only predictor of long-term functional impairment for CRPS-1 in the hand was a delayed treatment compared to symptoms onset (p=0.02). No predictors were found for foot localization. No patients reported the occurrence of osteonecrosis of the jaw or atraumatic fractures/atypical fracture features. Conclusion: IVNer maintained a good long-term effectiveness and safety profile in the treatment of CRPS-1. The effectiveness of IVNer is maintained on both pain symptoms and function, in terms of reductions in the VAS, McGQ and in hand and foot disability scores.