Abstract
BackgroundInflammation is a major feature of sickle cell disease (SCD). Low-dose methotrexate (MTX) has long been used in chronic inflammatory diseases. This pilot study examined the MTX effect on acute vaso-occlusive pain crises (VOC) in SCD patients.MethodsFourteen adults on hydroxyurea with severe and refractory VOC received one intramuscular injection of 10 mg of MTX per week for 12 weeks. A single weekly dose of 5 mg of leucovorin was administered orally 48 h after each MTX injection. The primary outcome was reduction in number/intensity of acute pain episodes. The secondary outcomes were improvement of quality of life (QOL) and reduction of the inflammatory status.ResultsMTX did not significantly change the median VOC frequency (12 before vs 10.5 during treatment, P = 0.6240) or the median McGill pain index (45 at week 0 vs 39.5 at week 12, P = 0.9311). However, there was a decrease of ≥50% in chronic pain resulting from avascular osteonecrosis (AVN) in 5 out of 7 patients with radiologic evidence of AVN, with the perception of longer pain-free periods. There was a 44.4% median gain in physical function in the SF-36 QOL questionnaire (P = 0.0198). MTX treatment up-regulated two C-X-C motif chemokines (CXCL), CXCL10 (P = 0.0463) and CXCL12 (P < 0.0001), without significant effect on 14 additional plasma inflammatory markers. Adverse events: One individual had fever of unknown origin. Respiratory tract infections were recorded in five patients. Among the latter, one also had dengue fever and another had a central venous line infection and died of pneumonia and septic shock. Three patients with previous history of hydroxyurea-induced hematological toxicity developed low blood platelet counts while receiving simultaneously MTX and hydroxyurea.ConclusionsAlthough MTX did not reduce acute VOC frequency/intensity, it decreased chronic pain and led to QOL improvement.Trial registrationhttp://www.who.int/ictrp/en/ and http://www.ensaiosclinicos.gov.br, RBR-2s9xvn, 19 December 2016, retrospectively registered
Highlights
Inflammation is a major feature of sickle cell disease (SCD)
Patients and study design This was a prospective pilot study that enrolled young adult patients with sickle cell disease who were under chronic hydroxyurea treatment and had more than 3 severe vaso-occlusive pain crises (VOC) episodes/year, that were refractory to opioids for periods longer than 3 weeks duration
Effect of MTX treatment on pain intensity and frequency of acute VOC episodes The number of VOC episodes during the 12-week methotrexate treatment was not significantly different from that recorded in a preceding trimester: the medians were 12 and 10.5, respectively, (P = 0.6240; Fig. 1a)
Summary
Inflammation is a major feature of sickle cell disease (SCD). Low-dose methotrexate (MTX) has long been used in chronic inflammatory diseases This pilot study examined the MTX effect on acute vaso-occlusive pain crises (VOC) in SCD patients. Vaso-occlusive crises (VOC) are important features of sickle cell disease (SCD), which is characterized by ischemic injury of potentially all major organs in the body [1,2,3]. Brandalise et al Exp Hematol Oncol (2017) 6:18 osteonecrosis often located in the femoral and humeral heads [5, 6] Another important aspect of SCD is the chronic hemolysis occurrence [3, 7]. The second pathway is MyD88-mediated NF-κB activation and subsequent transcription of several responsive genes, notably those encoding pro-inflammatory mediators, such as: IL-1, IL-6, IL-8, VCAM-1, ICAM-1, P-selectin and E-selectin [4, 11,12,13]
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