Complement-Mediated Diseases

The complement system is a part of the body’s immune system which acts as our first line of defence against infections.1 When the complement system is not properly regulated, it can cause a wide range of diseases, known as complement-mediated diseases. Understanding the science behind the complement system is key to addressing the challenges faced by people with these conditions.

The complement system enhances the body’s ability to fight disease.1 It’s like an amplifier for the immune system, helping it to remove any foreign microorganisms, such as viruses, bacteria, or other organisms that can cause disease (pathogens), as well as damaged cells and tissue. The complement system is made up of a tightly regulated chain of more than 30 proteins. When functioning correctly, this internal system leads to the destruction of foreign or damaged cells, while ensuring the destruction stops once the threat is removed; before causing damage to healthy cells and tissue.1

Life-altering complications in the complement system

Unfortunately, the complement system doesn’t always function correctly. In some people, internal or external factors disrupt the balance of the proteins, causing dysregulation. This can lead to the complement system mistakenly destroying healthy cells and tissue, which can cause a range of complement-mediated conditions.1,2 These diseases are often associated with debilitating symptoms that people experience throughout their lifetime, resulting in significant burden on them and their families.3 Some people living with these diseases may also require extensive or life-long treatment, which can be invasive, inconvenient, and in some cases, might not eliminate symptoms completely.4

C5 is split, forming a MAC, leading to the destruction of target cells

The final step in the destruction of foreign or damaged cells by the complement system is the formation of a structure called the membrane attack complex (MAC). The MAC punctures holes in the foreign or damaged cell walls, destroying them – a process known as ‘cell lysis’. A complement system protein known as complement 5 (C5) is a crucial element of MAC formation, making C5 an important target when looking to (temporarily) stop the destructive power of a dysregulated complement system.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare and life-threatening blood condition, where a mutation in bone marrow stem cells causes red blood cells to be produced without certain proteins on their surface. The absence of these specific proteins causes the complement system to recognise the red blood cells as foreign, kicking off the chain of events that ultimately leads to their destruction.5,6

While the symptoms and complications of PNH can vary greatly from person to person, they can dramatically affect quality of life.3 The most common are anaemia, fatigue, blood clots and kidney disease, as well as bruising, shortness of breath and headaches, which may come and go without warning, throughout a person’s life.5 Although PNH can develop at any age, it is often diagnosed in people around 30-40 years old, which means many people will suffer the effects of the disease for decades.3

Currently, PNH is primarily treated with C5 complement inhibitors, which work by targeting the C5 protein in the complement system, stopping the system from destroying healthy red blood cells.4 This currently involves frequent, life-long medicine, given intravenously (via IV), although some people may still experience disease symptoms such as anaemia,7,8 and may require high (or off-label) doses to achieve adequate symptom control.4,9,10 Furthermore, there remains a small proportion of the treated population whose medical needs are not met, as they are resistant to current C5 inhibitors.4

Atypical haemolytic uremic syndrome – an ultra-rare clotting disorder

Atypical haemolytic uremic syndrome (aHUS), is another complement-mediated disease where the normal function of the complement system is disrupted. In many people with aHUS, it is caused by either genetic mutations, or auto-antibodies to complement system proteins.11

Although people with aHUS may not experience any symptoms for most of their lives, factors that trigger the complement system – such as pathogens, infection, or other events (like pregnancy and diarrhoea)12 – can cause a severe and sudden overdrive of the complement system. This can result in an attack of the lining of blood vessels, the destruction of red blood cells (haemolysis) and the formation of small blood clots.13 These clots prevent blood flow, leading to internal organ damage and chronic complications.14

People with aHUS are often diagnosed when they present with a sudden, and sometimes life-threatening onset, characterised by a deterioration in kidney function, extremely high blood pressure, abdominal pain, and diarrhoea. Stroke, confusion and, in some cases, eye damage are also frequently reported. Due to the rapid and progressive nature of these symptoms, many patients require emergency hospitalisation.13,11

aHUS attacks can occur at any age, and affect males and females equally in childhood, but are more common in females during adulthood.14

As with PNH, aHUS is mostly treated with frequent IV C5 inhibitors, where available,15 and many patients might require long term or even life-long therapy to prevent relapse. Additionally, availability of C5 inhibitors is limited; in countries where C5 inhibitors are not available, aHUS treatment consists of regular intravenous infusions of frozen plasma or plasma exchange.7

Sickle cell disease – a group of inherited diseases affecting red blood cells

Sickle cell disease (SCD) is the term used for a group of genetic diseases that affect red blood cells’ physical shape, as well as their ability to bind and carry oxygen to be circulated around the body.16,17 Healthy red blood cells are shaped like smooth, flexible discs, allowing them to move easily through small blood vessels. In SCD, red blood cells form a rigid “sickle” shape, which stops them from flowing easily, so they become stuck to the walls of blood vessels, blocking blood flow.18,19

Blocked blood vessels can often cause serious complications, such as stroke, infections, eye and kidney problems, anaemia, and severe pain.17 Complement pathway dysregulation has been linked to several of these complications,20 including ‘sickle cell crises’ (episodes of pain; also known as vaso-occlusive episodes or crisis; VOE or VOC) - one of the most common and distressing symptoms of SCD.21 Patients with VOE can present with pain, which varies in frequency and intensity (moderate to severe). Most people with SCD experience pain related to VOEs by the age of only six years old. VOEs are often triggered by causes such as cold temperature, low humidity, stress, or dehydration.21 These episodes can occur at any time and often require hospitalisation.18

SCD disproportionately affects people living in – or with ancestors from – sub-Saharan Africa, South Asia, the Middle East, and the Mediterranean.19

Currently, care for VOEs in SCD is mostly palliative and relies on complication management,22 using painkillers.23

Learn from Nature: PNH - When blood machinery goes wrong
Roche in complement-mediated diseases

Roche has a history of developing innovative antibody therapies to address some of the highest unmet medical needs. Today, we continue to invest in our efforts to bring innovative treatment options to people with complement-mediated diseases, such as PNH, aHUS and SCD, where treatment options are limited.

At Roche we are committed to understanding the intricacies of the complement system, with the ultimate goal of combating complement-mediated diseases. We believe that by matching our scientific expertise with our patient-focused philosophy, we can potentially transform the lives of people living with these conditions.

Paroxysmal nocturnal haemoglobinuria – a rare, blood cell-destroying disease

References

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