Leg Ulcers among Patients with Sickle Cell Disease on Hydroxyurea Therapy.
Authors: Mendpara Suresh , Clair Betsy , Raza Mudusar , Daitch Lisa , Smith David , Kutlar Abdullah 
Published: October 2019

Abstract
Leg ulcers remain a debilitating complication of Sickle Cell Disease (SCD): significant pain, tendency to polymicrobial infection, difficult to heal, and tendency to recur in ~ 50% of patients. According to CSSCD data, 2.5% of 2075 patients had leg ulcers at study entry; overall incidence was 9.97 per 100-person years in patients without concomitant alpha thalassemia (thal), and 5.73 per 100 person years in those with alpha thal.
Hydroxyurea (HU) is an approved therapeutic agent for adults with SCD; it has been shown to decrease frequency of pain crises and acute chest syndrome and decrease transfusion requirements. Recently, HU was associated with a 40% reduction in mortality. There have been reports of an association between HU therapy and leg ulcers in patients with myeloproliferative disorders (MPD) and more recently with SCD. A retrospective study from the Mayo Clinic (Best et al, Ann. Intern. Med., 128:29, 1998) found that among 115 patients with various forms of MPD, 14 developed leg ulcers after an average HU exposure of 6 years; all ulcers healed after stopping HU, and 2 patients had recurrences of their ulcers after resuming HU. Chaine et al (Arch. Dermatol, 137: 467, 2001) reported that 5/17 (29%) patients with SCD on HU developed leg ulcers. If HU, the most effective available therapeutic agent for SCD is indeed causative of leg ulcers, this should raise serious concerns. In an effort to further clarify this problem, we performed a retrospective analysis. 421 adult SCD patients (age 16–60) formed the subject of this study. 152 were treated with HU for a minimum of 6 months. 269 patients were not exposed to HU. A total of 25 patients (5.9%) had leg ulcers; 17 were treated with HU, 8 were not. Thus, the frequency of leg ulcers was 11.2% among HU treated patients, as opposed to 2.9% among those who did not receive HU therapy (p<0.001). However, of the 17 patients with ulcers, 16(94%) had a history of ulcers prior to HU exposure. Only one patient developed ulcers for the first time after starting HU therapy. 6/17 patients experienced healing of their ulcers despite continuing HU. Among the patients treated with HU, those who had ulcers were more anemic (pre-treatment Hb 7.4 vs 8.2 g/dl, p=0.01) and were older (mean age 40.5 vs 33.0, p<0.001), confirming previous observations. Logistic regression analyses showed that only age and prior history of leg ulcers were significant risk factors for the development of ulcers in patients with SCD under HU therapy.
Our data on a large number of patients does not suggest that HU therapy alone is causative of leg ulcers in SCD patients. The supporting evidence for this conclusion comes from our observations that 1) a vast majority of patients (16/17; 94%) who developed leg ulcers after starting HU had a previous history of ulcers. This is also true of the report by Chaine et al, where 4/5 patients with leg ulcers had a prior history; 2) in 6/17 patients (35.3%) ulcers healed with conventional therapy despite continuation of HU. Furthermore, it should be noted that patients with leg ulcers represent a more severe group and are thus more likely candidates for HU therapy. We conclude that HU therapy alone is not causative of leg ulcers in patients with SCD. In addition, HU does not appear to prevent recurrence of leg ulcers in patients with a prior history; nor does it expedite ulcer healing. Other as yet unknown factors, some of which are likely genetic, play an important role in determining the risk for developing leg ulcers.