Bodor Gergely, Bocskai Márta, Dura Ágnes, Kovács László, Váradi András, Kozák Eszter
Albert Szent-Györgyi Medical School and Health Centre, University of Szeged, Szeged, Hungary.
Central Pharmacy, Albert Szent-Györgyi Health Centre, University of Szeged, Szeged, Hungary.
ACR Open Rheumatol. 2025 Apr;7(4):e70036. doi: 10.1002/acr2.70036.
Calcinosis is a manifestation of systemic sclerosis with a severe negative impact on quality of life. Efforts to find a treatment for calcinosis have been hindered by our limited understanding of the underlying pathomechanism. We propose that extracellular pyrophosphate deficiency may have a causal role in the formation of these mineralized deposits, because pyrophosphate inhibits the deposition of hydroxyapatite-the major constituent of calcinosis-and supplementing pyrophosphate may have therapeutic potential in the treatment of calcinosis.
Systemic sclerosis patients were treated with a single dose of 50 mg/kg disodium pyrophosphate (cohort 1, n = 10), or a daily dose of 25 mg/kg disodium pyrophosphate for seven consecutive days (cohort 2, n = 10). Safety of oral pyrophosphate treatment was assessed with special focus on gastrointestinal tolerance, serum phosphate and calcium levels, and potential electrocardiography abnormalities. Absorption kinetics and peak plasma pyrophosphate concentrations were measured by the adenosine triphosphate sulfurylase method.
Gastrointestinal adverse effects associated with oral pyrophosphate treatment were rare and mild. The only consistent abnormality among the serum parameters studied was a transient elevation of serum phosphate levels (change: 0.2 to 0.62 and 0.15 to 0.44 mmol/L in cohorts 1 and 2, respectively). Based on electrocardiography results, both doses can be regarded as safe in terms of corrected QT interval prolongation in short-term treatment. Serum pyrophosphate levels increased significantly in both cohorts.
Oral pyrophosphate treatment was found to be safe in patients with systemic sclerosis and resulted in elevated plasma concentrations comparable to results obtained in healthy volunteers. This provides rationale to test the therapeutic potential of pyrophosphate against calcinosis.
钙质沉着症是系统性硬化症的一种表现，对生活质量有严重负面影响。由于我们对其潜在发病机制的了解有限，寻找钙质沉着症治疗方法的努力受到了阻碍。我们提出细胞外焦磷酸盐缺乏可能在这些矿化沉积物的形成中起因果作用，因为焦磷酸盐可抑制羟基磷灰石（钙质沉着症的主要成分）的沉积，补充焦磷酸盐可能对钙质沉着症的治疗具有潜在的治疗价值。
系统性硬化症患者接受单次剂量50mg/kg焦磷酸二钠治疗（第1组，n = 10），或连续7天每日剂量25mg/kg焦磷酸二钠治疗（第2组，n = 10）。评估口服焦磷酸盐治疗的安全性，特别关注胃肠道耐受性、血清磷酸盐和钙水平以及潜在的心电图异常。通过三磷酸腺苷硫酸化酶法测量吸收动力学和血浆焦磷酸盐峰值浓度。
与口服焦磷酸盐治疗相关的胃肠道不良反应罕见且轻微。在所研究的血清参数中，唯一一致的异常是血清磷酸盐水平短暂升高（第1组和第2组的变化分别为0.2至0.62mmol/L和0.15至0.44mmol/L）。根据心电图结果，就短期治疗中校正QT间期延长而言，两种剂量均可视为安全。两组的血清焦磷酸盐水平均显著升高。
发现口服焦磷酸盐治疗对系统性硬化症患者是安全的，并且血浆浓度升高，与健康志愿者获得的结果相当。这为测试焦磷酸盐对钙质沉着症的治疗潜力提供了理论依据。
