Durable engraftment after pharmacological pre-transplant immune suppression followed by reduced-toxicity myeloablative haploidentical stem cell transplantation in highly HLA-immunized adults with sickle cell disease.

Allogeneic stem cell transplantation (Allo-SCT) is the only rapidly available curative treatment modality in patients with severe sickle cell disease (SCD). The development of reduced-toxicity myeloablative conditioning (RT-MAC) regimen and the use of partially matched family donors with post-transplantation cyclophosphamide (PT-Cy) have widened the access to Allo-SCT. Antibodies against donor-specific HLA (DSA) increase the risk of engraftment failure in HLA mismatched Allo-SCT. We report the results of five patients with SCD, whereas three with DSA, who underwent an unmanipulated haploidentical stem cell transplantation (Haplo-SCT) after a busulfan-based RT-MAC regimen with PT-Cy. To reduce the risk of engraftment failure, a sequential two courses pharmacological pre-transplant immune suppression (PTIS) phase was added prior to the conditioning regimen. All patients engrafted successfully. The procedure was well tolerated. None of the patients developed acute GVHD, whereas one developed moderate chronic GVHD. After a median follow-up of 5 years (range, 2.2-9), all patients are free of pain with excellent quality of life. Our report shows that Haplo-SCT after a RT-MAC regimen is feasible and safe with stable long-term engraftment and excellent disease control. The risk of graft failure can be abrogated by adding a PTIS phase prior to initiating the conditioning regimen.

Pain Control for Sickle Cell Crisis, a Novel Approach? A Retrospective Study.

Background and Objectives: Pain management poses a significant challenge for patients experiencing vaso-occlusive crisis (VOC) in sickle cell disease (SCD). While opioid therapy is highly effective, its efficacy can be impeded by undesirable side effects. Local regional anesthesia (LRA), involving the deposition of a perineural anesthetic, provides a nociceptive blockade, local vasodilation and reduces the inflammatory response. However, the effectiveness of this therapeutic approach for VOC in SCD patients has been rarely reported up to now. The objective of this study was to assess the effectiveness of a single-shot local regional anesthesia (LRA) in reducing pain and consequently enhancing the management of severe vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD) unresponsive to conventional analgesic therapy. Materials and Methods: We first collected consecutive episodes of VOC in critical care (ICU and emergency room) for six months in 2022 in a French University hospital with a large population of sickle cell patients in the West Indies population. We also performed a systematic review of the use of LRA in SCD. The primary outcome was defined using a numeric pain score (NPS) and/or percentage of change in opioid use. Results: We enrolled nine SCD adults (28 years old, 4 females) for ten episodes of VOC in whom LRA was used for pain management. Opioid reduction within the first 24 h post block was -75% (50 to 96%). Similarly, the NPS decreased from 9/10 pre-block to 0-1/10 post-block. Five studies, including one case series with three patients and four case reports, employed peripheral nerve blocks for regional anesthesia. In general, local regional anesthesia (LRA) exhibited a reduction in pain and symptoms, along with a decrease in opioid consumption post-procedure. Conclusions: LRA improves pain scores, reduces opioid consumption in SCD patients with refractory pain, and may mitigate opioid-related side effects while facilitating the transition to oral analgesics. Furthermore, LRA is a safe and effective procedure.

A study of 28 pregnant women with sickle cell disease and COVID-19: elevated maternal and fetal morbidity rates.

Not available.

HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease.

Red blood cell (RBC) transfusion remains a critical component in caring for the acute and chronic complications of sickle cell disease (SCD). Patient alloimmunisation is the main limitation of transfusion, which can worsen anaemia and lead to delayed haemolytic transfusion reaction or transfusion deadlock. Although biological risk factors have been identified for immunisation, patient alloimmunisation remains difficult to predict. We aimed to characterise genetic alloimmunisation factors to optimise the management of blood products compatible with extended antigen matching to ensure the self-sufficiency of labile blood products. Considering alloimmunisation in other clinical settings, like pregnancy and transplantation, many studies have shown that HLA Ib molecules (HLA-G, -E, and -F) are involved in tolerance mechanism; these molecules are ligands of immune effector cell receptors (LILRB1, LILRB2, and KIR3DS1). Genetic polymorphisms of these ligands and receptors have been linked to their expression levels and their influence on inflammatory and immune response modulation. Our hypothesis was that polymorphisms of HLA Ib genes and of their receptors are associated with alloimmunisation susceptibility in SCD patients. The alloimmunisation profile of thirty-seven adult SCD patients was analysed according to these genetic polymorphisms and transfusion history. Our results suggest that the alloimmunisation of SCD patients is linked to both HLA-F and LILRB1 genetic polymorphisms located in their regulatory region and associated with their protein expression level.

Outcomes of Pregnancy in Sickle Cell Disease Patients: Results from the Prospective ESCORT-HU Cohort Study.

Sickle cell disease (SCD) refers to a group of inherited hemoglobin disorders in which sickle red blood cells display altered deformability, leading to a significant burden of acute and chronic complications, such as vaso-occlusive pain crises (VOCs). Hydroxyurea is a major therapeutic agent in adult and pediatric sickle cell patients. This treatment is an alternative to transfusion in some complications. Indeed, it increases hemoglobin F and has an action on the endothelial adhesion of red blood cells, leukocytes, and platelets. Although the safety profile of hydroxyurea (HU) in patients with sickle cell disease has been well established, the existing literature on HU exposure during pregnancy is limited and incomplete. Pregnancy in women with SCD has been identified as a high risk for the mother and fetus due to the increased incidence of maternal and non-fetal complications in various studies and reports. For women on hydroxyurea at the time of pregnancy, transfusion therapy should probably be initiated after pregnancy. In addition, there is still a significant lack of knowledge about the incidence of pregnancy, fetal and maternal outcomes, and management of pregnant women with SCD, making it difficult to advise women or clinicians on outcomes and best practices. Therefore, the objective of this study was to describe pregnancy outcomes (n = 128) reported in the noninterventional European Sickle Cell Disease COhoRT-HydroxyUrea (ES-CORT-HU) study. We believe that our results are important and relevant enough to be shared with the scientific community.

Plasma levels of E-selectin are associated with retinopathy in sickle cell disease.

BACKGROUND: The vascular endothelium is markedly disrupted in sickle cell disease (SCD) and is the converging cascade of the complex pathophysiologic processes linked to sickle cell vasculopathy. Circulating endothelial activation and/or apoptotic markers may reflect this endothelial activation/damage that contributes to the pathophysiology of the SCD vascular complications. METHODS: Plasmatic levels of circulating endothelial cells (CECs), E-selectin, progenitor's endothelial cells (EPCs), and circulating extracellular vesicles (EVs) were evaluated in 50 SCD patients, 16 with vasculopathy. The association between these markers and the occurrence of disease-related microvascular injuries of the eye (retinopathy), kidney (nephropathy), and skin (chronic active ulcers) was explored. RESULTS: Among the endothelial activation markers studied, only higher plasma levels of E-selectin were found in SCD patients with vasculopathy (p = .015). Increased E-selectin levels were associated with retinopathy (p < .001) but not with nephropathy or leg ulcers. All patients, at steady state, with or without vasculopathy, did not display a high count of CEC and EPC, markers of endothelial injury and repair. We did not show any significant differences in EVs levels between vasculopathy and not vasculopathy SCD patients. CONCLUSIONS: Further studies will be required to determine whether the E-selectin could be used as an early biomarker of retinopathy sickle cell development.

Case Report of Myelodysplastic Syndrome in a Sickle-Cell Disease Patient Treated with Hydroxyurea and Literature Review.

The safety profile of hydroxyurea (HU) in patients with sickle-cell disease (SCD) is relatively well known. However, despite the suspected association of HU with myeloid neoplasms in myeloproliferative neoplasms (MPN), and the publication of sporadic reports of myeloid malignancies in SCD patients treated with HU, the possible excess risk imparted by HU in this population having an increasing life expectancy has failed to be demonstrated. Herein, we report one case of myelodysplastic syndrome emanating from the results on safety and effectiveness of HU on the largest European cohort of 1903 HU-treated adults and children who were followed-up prospectively in an observational setting over 10 years, accounting for a total exposure of 7309.5 patient-years. A comparison of this single case with previously published similar cases did not allow us to draw any significant conclusions due to the paucity of these events.

Sickle cell disease patients with COVID-19 in Guadeloupe: Surprisingly favorable outcomes.

We investigate risk factors for hospitalization and difference between sickle cell syndromes in a cohort of COVID-19 sickle cell disease (SCD) adult patients managed in the Reference Center of Guadeloupe. We retrospectively collected data of symptomatic SCD adult patients infected with SARS-CoV-2 between March and December 2020. Thirty-eight SCD adult patients with symptomatic COVID-19 infection were included during the first wave, representing 9.6% of the active patient file at our center. The median age (IQR) was 39 years (24-47). Four patients were obese and two had moderate renal failure. The median duration of symptoms (IQR) was 10 days (5-15). Seventeen (44.7%) patients were hospitalized, including two in intensive care unit (ICU) for acute chest syndrome. An 85-year-old SC patient with prostate cancer died. No difference was detected between inpatient and outpatient groups in terms of age, gender, BMI, SCD clinical complications, and in history SCD treatment. There was no difference for severity, hospitalization, length of stay, ICU stay, or death between SS or Sß°-thal patients and SC or Sß+-thal patients. These overall favorable outcomes among symptomatic patients may be related to the low prevalence of comorbidity known to be linked to the more severe forms of COVID-19, but also to the prompt coordinated management of SCD patients in the Reference Center.

[The place of therapeutic education in the care of the sickle cell patient]. / Place de l'éducation thérapeutique dans le parcours de soins du patient drépanocytaire.

Therapeutic education is an integral part of the management of sickle cell patients. It includes the medical aspects but also the psychological, family and social repercussions of their chronic disease. It allows, at every stage of the patient's life, a care practice centred on the patient as a subject by offering him tools to become an effective actor of the management of complications, in the search for an acceptable quality of life.

Acute severe hepatitis in adult-onset Still's disease: case report and comprehensive review of a life-threatening manifestation.

Acute severe hepatitis is a rare complication of adult-onset Still's disease (AOSD). This condition is poorly characterized. We performed a review of the medical literature to describe clinical, biological, pathological, and treatment characteristics from AOSD patients with acute severe hepatitis. Their characteristics were compared with AOSD patients without severe hepatitis. Twenty-one cases were collected including a new case reported here. Patients with severe hepatitis were mostly young adults with a median age of 28 years (range: 20 to 55 years). Overall, patients with severe hepatitis had less arthritis, macular rash, sore throat, lymphadenopathy, or splenomegaly than patients without severe hepatitis. Cytopenia was more frequent in case of severe hepatitis. Most patients were treated with steroids, and the use of biotherapies has increased over the last decade. Despite treatment, 49% of patients required liver transplantation and 24% died. Key Points • Acute severe hepatitis in adult-onset Still's disease (AOSD) is associated with liver transplantation and/or death in, respectively, 43% and 24% of cases. • Severe hepatitis is the inaugural manifestation of AOSD in half of cases. Diagnosis is difficult when extra-hepatic clinical manifestations are lacking. • The mechanism of hepatic necrosis in AOSD with severe hepatitis is unknown. Liver biopsy is not specific and should not delay treatment initiation.

In vivo muscle function and energetics in women with sickle cell anemia or trait: a 31P-magnetic resonance spectroscopy study.

Sickle cell anemia (SCA) is a genetic hemoglobinopathy associated with an impaired oxygen delivery to skeletal muscle that could alter ATP production processes and increase intramuscular acidosis. These alterations have been already reported in the Townes mouse model of SCA but the corresponding changes in humans have not been documented. In the present study, we used 31-phosphorus magnetic resonance spectroscopy to investigate in vivo the metabolic changes induced by a moderate-intensity exercise in twelve SCA patients, eight sickle cell trait (SCT) carriers, and twelve controls women. The rest-exercise-recovery protocol disclosed slight differences regarding phosphocreatine (PCr) consumption and lactate accumulation between SCA patients and controls but these differences did not reach a statistical significance. On that basis, the in vivo metabolic changes associated with a moderate-intensity muscle exercise were slightly altered in SCA patients and SCT carriers but within a normal range. The present results strongly support the fact that a moderate-intensity exercise is safe and could be recommended in stable SCA patients and SCT subjects.NEW & NOTEWORTHY The main finding of the present study was that the metabolic changes associated with a moderate-intensity muscle exercise were slightly modified in stable sickle cell anemia patients and sickle cell trait carriers as compared to controls but still in the normal range. The present results strongly support the safety of a moderate-intensity exercise for stable sickle cell anemia patients and sickle cell trait carriers.

[Allogeneic hematopoietic stem cell transplant in children and adults with sickle cell disease: Indications and modalities]. / Allogreffe de cellules souches hématopoïétiques dans la drépanocytose de l'enfant et de l'adulte : indications et modalités.

Sickle cell disease is associated with severe complications and early mortality in adults. In children, hematopoietic stem cell transplant from HLA-identical sibling can stop the progression of the disease and leads to more than 95% long-term free survival without sickle cell disease. The aim of this workshop was to define indications and modalities of allogeneic hematopoietic stem cell transplant in children and adults with sickle cell disease. Patient and sibling HLA typing should be proposed, early in the course of the disease, when intensification therapies are required. Indications of transplant from HLA-identical sibling in children and adults are, cerebral vasculopathy, occurrence of vaso-occlusive events despite hydroxycarbamide, renal and hepatic diseases related to SCD, chronic anemia<7g/dL despite hydroxycarbamide, need to maintain transfusion programs longer than six months, and major transfusion difficulties related to red blood cell alloimmunization. In children with an HLA-identical sibling donor, we recommend a myeloablative conditioning regimen associating high dose busulfan, cyclophosphamide and ATG, considering the excellent results of this approach In patients over 15 years of age, we recommend the NIH approach consisting of a reduced intensity conditioning regimen by alemtuzumab, and 3Gy total body irradiation, followed by peripheral hematopoietic stem cells and post-transplant immunosuppression by sirolimus In the absence of HLA-identical sibling donor, there is no definitive data for preferring transplant from unrelated versus haplo-identical donors but we recommend to evaluate these approaches in prospective trials.

Use of Direct Oral Anticoagulants in Patients with Sickle Cell Disease and Venous Thromboembolism: A Prospective Cohort Study of 12 Patients.

Patients with sickle cell disease have an increased risk of venous thromboembolism (VTE) and with a mortality 2-fold higher. The anticoagulation of VTE in a young population is an important question. Indeed, hemorrhagic complications of anticoagulation may occur more frequently than in the general population. The use of a direct oral anticoagulant (DOAC) is not recommended for VTE in patients with sickle cell disease because those patients were not included in the clinical studies. We aimed to study the safety of using DOACs in a prospective cohort of patients with sickle cell disease and VTE. We prospectively followed the cohort of all sickle cell disease patients undergoing recent DOAC treatment for VTE at a sickle cell disease reference center. Twelve patients received rivaroxaban for VTE (eight women and four men). The median age was 27 years (20-45). The sickle cell disease variants included homozygous Hb SS (HBB: c.20A>T) in eight patients, Hb S-ß+-thalassemia (Hb S-ß+-thal) in two, Hb S-ß0-thal in one and Hb S-Hb C (HBB: c.19G>A) in one. The cumulative duration of follow-up was 3134 days under rivaroxaban treatment. There were two thrombotic events, including a patient with a double positivity of antiphospholipid antibodies. No major bleeding was observed, and 6/12 patients presented minor bleeding (epistaxis: n = 4; anal fissure bleeding: n = 1; menorrhagia n = 4). Of these, 3/6 required their treatment to be switched to apixaban, which stopped the bleeding. Direct oral anticoagulants may be an alternative treatment for VTE in patients with sickle cell disease, except for an associated antiphospholipid syndrome.

Nailfold videocapillaroscopy alterations in dermatomyositis, antisynthetase syndrome, overlap myositis, and immune-mediated necrotizing myopathy.

INTRODUCTION/OBJECTIVES: The aim of our study was to investigate possible differences in nailfold videocapillaroscopy (NVC) features between patients with dermatomyositis (DM), overlap myositis (OM), antisynthetase syndrome (ASS), and immune-mediated necrotizing myopathy (IMNM). METHODS: We performed a cross-sectional monocentric study. All patients with inflammatory myopathies (IMs) over a 6-month period were analyzed by NVC for giant and ramified capillaries, tortuosities, capillary density, disorganization, and scleroderma pattern. Clinical, biological, and pathological characteristics were retrospectively recorded. Patients were classified as having DM, OM, ASS, or IMNM for comparison. Patients were also compared with a group of patients with systemic sclerosis (SSc). RESULTS: NVC was analyzed in DM (n = 17), OM (n = 8), ASS (n = 12), and IMNM (n = 6). Vascular disorganization and avascular zones were observed only in DM (11.8%) and OM (62.5%). The percentage of patients with giant capillaries was higher in OM (n = 4/8) than in DM (n = 3/17) and absent in ASS and IMNM. Frequency of ramified capillaries, tortuosities, hemorrhages, or thrombosis was not different between subgroups. A scleroderma pattern was only observed in OM patients. CONCLUSION: In this limited series of patients, we observed that DM and OM NVC abnormalities are different from ASS and IMNM. We could not determine NVC specific patterns associated with myositis-specific antibody subtypes of DM because of the small number of patients.Key Points• Nailfold videocapillaroscopy abnormalities are different in subgroups of inflammatory myopathies.• Giant capillaries, disorganization, and major capillary loss are observed in overlap myositis and dermatomyositis but not in antisynthetase syndrome (ASS) or immune-mediated necrotizing myopathy.• Nailfold videocapillaroscopy abnormalities in overlap myositis (with the exclusion of ASS) are close to systemic sclerosis.

Clinical presentation, treatment and outcome of IgG4-related pachymeningitis: From a national case registry and literature review.

Pachymeningitis is rare, either idiopathic or secondary to inflammatory disorders, after tumoral, surgical or infectious causes have been excluded. The fibroinflammatory IgG4-related disease is one of the etiologies of pachymeningitis with only few cases reported yet. From a single referral regional center, we evaluated the frequency of IgG4-related disease as the cause of inflammatory pachymeningitis in 10% of cases. From a National case registry of IgG4-related disease the pachymeningitis frequency was 4.1%. We report eight new cases with cranial, spinal or both involvements and a literature review of 46 pathological proven cases. We observed that IgG4-related pachymeningitis is in most cases not associated to extra-neurological manifestations of the disease. Only 27% of spinal and 40% of cranial IgG4-related pachymeningitis are associated with other disease localizations. First line treatment strategies included surgery and steroids. The use of immunosuppressants or rituximab was necessary in 18% of spinal and 54% of cranial localizations. Some patients remained with sequellae and clinical and/or radiological improvement can be difficult to obtain.

Autoimmune diseases in myelodysplastic syndrome favors patients survival: A case control study and literature review.

BACKGROUND: We conducted a monocentric retrospective study of patients with myelodysplastic syndromes (MDS) and autoimmune or inflammatory disorders (AIMs) and a literature review. We analyzed the association with subgroups of the WHO 2016 MDS classification and patient's survival in a case control study. Risk factors associated with survival were analyzed by uni- and multivariate analysis. RESULTS: From all MDS patients 11% presented with AIMs. These were heterogeneous and the most frequent where polyarthritis (25%) and autoimmune cytopenias (17%). No difference for frequency and type of AIMs was observed for the WHO 2016 MDS subgroups (p = .3). In the case control study WHO classification, karyotype abnormalities, IPSS-R and IPSS were similar in both groups. The overall survival from MDS diagnosis was better in the group with AIMs [10.3 ±â€¯0.6 (IC95% 6.2-12.9) versus 4.8 ±â€¯1.1 years (IC95% 4.2-8.7), p = .04]. The better survival was restricted to MDS with low or intermediate-1 IPSS [11.1 ±â€¯1.5 (IC95% 9.9-NR) versus 8.7 ±â€¯1.3 years (IC95% 4.8-10.3), p = .006]. The better survival was only observed when AIMs diagnosis was timely associated or appeared after MDS diagnosis (p = .04). Factors associated with a better overall survival and survival without AML were steroid dependence [respectively HR = 0.042, p = .003, (IC95% 0.005-0.33) and HR = 0.07, p = .002, (IC95% 0.013-0.39)], a diagnosis of AIMs and MDS timely associated [respectively HR = 0.05, p = .009, (IC95% 0.006-0.478) and HR = 0.1, p = .008, (IC95% 0.018-0.54)] or a diagnosis of AIMs after MDS [respectively HR = 0.024, p = .009, (IC95% 0.001-0.39) and HR = 0.04, p = .008, (IC95% 0.003-0.43)]. CONCLUSION: Autoimmune and inflammatory diseases associated to MDS are heterogeneous. AIMs diagnosed after or concomitantly to MDS seems associated with a better survival. Prospective studies are necessary to demonstrate that autoimmunity is associated to a better control of the MDS clone.