Therapeutic areas

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, life-threatening disease characterised by the chronic destruction of red blood cells and the increased risk of thrombosis.^1,2

The name of the condition is something of a misnomer. In reality, PNH is neither paroxysmal nor nocturnal, as it is present constantly, and not all patients experience the dark red or black urine caused by haemoglobinuria.³

Prevalence of PNH

Haemolytic PNH affects approximately 5 people per million globally in the general population. Another 10 people per million have a small PNH clone, but few symptoms.⁴

Aetiology of PNH

PNH is a clonal disorder caused by a somatic mutation in the phosphatidylinositol glycan class A (PIG-A) gene in haematopoietic stem cells.^1,2 This mutation in PIG-A, which is located on the X chromosome, prevents cells from synthesising glycosylphosphatidylinositol (GPI) anchors, which are covalently linked protein modifications to anchor proteins on the cell surface.^1,5 At least two of the missing GPI-linked proteins, CD55 and CD59, are key regulators of the complement pathway that protect host cells from haemolysis. Dysregulation of this system therefore leaves red blood cells susceptible to complement-mediated removal – in other words, the chronic haemolysis characteristic of PNH.²

Figure 1. Normal vs PNH red blood cells.
Figure adapted from Hill, et al. 2017 ⁶

The PNH clone

Both red and white blood cells can be affected in PNH, and detection of these cells through flow cytometry is how the disease is diagnosed. The PNH clone is the proportion of PNH cells compared to normal cells. All blood cell types are measured during the diagnostic stage, but an emphasis is put on the white cells (neutrophils, granulocytes, monocytes) and on the red cells.⁷

The percentage of PNH granulocytes is generally the best way to assess the PNH clone size, as white cells, unlike red cells, are not affected by haemolysis or transfusion. The PNH clone (proportion of PNH granulocytes) can vary in size, from 0.01- 100% between different patients. The size of the PNH clone can impact the symptoms an individual patient experiences, but the effects can be very variable.⁷

Intravascular versus extravascular haemolysis

There are two mechanisms by which haemolysis occurs in PNH: intravascular haemolysis (IVH) and extravascular haemolysis (EVH).^1,2

CD59 deficiency leads to the uncontrolled formation of membrane attack complexes (MAC), resulting in complement-mediated IVH. This causes the haemoglobinuria after which PNH is named.^2,5

CD55 deficiency leads to EVH, as decreased C3-convertase enzyme dissociation increases production of C3 fragments. The subsequent C3 opsonisation of red bloods causes them to be cleared in by the reticulo-endothelial system in the liver and spleen.^2,5

Figure 2. PNH mechanism of disease.
Figure adapted from Hill, et al. 2017 ⁶
GPI-AP, glycosylphosphatidylinositol anchored protein; HSC, haematopoietic stem cell; PNH, paroxysmal nocturnal haemoglobinuria; RBC, red blood cell.

The complement system

The complement system is part of the innate immune system, and serves as a first line of defence against foreign and altered host cells. It is composed of proteins synthesised mainly by the liver, or by cell surface membrane proteins. Complement proteins operate in the blood plasma, in tissues, and within cells.⁸

When the complement cascade is triggered, these proteins collaborate to opsonise pathogens and induce a series of inflammatory responses that help to fight infections and maintain homeostasis. There are three distinct pathways by which the complement system can be initiated – classical (CP), lectin (LP), and alternative (AP) – but all lead to a common terminal pathway.⁸

Figure 3. Complement pathways.
Figure adapted from: Brodksy 2014; Hill, et al. 2017; Merle, at al. 2015; Dunkelberger & Song, 2010; and Patriquin & Kuo, 2019 ^5,6,9,10
C3, complement 3; C5, complement 5, PNH, paroxysmal nocturnal haemoglobinuria; RBC, red blood cell.

Classification of PNH

The International PNH Interest Group (IPIG) defined three major categories of PNH:^5,11 

1. Classical PNH (otherwise known as Haemolytic PNH)
2. PNH in the context of other primary bone marrow disorders, such as aplastic anaemia or myelodysplastic syndrome
3. Subclinical PNH, in which patients have small PNH clones but do not demonstrate any evidence of haemolysis or thrombosis

It should be noted, however that some degree of bone marrow failure underpins virtually all cases of PNH.⁵

Figure 4. IPIG categories of PNH. Percentages indicate the size of the PNH clone. Figure adapted from Parker, 2005 ¹²
IPIG, International PNH Interest Group; PNH, paroxysmal nocturnal haemoglobinuria

Clinical manifestations of PNH

Signs and symptoms of PNH may include:^1,6

• Fatigue
• Anaemia
• Thrombosis
• Haemoglobinuria
• Renal insufficiency
• Bone marrow failure
• Smooth muscle dystonia
• Pulmonary hypertension
• Dyspnoea
• Abdominal pain
• Chest pain
• Quality of life impacts

Not all individuals with PNH experience symptoms. However, for those that do, haemolysis is responsible for many of the symptoms seen with this condition.⁴

Diagnosis of PNH

Historically, PNH was diagnosed using the Ham test, the purpose of which was to show whether red blood cells were susceptible to complement-mediated haemolysis in vitro.¹¹

Nowadays, flow cytometry is the established diagnostic assay. It enables high-sensitivity detection of GPI-AP deficient populations in all blood lineages.¹¹

Time to diagnosis may vary greatly. Based on a 2017 survey of 163 PNH patients, while the majority received a diagnosis within the first 2 years after symptom onset (38% in 1 year, 24% between 1 and 2 years), the remaining 37% were diagnosed more than 2 years from symptom onset, with the majority of that subset receiving their diagnosis after more than 5 years.¹³
 

Treatment of PNH
 

The history of PNH treatment

The only curative treatment for PNH remains haematopoietic stem cell transplantation (HSCT), but this process is associated with high morbidity and mortality. In a large retrospective study of 211 PNH patients transplanted between 1978 and 2007, the European Society for Blood and Marrow Transplantation reported 30% overall mortality.¹¹

Before specific treatments became available, PNH resulted in the death of approximately half of all patients, mainly due to thrombotic complications. Patients presenting with classical PNH had a particularly poor prognosis.¹¹

Historically, treatment options for PNH were limited to blood transfusions, anticoagulation, and supplementation with folic acid or iron.¹⁴

Now, however, there are complement inhibitor treatments available:

C5 inhibitors

In 2007, the C5 inhibitor (C5i) eculizumab became available. Eculizumab is indicated in adults and children for the treatment of PNH and targets the C5 component of the complement cascade, thereby providing a way to address IVH^*.^{1,2,11,14,17,18}

In 2019, a long-acting C5 inhibitor called ravulizumab▼ became available in Europe. Ravulizumab acts on the complement cascade in the same way as eculizumab, but has modifications that extend its half-life, and therefore the maintenance dose can be given at less frequent intervals than eculizumab. Ravulizumab is indicated in adults and paediatric patients with a body weight of >10 kg, in those who have remained clinically stable after treatment with eculizumab for at least 6 months^*. ^1,15,16

C3 inhibitors

In 2021, pegcetacoplan▼ received a European license. By targeting C3, a proximal complement protein upstream of C5, pegcetacoplan provides a way to help address both IVH and EVH. Pegcetacoplan is indicated in adults with PNH who are anaemic after treatment with a C5 inhibitor for at least 3 months^*.¹⁹

^*Please visit the relevant SmPC for more information of posology and indications.

Summary

• Paroxysmal nocturnal haemoglobinuria (PNH) is a rare disease characterised by haemolysis and thrombosis¹
• Despite the name, symptoms can be present constantly and at any time, and not all patients experience haemoglobinuria⁴
• Other common symptoms include fatigue and anaemia¹
• Diagnosis is reached via flow cytometry¹¹
• Symptomatic patients can be treated with complement inhibitors¹

References

1. Dingli D, et al. Ann Hematol. 2022;101(2):251-263.
2.Hillmen P, et al. N Engl J Med. 2021;384:1028–1037.
3.Birmingham Heartlands Hospital 2019, Flow cytometric testing for GPI-deficient populations and Paroxysmal Nocturnal Haemoglobinuria (PNH). Available at: https://www.heftpathology.com/images/files/Birmingham_Heartlands_Hospital_MEGS.pdf. Accessed July 2023.
4.PNH National Service 2022, What is PNH?. Available at: https://pnhserviceuk.co.uk/patient-information/what-is-pnh/. Accessed July 2023.
5.Brodsky RA. Blood. 2014;124(18):2804–2811.
6.Hill A, et al. Nat Rev Dis Primers. 2017;3:17028.
7.PNH National Service 2022, What is PNH?. Available at: https://pnhserviceuk.co.uk/patient-information/what-is-pnh/frequently-asked-questions/. Accessed July 2023.
8.Merle NS, et al. Front Immunol. 2015;6:257.
9.Dunkelberger JR and Song W-C. Cell Res. 2010;20(1):34-50.
10.Patriquin C and Kuo KHM. Transfus Med Rev. 2019;33(4):256-265.
11.Risitano AM and Peffault de Latour R. Br J Haematol. 2022;196(2):288-303.
12.Parker C, et al. Blood. 2005;106(12):3699-709.
13.Mitchell R, et al. SM Clin Med Oncol. 2017;1(1):1001.
14.Röth A and Dührsen U. Eur J Haematol. 2011;87(6):473-9.
15.Alexion press release June 2021. Available at: https://media.alexion.com/news-releases/news-release-details/alexion-announces-fda-approval-ultomirisr-ravulizumab-cwvz. Accessed July 2023.
16.NICE Guidance TA698 2021, Ravulizumab for treating paroxysmal nocturnal haemoglobinuria. Available at: https://www.nice.org.uk/guidance/ta698/resources/ravulizumab-for-treating-paroxysmal-nocturnal-haemoglobinuria-pdf-82609447238341. Accessed July 2023.
17.Soliris SmPC 2022. Available at: https://www.medicines.org.uk/emc/product/362/smpc#gref. Accessed July 2023.
18.Ultomiris SmPC 2022. Available at: https://www.medicines.org.uk/emc/product/11945/smpc#gref. Accessed July 2023.
19.Wong R. Ther Adv Hematol. 2022;13:20406207221114673.