A proposed treatment algorithm for adults with Haemoglobin <scp>SC</scp> disease

The conclusions raised by Pecker et al (2017) echoes the observations noted in our cohort of adult Haemoglobin SC disease (HbSC) patients followed at a comprehensive sickle cell centre in Toronto, Canada. We concur that HbSC is associated with significant comorbidities; hence, offering therapy is justified. Despite the paucity of data regarding optimal management of HbSC, recent insights into the pathophysiology and natural history argue for potential benefits with Hydroxycarbamide and/or phlebotomy. Based on published observations, we propose a treatment algorithm for adults with HbSC disease. This retrospective analysis included 104 adults (40 males, 64 females) followed between 1994 and 2013, mean age of 34 years (range 18–68) with a 5-year mean duration of follow-up. Routine screening included yearly biochemistry and urinalysis, ophthalmology assessment, transthoracic echocardiogram and bone mineral density. Bone X-ray and magnetic resonance imaging (MRI) were ordered in patients with symptomatic osteonecrosis, and brain MRI/magnetic resonance angiography only if neurological symptoms were present. Baseline characteristics were similar to those presented by two other groups, of French (Lionnet et al, 2012) and Brazilian cohorts (Gualandro et al, 2015). Indeed, median haemoglobin was 119 g/l, haematocrit was 34% and mean haemoglobin F (HbF) level was 1·15%. Vaso-occlusive pain (VOC) episode, as defined by requiring an emergency department visit, was the most frequent acute complication of HbSC (23·5%). Acute chest syndrome (ACS) and priapism were frequent (7·7% and 7·5%, respectively), although less so than in the French cohort (20%). Rates of bacterial sepsis and acute thrombosis were similar to those previously observed (Table 1). Retinopathy (55·8%) and symptomatic avascular necrosis (AVN, 27·9%) were the most prevalent chronic comorbidities found in HbSC. Low bone density was seen in 21·6% of patients. We found a substantial rate of renal involvement (glomerular filtration rate <60 ml/min/1·73 m2, and proteinuria (protein/creatinine ratio >3·0 g/l). No patient had evidence of pulmonary hypertension based on transthoracic echocardiogram and right heart catheterization if necessary (for tricuspid regurgitation jet velocity >2·5 m/s). Leg ulcers were rare, affecting 1% of patients. Sensorineural deficit, frequently observed by Lionnet et al (2012) and Gualandro et al (2015), was not part of our routine screening (Table 1). Logistic regression of the main chronic complications, retinopathy and AVN, revealed that advanced age and higher haemoglobin level were correlated with retinopathy (P = 0·001 and 0·037, respectively). Chronic opioid use was associated with symptomatic AVN (P = 0·004). Baseline HbF level, gender and history of VOC were not significant factors for development of either complication. A feature of our cohort relates to treatment modalities. Among all disease-modifying therapies, hydroxycarbamide was most often used, followed by chronic manual exchange transfusion and therapeutic phlebotomy (28·8%, 6·7% and 5·8%, respectively). The frequent use of hydroxycarbamide in this cohort is quite unique compared to published experience. Median duration of therapy was 8 months (range 0–156 months), as this strategy was adopted in most patients in the last year of study. 10% (n = 3) of patients discontinued it as they felt no improvement and 6·7% because of side effects. There was some biochemical response in patients treated with hydroxycarbamide, expressed by a median HbF of 2·7% (range <1 to 16), mean raised mean cell volume (MCV) of 97 fl and an absolute neutrophil count nadir of 2·0 × 109/l. It is beyond the scope of this study to establish whether the rate of complications was lessened after introduction of hydroxycarbamide. 6·7% of patients were placed on chronic exchange transfusion. The main reason for initiation of any disease-modifying therapy was frequent pain. Two patients died, both from sepsis. Within this large North American cohort of adult HbSC patients, the findings are consistent with previous conclusions that VOC, retinopathy and osteonecrosis are among the most prevalent complications found in this population (Koduri et al, 2001; Gualandro et al, 2015). Hence, treatment and prevention of end-organ damage is warranted. However, knowledge gaps in the pathophysiology of HbSC and the lack of dedicated high-quality trials restrict the development of management guidelines. It has been postulated that hyperviscosity plays a major role in HbSC (Tripette et al, 2009), and therapeutic phlebotomy has been used as disease-modifying therapy in certain patients (Lionnet et al, 2012). We concur that raised haemoglobin was associated with retinopathy (Tripette et al, 2009). Hydroxycarbamide has been shown to be beneficial in sickle cell anaemia to improve survival and decrease rates of VOC and ACS, but HbSC patients were excluded (Steinberg et al, 2010). By extrapolation, we hypothesize that hydroxycarbamide, through raised HbF and depressed cellular density (Steinberg et al 1997) may provide an alternate pathway to phlebotomy for disease modification. Hence, we have put in a place a treatment algorithm for adults with HbSC disease (Fig 1). We recommend phlebotomies to aim for a haematocrit below 0·32–0·35, values extrapolated from previous data that elevated haemoglobin is linked to higher ACS rates (Castro et al, 1994). However, increasing knowledge regarding red cell rheology revealed that haematocrit level alone is far from being the sole indicator of viscosity, which is also influenced by red cell deformability and aggregate strength (Renoux et al, 2016), two measures that are not readily available and were not evaluated in our patient population. Patients with a low baseline haematocrit and/or HbF >2% will be considered for hydroxycarbamide. Both therapeutic strategies may be deployed if both conditions are encountered in the same patient as this may target several pathways of disease. The concern of increasing viscosity due to higher haematocrit with hydroxycarbamide may not be justified in HbSS patients, but no data has been produced to support this for HbSC patients (Lemonne et al, 2015). We do recognize, however, that HbF is uncommonly elevated in adult SC patients and that multiple genetics determinants modulate its level. These have not been entirely established, and our patients were not deep sequenced to identify these factors. Proposed treatment algorithm for adults with Hemoglobin SC disease. ACS, acute chest syndrome; Hb, haemoglobin; Hct, haematocrit; MTD, maximal tolerated dose; RBC, red blood cell; VOC, Vaso-occlusive crisis. *Instalment of disease-modifying therapy must be made on clinical decision. High-quality data regarding treatment and prevention of other sickle cell disease complications, including priapism, renal disease, leg ulcer, pulmonary hypertension, is lacking even with extrapolation from sikcle cell anaemia research trials. Any patient with a history of acute cerebrovascular event should be considered for chronic exchange transfusion regimen. In conclusion, HbSC disease is not a benign disorder and most patients warrant disease-modifying therapy. Prospective trials exploring therapeutic phlebotomy targets and hydroxycarbamide as treatment modalities are required in order to develop evidence-based treatment guidelines. Dr. Naessens analyzed the data and wrote the paper. Dr Ward designed the research study and reviewed the manuscript. Dr Kuo performed the statistical analysis.

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