Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor–naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), −4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (−76.8% vs −76.0%; difference [95% CI], −0.83% [−5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [−1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], −6.7% [−14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [−8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Recent studies have recognised the importance of pulmonary hypertension (PH) in sickle cell disease (SCD). The aim of this study was to determine the prevalence and prognostic impact of PH and its features in patients with SCD.80 patients with SCD underwent baseline clinical evaluation, laboratory testing, 6-min walk tests (6MWTs) and echocardiography. Patients with a peak tricuspid regurgitant jet velocity (TRV) of o2.5 m?s -1 were further evaluated through right heart catheterisation (RHC) to assure the diagnosis of PH. Our study evidenced a 40% prevalence of patients with elevated TRV at echocardiography. RHC (performed in 25 out of 32 patients) confirmed PH in 10% (95% CI 3.4-16.5%) of all patients, with a prevalence of post-capillary PH of 6.25% (95% CI 0.95-11.55%) and pre-capillary PH of 3.75% (95% CI -0.4-7.9%). Patients with PH were older, had worse performance in 6MWTs, and more pronounced anaemia, haemolysis and renal dysfunction. Survival was shorter in patients with PH.Our study reinforced the use of echocardiography as a screening tool for PH in SCD and the mandatory role of RHC for proper diagnosis. Our findings confirmed the prognostic significance of PH in SCD as its association to pronounced haemolytic profile.

We studied 21 bone marrow specimens from 21 patients with systemic lupus erythematosus (SLE) and peripheral cytopenias: anaemia (Hb < 10 g/dl), and/or leucopenia (white blood cell count < 4 x 10(9)/l), and/or thrombocytopenia (platelets < 150 x 10(9)/l). None of the patients had used immunosuppressive drugs in the 2 months before the study, and 11 (52.4%) had never used these drugs. The global and specific series cellularity, degree of fibrosis and necrosis were evaluated by bone marrow trephine; morphological abnormalities and iron stores were evaluated by cytological smears. The most important abnormalities viewed in bone marrow biopsies were: global hypocellularity (47.6%), increased reticulin proliferation (76.2%) with myelofibrosis in one patient, and necrosis (19.0%). The marrow aspirates were difficult to obtain in four patients, who showed an increased reticulin proliferation on histological analysis. Plasmocytosis was present in 26.7% of cases and in one there was a serum monoclonal component (IgG kappa). Iron stores were normal or increased in 26.7% of specimens and decreased or absent in 73.3%. The most frequent peripheral abnormality was leucopenia in 90.4% (19/21) and granulocytic hypoplasia was observed in 47.3% (9/19) of these patients. We conclude that the bone marrow may be a target organ in SLE with cytopenias.

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The majority of the chromosomes with the ␤ S gene have one of the five common haplotypes, designated as Benin, Bantu, Senegal, Cameroon, and Arab-Indian haplotypes. However, in every large series of sickle cell patients, 5-10% of the chromosomes have less common haplotypes, usually referred to as "atypical" haplotypes. In order to explore the genetic mechanisms that could generate these atypical haplotypes, we extended our analysis to other rarely studied polymorphic markers of the ␤ S -gene cluster, in a total of 40 chromosomes with uncommon haplotypes from Brazil and Cameroon. The following polymorphisms were examined: seven restriction site polymorphisms of the ␥␦␤-cluster, the pre-G ␥ framework sequence including the 6-bp deletion/insertion pattern, HS-2 LCR (AT)xR(AT)y and pre-␤ (AT)xTy repeat motifs, the GC/TT polymorphism at −1105-1106 of G ␥-globin gene, the C/T polymorphism at −551 of the ␤-globin gene, and the intragenic ␤-globin gene framework. Among the Brazilian subjects, the most common atypical structure (7/16) was a Bantu 3-subhaplotype associated with different 5-sequences, while in two chromosomes a Benin 3-subhaplotype was associated with two different 5-subhaplotypes. A hybrid Benin/Bantu configuration was also observed. In three chromosomes, the atypical haplotype differed from the typical one by the change of a single restriction site. In 2/134 chromosomes identified as having a typical Bantu RFLPhaplotype, a discrepant LCR repeat sequence was observed, probably owing to a crossover 5 to the -gene. Among 80 ␤ S chromosomes from Cameroon, 22 were associated with an atypical haplotype. The most common structure was represented by a Benin haplotype (from the LCR to the ␤-gene) with a non-Benin segment 3 to the ␤-globin gene. In two cases a Bantu LCR was associated with a Benin haplotype and a non-Benin segment 3 to the ␤-globin gene. In three other cases, a more complex structure was observed that can be considered as a hybrid of Benin, Bantu, Senegal, or other chromosomes was observed. These data suggest that the atypical ␤ S haplotypes are not uncommon in America and in Africa. These haplotypes are probably generated by a variety of genetic mechanisms including (a) isolated nucleotide changes in one of the polymorphic restriction sites, (b) simple and double crossovers between two typical ␤ S haplotypes or much more frequently between a typical ␤ S haplotype and a different ␤ Aassociated haplotype that was present in the population, and (c) gene conversions. Am.