Management of paroxysmal nocturnal haemoglobinuria: a personal view

Paroxysmal nocturnal haemoglobinuria (PNH) is a serious form of acquired haemolytic anaemia with several features that make it unique, including the fact that it is caused by clonal expansion, in the context of bone marrow failure, of a haematopoietic stem cell that has a somatic mutation in a gene crucial for the synthesis of glycosylphosphatidylinositol anchors; and that this also produces a life-threatening acquired thrombophilic state. Until recently, the two only main options for patients with PNH were either allogeneic bone marrow transplantation or supportive management, including blood transfusion: both options require some skill and good patient-doctor collaboration. Since the start of this millennium a major advance has been the introduction of eculizumab, a monoclonal antibody that targets the C5 protein of the complement system: blockade of C5 prevents activation of the complement distal pathway, and thus abrogates the complement-mediated intravascular haemolysis that severely plagues patients with PNH. This review outlines an approach to the management of all three major components of the clinical picture of PNH--namely haemolysis, thrombosis and bone marrow failure--based on the literature and on personal experience. We consider specifically how the use of eculizumab has modified other aspects of the management of PNH, and even the pathophysiology itself of this disease. Finally, we develop a treatment algorithm which others might find helpful.     

Paroxysmal nocturnal hemoglobinuria with copy number‐neutral 6pLOH in GPI (+) but not in GPI (−) granulocytes

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired bone marrow disorder caused by expansion of a clone of hematopoietic cells lacking glycosylphosphatidylinositol (GPI)‐anchored membrane proteins. Multiple lines of evidence suggest immune attack on normal hematopoietic stem cells provides a selective growth advantage to PNH clones. Recently, frequent loss of HLA alleles associated with copy number‐neutral loss of heterozygosity in chromosome 6p (CN‐6pLOH) in aplastic anemia (AA) patients was reported, suggesting that AA hematopoiesis ‘escaped’ from immune attack by loss of HLA alleles. We report here the first case of CN‐6pLOH in a Japanese PNH patient only in GPI‐anchored protein positive (59%) granulocytes, but not in GPI‐anchored protein negative (41%) granulocytes. CN‐6pLOH resulted in loss of the alleles A*02:06‐DRB1*15:01‐DQB1*06:02, which have been reported to be dominant in Japanese PNH patients. Our patient had maintained nearly normal blood count for several years. Our case supports the hypothesis that a hostile immune environment drives selection of resistant hematopoietic cell clones and indicates that clonal evolution may occur also in normal phenotype (non‐PNH) cells in some cases.     

Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones

Because of the insensitivity of the Ham test, paroxysmal nocturnal haemoglobinuria (PNH) has been inaccurately viewed as a late clonal complication of aplastic anaemia (AA). To clarify the relationship between PNH and marrow failure, we tested for the presence of glycosylphosphatidyl-anchored protein-deficient (GPI-AP) granulocytes in large cohorts of patients with AA, myelodysplasia (MDS), and pure haemolytic PNH. A PNH clone was detected in 32% of new AA patients and 18% of MDS patients. In serial studies, this proportion did not change up to 15 years after diagnosis, suggesting that expansion of aberrant cells is an early event (i.e. prior to initial presentation). For all patients with a PNH clone, on average 14% of PNH granulocytes were found on presentation and 37% at 10 years. Patients with PNH but without cytopenia showed higher percentages of GPI-AP-deficient cells than did those with the AA/PNH syndrome. After immunosuppression, there was no change in the contribution of PNH clone to blood production, arguing against the "immune-escape" theory in PNH. Clinically, a high proportion of GPI-AP-deficient cells correlated with marrow hypercellularity. GPI-AP-deficient cells were similarly present in patients with and without karyotypic abnormalities. Our results indicate that the GPI-AP-deficient clones show quantitative and kinetic differences between classic haemolytic PNH and PNH with marrow failure, in which the evolution rate is low later in the course of the disease.     

Update on paroxysmal nocturnal haemoglobinuria: on the long way to understand the principles of the disease

The understanding of the clinical manifestations in paroxysmal nocturnal haemoglobinuria (PNH) has made great progress. The main symptoms of this disease such as abdominal pain, renal failure or pulmonary hypertension and even the basis of the dramatic thrombophilia can be related to intravascular haemolysis and liberation of free haemoglobin resulting in NO depletion. In addition, there has been a recent great progress in elucidating the pathophysiology of clonal expansion within PNH bone marrow. In the majority of patients with haemolytic PNH, there are additional mutations within genes beyond PIG‐A and rather affecting growth and differentiation of clonal bone marrow cells. In contrast to the formerly proposed single mechanism hypotheses such as immune selection or intrinsic gain of clonal dominance, this appears to follow a pattern of a complex clonal hierarchy putatively integrating both earlier anticipated mechanisms. Treatment of PNH is mainly supportive. The only curative approach as allogeneic stem cell transplantation should only be applied to patients with complications such as secondary bone marrow aplasia or transformation into MDS or AML. Symptomatic haemolytic PNH will be treated with eculizumab, an inhibitor of the terminal complement cascade. Treatment with eculizumab can significantly prevent PNH‐related symptoms including the abnormal thrombophilia. Recently, it was demonstrated that in contrast to untreated historic PNH patients, meanwhile a normal life expectancy is observed in eculizumab‐treated patients. The recently approved vaccine against meningococci type B by the European Medical Agency (EMA) could probably further help to prevent meningococcal sepsis due to the induced complement deficiency by eculizumab.     

Sensitive and accurate identification of PNH clones based on ICCS/ESCCA PNH Consensus Guidelines—A summary

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder resulting from the somatic mutation of the X‐linked phosphatidyl‐inositol glycan complementation Class A (PIG‐A) gene. Depending on the severity of the mutation in the PIG‐A gene, there is a partial or absolute inability to make glycosylphosphatidyl‐inositol (GPI)‐anchored proteins including complement‐defense structures such as CD55 and CD59 on RBCs and WBCs. Flow cytometric detection of PNH clones has become the gold standard and has played an increasingly important role in the diagnosis, monitoring, and clinical management of patients with PNH. Recently, a 4‐part set of Consensus Guidelines have been published by flow experts in the field to address the key assay‐specific considerations for the identification of PNH clones in RBC and WBC, how to report such data and a full validation document for the assays described. Below, we have summarized the most significant aspects of this International effort.     

Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by the expansion of a haematopoietic stem cell clone with a PIG-A mutation (the PNH clone) in an environment in which normal stem cells are lost or failing: it has been hypothesized that this abnormal marrow environment provides a relative advantage to the PNH clone. In patients with PNH, generally, the karyotype of bone marrow cells has been reported to be normal, unlike in myelodysplastic syndrome (MDS), another clonal condition in which cytogenetic abnormalities are regarded as diagnostic. In a retrospective review of 46 patients with a PNH clone, we found a karyotypic abnormality in 11 (24%). Upon follow-up, the proportion of cells with abnormal karyotype decreased significantly in seven of these 11 patients. Abnormal morphological bone marrow features reminiscent of MDS were common in PNH, regardless of the karyotype. However, none of our patients developed excess blasts or leukaemia. We conclude that in patients with PNH cytogenetically abnormal clones are not necessarily malignant and may not be predictive of evolution to leukaemia.     

Development of a disease-specific quality of life questionnaire for patients with aplastic anemia and/or paroxysmal nocturnal hemoglobinuria (QLQ-AA/PNH)—report on phases I and II

Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are interrelated ultra-rare diseases. Quality of life (QoL) evaluation tools used in studies for AA and PNH are unspecific and designed for cancer patients (e.g., the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, EORTC QLQ-C30). Given the complexity of AA and PNH, variation in symptoms and treatments, younger age of many patients, and the fact that AA and PNH are not classified as malignant diseases, it is likely that cancer-specific questionnaires are inappropriate. We generate an AA/PNH-specific QoL questionnaire (QLQ-AA/PNH), performed according to EORTC guidelines. QoL issues were obtained from the literature and interviews with patients and physicians (phase I), then ranked by patients and physicians. In phase II, items were created. Patients in more than 25 German and Swiss cities were interviewed face to face. In phase I, interviews of 19 patients and 8 physicians specialized in AA/PNH treatment resulted in 649 QoL issues; these were condensed to 175 and graded according to their importance by 30 patients and 14 physicians (phase II). Five physicians took part in phases I and II. Altogether, 97 issues were rated important. Twelve EORTC QLQ-C30 items were not rated important, while several new QoL aspects were brought up. Modifications in wording and phrasing led to two questionnaires with 77 items regarding general QoL aspects and 20 items regarding medical care. Important QoL aspects of PNH/AA patients are inappropriately captured with available QoL tools. Developing a new QoL questionnaire specific for this patient group is warranted.     

Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two‐centre prospective study

Paroxysmal nocturnal haemoglobinuria (PNH) clones are frequently detected in patients with aplastic anaemia (AA). To evaluate the prognostic role of PNH clone presence we conducted a prospective study in 125 AA patients treated with combined immunosuppressive therapy (IST). Seventy‐four patients (59%) had a PNH clone (PNH+ patients) at diagnosis, with a median clone size of 0·60% in granulocytes and 0·15% in red blood cells. The response rate at 6 months was higher in PNH+ patients than that in PNH‐ patients, both after first‐ and second‐line IST: 68% vs. 45%, P = 0·0164 and 53% vs. 13%, P = 0·0502 respectively. Moreover, 42% of PNH+ patients achieved complete remission compared with only 16% of PNH‐ patients (P = 0·0029). In multivariate logistic regression analysis, PNH clone presence (odds ratio 2·56, P = 0·0180) and baseline absolute reticulocyte count (ARC) ≥30 × 10⁹/l (odds ratio 5·19, P = 0·0011) were independent predictors of response to treatment. Stratification according to PNH positivity and ARC ≥30 × 10⁹/l showed significant distinctions for cumulative incidence of response, overall and failure‐free survival. The results of this prospective study confirmed the favourable prognostic value of PNH clone presence in the setting of IST for AA.     

苏州市医务人员主动提供的HIV检测咨询服务实施状况的定性研究

目的从医生角度了解苏州市医务人员主动提供的艾滋病病毒（HIV）检测咨询服务（PITC）的实施情况及存在问题,探讨PITC的影响因素。方法采用深入访谈的方法,对苏州市辖区内12个区县的13家综合医院PITC门诊医生进行访谈。结果共有40名来自皮肤性病科、妇产科、泌尿科、肛肠科和结核病防治科的门诊医生接受访谈。访谈结果表明,整体来说就诊者PITC接受性不高。实施过程中主要的困难有：门诊工作量大无暇顾及PITC,如何最大限度地保护就诊者的隐私,以及避免误解等方面的问题。结论亟需加强对医务人员的培训,优化服务流程,明确PITC检测重点人群,加强HIV防治知识的宣传和PITC政策的公示,从而提高PITC的接受度。     

Bone marrow transplants for paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal haematological disorder characterized by intravascular haemolysis and increased risk of thrombosis. PNH is associated with bone marrow failure syndromes including aplastic anaemia, myelodysplasia and leukaemia. Bone marrow transplants are sometimes used to treat PNH, but small series and reporting biases make assessment of transplant outcome difficult. The outcome of 57 consecutive allogeneic bone marrow transplants for PNH reported to the International Bone Marrow Transplant Registry (IBMTR) between 1978 and 1995 was analysed. The 2-year probability of survival in 48 recipients of HLA-identical sibling transplants was 56% (95% confidence interval 49-63%). Two recipients of identical twin transplants remain alive 8 and 12 years after treatment. One of seven recipients of alternative donor allogeneic transplants is alive 5 years after transplant. The most common causes of treatment failure were graft failure and infections. Our results indicate that bone marrow transplantation can restore normal bone marrow function in about 50% of PNH patients.     

Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is widely regarded as an archetypal complement-mediated disorder that has propelled complement drug discovery in recent decades. Its pathology is driven by chronic complement dysregulation resulting from the lack of the glycosyl phosphatidyl inositol-linked regulators DAF and CD59 on susceptible erythrocytes. This complement imbalance fuels persistent C3 activation on affected erythrocytes, which culminates in chronic complement-mediated intravascular hemolysis. The clinical application of eculizumab, a humanized anti-C5 antibody that blocks terminal pathway activation, has led to drastic improvement of therapeutic outcomes but has also unveiled hitherto elusive pathogenic mechanisms that are now known to contribute to the clinical burden of a significant proportion of patients with PNH. These emerging clinical needs have sparked a true resurgence of complement therapeutics that offer the promise of even more effective, disease-tailored therapies for PNH. Here, we review the current state of complement therapeutics with a focus on the clinical development of C3-targeted and alternative pathway-directed drug candidates for the treatment of PNH. We also discuss the relative advantages and benefits offered by each complement-targeting approach, including translational considerations that might leverage a more comprehensive clinical intervention for PNH.     

Molecular Pathogenesis of Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH), although named for its marked fluctuations in the visibility of hemoglobinuria, is now classified as an acquired hematopoietic stem cell disorder. The clinical manifestations of PNH are very complicated, and include intravascular hemolytic anemia, venous thrombosis in unusual sites (abdomen, liver, cerebrum), deficient hematopoiesis, evolution to leukemia, and susceptibility to infection [1, 2]. The intravascular hemolysis is attributed to the enhanced susceptibility of erythrocytes to autologous complement [3]. The abnormal sensitivity is explained by a lack of complement regulatory membrane proteins such as decay-accelerating factor (DAF, CD55) and membrane inhibitor of reactive lysis (MIRL, CD59), which are covalently linked to the erythrocyte membrane through a glycosylphosphatidylinositol (GPI) anchor. The deficiency of the membrane proteins is caused by a synthetic defect in this anchor caused by impaired transfer of N- acetylglucosamine (GlcNAc) to phosphatidylinositol (PIns) [2]. Mutations of the phosphatidylinositol glycan class A (PIG-A) gene have been shown to contribute this abnormality in nearly all patients with PNH studied to date [4]. Recently, several reviews have been presented on various aspects of PNH [5–10]. This review focuses particularly on the recent elucidation of the molecular pathogenesis of GPI-anchor deficiency on PNH and related hematopoietic stem cell disorders.     

Separation of the acetylcholinesterase-deficient red cells in paroxysmal nocturnal hemoglobinuria

Blood of patients with paroxysmal nocturnal hemoglobinuria (PNH) most often contains two or more populations of erythrocytes--one population with normal sensitivity to lysis by complement (PNH I cells) and a second population of moderately abnormal cells (PNH II cells) or markedly abnormal cells (PNH III cells). PNH II and III cells exhibit moderately and markedly increased sensitivity to lysis by complement, respectively, as well as other membrane defects. We have devised a method for isolating pure, intact PNH II and III cells from mixed populations by use of monoclonal antibodies and cell affinity chromatography. Study of purified cell populations has led to the identification of a further subtype, PNH IIIb, of PNH erythrocytes. PNH IIIb erythrocytes are less sensitive to complement lysis than PNH IIIa cells but are lysed by fluid-phase activation of complement, unlike PNH II erythrocytes.     

Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haemopoietic stem cells for which the only curative treatment is bone marrow transplantation. There are few reports on the use of allogeneic transplantation for PNH, and nearly all of them include only a few patients. Between September 1978 and December 1997, 16 patients underwent marrow transplantation for PNH at the Hospital Saint Louis. The 5-year survival rate for the 16 patients was 58 +/- 13%. Two factors, an absolute neutrophil count >1.0 x 109/l and haemoglobin level >9 g/dl at transplant, were found to be statistically associated with a better outcome.     

Treatment of paroxysmal nocturnal hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hematopoietic stem cell in which intravascular hemolysis is due to an intrinsic defect in the membrane of red cells that makes them increasingly susceptible to lysis by complement. The phenotypic hallmark of PNH cells is an absence or marked deficiency of GPI-anchored proteins such as CD 59+, CD 55+ and others which normally protect cells from the action of complement. PHN is closely associated with aplastic anemia. Some degree of bone marrow failure is always present. Management of PNH is complicated by a highly variable clinical picture and course. Some patients have severe anemia aggravated by hemolytic crises and associated thromboses. Bone marrow failure is accompanied with frequent infections and hemorrhagic manifestations due to thrombocytopenia. With the exception of marrow transplantation, no definite therapy is available. In the exceptional circumstance in which the patient has a syngeneic twin, bone marrow transplantation is the most appropriate therapy for severe PNH because of absence of graft-versus-host disease. In general syngeneic transplantation without preconditioning has been unsuccessful because abnormal hematopoiesis returns. Allogeneic bone marrow transplantation has been used, but the transplant-associated morbidity and mortality are high due mainly to the fatal graft-versus-host disease and severe posttransplant marrow failure. Use of an unrelated donor transplant has to be considered as contraindicated. PNH is associated with striking predisposition to intravascular thrombosis which often involves the portal system or the brain. Fatal thromboses account for about 40-50% of all deaths in patients with PNH. The etiology of the thrombophilia in PNH is not fully clarified. Anticoagulation or thrombolytic therapy is required for treatment of venous thrombosis, the latter vena cava. Prophylactic anticoagulation in patients without contraindications such as severe thrombocytopenia seems to be justified. However, whether such therapy may be efficacious in reducing the incidence of thromboses or affect survival is conjectural. PNH patients have varying degree of platelet activation and some authors suggest that antiplatelet therapy might be efficacious in reducing the incidence and severity of venous thrombosis in PNH. Pregnancy is hazardous. Female patients should avoid the use of oral contraceptives. Pregnant patients require combined care of an experienced hematologist and obstetrician specialized in the management of high-risk pregnancies.     

Laboratory tests for disorders of complement and complement regulatory proteins

The complement pathway is a cascade of proteases that is involved in immune surveillance and innate immunity, as well as adaptive immunity. Dysfunction of the complement cascade may be mediated by aberrations in the pathways of activation, complement regulatory proteins, or complement deficiencies, and has been linked to a number of hematologic disorders, including paroxysmal noctural hemoglobinuria (PNH), hereditary angioedema (HAE), and atypical hemolytic‐uremic syndrome (aHUS). Here, current laboratory tests for disorders of the complement pathway are reviewed, and their utility and limitations in hematologic disorders and systemic diseases are discussed. Current therapeutic advances targeting the complement pathway in treatment of complement‐mediated hematologic disorders are also reviewed. Am. J. Hematol. 90:1180–1186, 2015. © 2015 Wiley Periodicals, Inc.     

Bone marrow failure in Shwachman-Diamond syndrome does not select for clonal haematopoiesis of the paroxysmal nocturnal haemoglobinuria phenotype

Bone marrow failure is believed to be the underlying condition that drives the expansion of the paroxysmal nocturnal haemoglobinuria (PNH) clone. Indeed, circulating PNH blood cells have been identified in patients with acquired aplastic anaemia and with hypoplastic myelodysplasia. Whether PNH blood cells are also present in patients with inherited aplastic anaemia has not been reported. We screened a large group of patients diagnosed with Shwachman-Diamond Syndrome (SDS) for PNH blood cells. None of the patients analysed had detectable circulating PNH blood cells, indicating that bone marrow failure in SDS does not select for PNH progenitor cells.     

Management of veno‐occlusive disease: the multidisciplinary approach to care

Although it is considered a relatively rare disorder, veno‐occlusive disease (VOD) is one of the main causes of overall, non‐relapse mortality associated with haematopoietic stem cell transplantation (HSCT). This article, based on the consensus opinion of haemato‐oncology nurses, haemato‐oncologists and pharmacists from both adult and paediatric services at the VOD International Multi‐Disciplinary Advisory Board at the European Society for Blood and Marrow Transplantation (EBMT) meeting, Istanbul, 2015, aims to explore the multidisciplinary approach to care for the management of VOD, with an emphasis on current challenges in this area. The careful monitoring of HSCT patients allows early detection of the symptoms associated with VOD and timely treatment, ultimately improving patient outcomes. As part of a multidisciplinary team, nurses have an essential role to play, from pretransplant assessment to medical management and overall care of the patient. Physicians and pharmacists have a responsibility to facilitate education and training so that nurses can work effectively within that team.     

The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab

In Paroxysmal nocturnal haemoglobinuria (PNH), pregnancy is associated with increased maternal and foetal complications to such an extent that the condition has been considered relatively contra‐indicated in PNH. Eculizumab has revolutionized the treatment of PNH. We evaluate its use in pregnancy to date. We report on seven patients exposed to eculizumab at different stages of pregnancy including the first two patients to receive the drug from conception to delivery. There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed.     

Bridging the Gaps in the Care of Psoriasis and Psoriatic Arthritis: the Role of Combined Clinics

Purpose of Review

Despite a robust therapeutic landscape, significant gaps exist in the quality of care of psoriatic disease. Thus, an improved understanding of the challenges in providing quality care and the implementation of effective strategies to overcome them is needed. In this review, we summarize the burden of psoriatic disease, discuss the challenges in the care of psoriatic patients, and outline how combined dermatology-rheumatology clinics bridge many of these gaps.

Recent Findings

Multiple challenges are faced in providing high-quality care to patients with psoriasis and psoriatic arthritis from the pre-diagnosis phase of disease to the follow-up period. Challenges are mainly driven by lack of education of patients and healthcare providers, inefficient communication between specialists, lack of a holistic approach to patients, and limitations of available therapies. The Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) is working on demonstrating the effectiveness of combined dermatology-rheumatology clinics in addressing some of these challenges. Recent findings show that combined clinic models may improve quality of care by raising awareness of psoriatic disease, fostering educational activities for both patients and physicians, and allowing for comprehensive evaluation and management of patients through improved communications between disciplines.

Summary

Psoriasis and psoriatic arthritis are complex diseases that often require an interdisciplinary approach. Thus, combined dermatology-rheumatology clinics and local-regional partnerships are potentially effective in improving quality of care in psoriatic disease.