GPA - The systemic disorder

Morbus Wegener

GPA and MPA lead to an infection of the blood-vessels in the body. Both diseases are considered so called ANCA-associated small-vessel vasculitides and rather rare: Annually 5 to 12 people fall ill of GPA (per one million people). The disease mostly affects people, men and women equally often, between the age of 40 and 50.
MPA is even rarer, with two to three (per one million people) newly affected people annualy. Most patients are over 50 when they receive their diagnosis and they are more frequently male.

*Quelle: Gibelin A et al.; Semin Respir Crit Care Med 2011; 32: 264–273

For your better understanding we highlighted some of the medical terminology and explain them. You get the explanations if you point your curser at the underlined words.

Granulomatosis with Polyangiitis

Facts about GPA

Vasculitis is an inflammatory disorder of the blood vessels. Vasculitides can affect the entire organism and emerge as a syndrome on its own without any known causes. GPA and microscopic polyangiitis (MPA) are so-called primary vasculitides. However, vasculitis may also be the result of another illness (e.g. rheumatoid arthritis) or arise as an unwanted side effect of medication; in which case, it would be secondary vasculitis.

Primary vasculitis, such as GPA and MPA, is medically classed as an inflammatory rheumatic illness. In all cases it requires support by a specialist; mostly a rheumatologist.

Since blood vessels are located all over the body, in principle, all vessels, and therefore also organs, can be affected by vasculitis, which explains the different complaints. Therefore, complaints sometimes manifest themselves so differently. This is also why it is referred to as a systematic illness – an illness in which the entire body is affected. As a result, well-being can be considerably limited.

GPA is also referred to as ‘Wegener’s granulomatosis’, named after the first person to describe it: the German physician Friedrich Wegener. Recently, experts agreed to use the term ‘granulomatosis with polyangiitis’. This is for the international standardisation of the terms.

The term ‘granulomatosis’ describes the characteristic changes frequently noticed in the respiratory tracts of GPA patients once the tissue is examined under a microscope. So-called granulomas – small lump-like accumulations of cells – are frequently the discovery of such examinations.

Polyangiitis means that many vessels are inflamed (Greek: poly = many; Latin: angiitis = vascular inflammation). ‘Microscopic polyangiitis (MPA)’ is referred to as such because the vessels primarily affected are very small and only visible under a microscope.

Both illnesses essentially manifest themselves with very similar symptoms. In contrast with GPA, however, no granulomas are found with MPA, and only very infrequently are the upper respiratory tract and the head affected.
Vasculitides may occur in a restricted location in the body, for example in the nose. This is then referred to as a localised form. On the other hand, if a great many blood vessels of the body are affected, this is then referred to as a generalised form.
Common signs of vasculitis
General indications:

  • Tiredness and weakness, fever, night sweats and loss of weight as an expression of inflammation or an unexplained inflammatory reaction in the blood (see ‘How is the diagnosis made?’).

In the ear, nose and throat (ENT) region:

  • Chronic inflammation of the nasal mucous membrane with a blocked nose, bloody discharge (nosebleeds) and bloody-crusty scab formation.
  • Chronic middle ear inflammation
  • Hearing impairment, hearing loss

In the eyes:

  • Inflammations in almost all parts of the eyes; typically, this is ‘bloodshot eye’, caused by scleritis.
  • Impaired vision
  • Pain in the back of the eye or even a bulging of the eyeball.
  • Watering eyes due to inflammation of the lacrimal duct

In the musculoskeletal system:

  • Pain and, more seldom, swelling of the joints
  • Muscle pains, reduced mobility
  • Morning stiffness, meaning reduced mobility of the joints in the mornings after getting up

On the skin:

  • Purple, spotty rash (purpura), mainly on the legs
  • Open ulcers on the skin and mucous membranes that heal poorly or not at all

If organs and the nervous system are affected:

  • Numbness and sensory disturbances right through to paralysis, especially to the feet if the peripheral nervous system is affected
  • Strokes or seizures, as well as paralysis if the central nervous system (CNS) is affected
  • Coughing up blood and shortness of breath if the lungs are affected
  • Foamy and reddish urine and accumulations of fluid in the legs (oedemas)
  • High blood pressure if the kidneys are affected
  • Bloody diarrhoea, often connected with spasmodic stomach ache, if the digestive system is affected (seldom)
  • Chest pain and shortness of breath if the heart is affected (seldom)

Typical symptoms for GPA in a localised form are chronic paranasal sinus inflammation and nosebleeds. Symptoms of the general form include coughing up blood, shortness of breath, pain in the joints and rashes. If the inflammation reaches the kidney vessels, this will manifest itself in changes to the urine through to kidney function failure.

Patients with MPA frequently complain of coughing up blood, purple, spotty rashes and joint pain. The kidneys are also commonly affected by MPA.

Precisely what triggers permanent vascular inflammation with primary vasculitides such as GPA and MPA is not entirely clear. What is clear, however, is that an overreaction of the immune system of our bodies plays a key role.

The healthy defence system

The body’s own defence system (the immune system) protects us from pathogens that get into our bodies from outside. Without an immune system, viruses or bacteria could multiply uncontrollably and lead to illnesses. The immune system therefore acts as a kind of ‘body police force’, with various ‘special departments’ and ‘special weapons’ at its disposal. One of the ‘body police force’s’ most important ‘special departments’ are the white blood cells (leukocytes). A special form of the white blood cells are the so-called T and B cells. B-cells mature into plasma cells, constituting the most important ‘special weapons’ in the fight against foreign invaders: bespoke proteins / antibodies.
Antibodies detect pathogens and attach to them, therefore rendering them harmless. The fight against the external enemy in the form of inflammation always follows the same pattern: the affected area reddens, overheats, swells and hurts.

Inflammation is therefore nothing more than the normal and sensible reaction of our body to a stimulus, such as pathogens. With the inflammation reaction, the stimulus is attacked and removed. If this happens, the inflammation heals up completely and the patient no longer has any complaints. The white blood cells which are heavily involved in the defensive and thus inflammatory reactions are also referred to as inflammatory cells. Above all, this includes the T and B cells.

In the event of a defence system overreaction, it becomes too strong. Now, not only does it combat pathogens that threaten us from outside, but also the body itself – specifically, the blood vessels. The ‘body police force’ therefore produces antibodies, which are directed against the body’s own tissue, thus triggering inflammation. These antibodies are referred to as autoantibodies (Greek: autos = self) and – like the correct antibodies in a healthy immune system – are also formed from the plasma cells, the mature B cells. In the event of vasculitis, autoantibodies can contribute to chronic inflammation, amongst other things.

Why this autoimmune reaction occurs and the immune system suddenly overreacts and attacks the body’s own constituent parts is – despite intensive research – still not fully clear.

In detail: what are ANCA-associated vasculitides?

It is assumed that a special form of autoantibodies, ANCAs, could be involved in the emergence of GPA and MPA. This is also why this is referred to as ANCA-associated vasculitides (AAV for short) or ANCA-positive vasculitides.
ANCAs target the inside (cytoplasm) of neutrophil granulocytes – a particular group of white blood cells. ANCAs are formed from plasma cells, which in turn mature from B cells. B cells thus play a crucial role in ANCA-positive vasculitides.

How do the ANCA then cause inflammation of the blood vessels?

It is assumed that the ANCAs attach to the neutrophil granulocytes, which subsequently release inflammatory neurotransmitters and activate other inflammatory cells, such as T cells. ANCAs attaching directly onto the vessel wall is also conceivable. The whole vessel wall swells as a result, which can lead to the narrowing and even to the closing of the vessel.

The consequence is that the tissue supplied by this vessel is no longer adequately supplied with blood, oxygen and nutrients and dies. Medical doctors refer to this as an infarct. Inflamed vessels cannot only narrow or shut, however, they can also form bulges (aneurysms) and burst (ruptures). There is then a risk of bleeding.

This explains why patients’ complaints are so varied and the immediate consequences can range from mildly detrimental to potentially fatal. The effects of vasculitis depend on how many vessels are affected, in which organ the inflammation is taking place and how large the inflamed vessel is. With smaller vessels, closures and/or bleeding in organs (e.g. a kidney) are the main issue; with medium-size and large vessels, vessel closures and infarcts occur, often initially without organ damage.

The insufficient supply of nutrients and oxygen of the body due to the vascular inflammation also makes itself noticeable with very general illness symptoms. Patients are often tired, exhausted, experience a loss of appetite and also often report inexplicable fever, night sweats and weight loss.

Due to the rarity of the illness and the ‘colourful pattern’ which vasculitis offers with its various complaints, it regularly takes a while until the illness is detected. This is because each individual symptom arising with vasculitis could have a multitude of other causes.

Vasculitides such as GPA and MPA are therefore mostly unable to be detected by means of one examination. Information concerning the complaints, different clinical findings and the results of examinations must be combined. In practice this is often difficult and requires close cooperation between a GP / specialist in internal medicine and other medical specialists. Everyone must look very precisely for signs of vasculitis in their area; signs which you as somebody affected might not even have noticed yourself.

Diagnostics – often a difficult search

Examinations have shown that years often pass between the presumed first symptom to the correct diagnosis of vasculitis. The first steps on the path to diagnosis are therefore an extensive discussion with a physician, in which possible earlier complaints are brought back to mind, and thorough physical examinations.

Blood test

  • Inflammation values: the inflammation, which occurs during vasculitis due to an overreacting immune system in the body, can mostly be determined from the blood. Typically, the inflammation values are increased. This includes blood cell sedimentation rate, or ESR or ‘sed rate’ for short, and the C-reactive protein, abbreviated to CRP. Both of these values increase if there is any inflammation in the body – not only in the event of vasculitis. An elevated ESR and increased CRP alone do not therefore permit a diagnosis of vasculitis. However, they could be a first sign of inflammation in the body. Both values are also very helpful for checking the progress of therapy, since they normalise with successful treatment.
  • ANCA evidence
  • Kidney values: these are split down into creatinine and urine. Both values must be measured at the start and then regularly during the course of monitoring the kidney functions. The disadvantage of these values is that they may only increase late on when much of the kidney tissue has already been destroyed. This is why it is very important to regularly examine urine.

Urine examination

Whether or not a vasculitis-induced inflammation of a kidney exists can most easily be determined by examining the urine. When trying to determine if the kidneys might be affected, the urine is mostly examined using a test strip in particular for protein and blood components; i.e. white blood cells and red blood cells (enthrocytes). Both of these are either not found at all or only in very small quantities in the urine of healthy people. Cylindrically deformed enthrocytes are also typical. If these changes are detected in the urine, this would indicate kidney damage. The urine must then be examined in more detail – ideally by a specialist. Further indications of the kidneys being affected may be increased blood pressure or an accumulation of water in the legs. You should therefore measure your blood pressure regularly yourself.

Imaging processes

Depending on the complaints, imaging examinations such as X-ray, ultrasound (medical sonography) and magnetic resonance imaging (MRI, but also referred to as magnetic resonance tomography, or MRT) examinations, as well as computer tomography (CT) may also be important on the path to diagnosis. In this way, for example, granulomas in the lungs or in the ENT region – typical in cases of GPA – can be discovered. Depending on your complaints, your physician will decide which examination should be performed on you.

Histological examination with a microscope

In the event of justified suspicion of GPA or MPA, a tissue sample will ideally be taken from the organ affected; for example, a kidney, the nose or a lung. This is referred to as a biopsy. The tissue sample is then examined under a microscope. This procedure is referred to as a histological examination – the microscopic study of tissue. With GPA, the inflammation of the vessels with the characteristic granulomas, which give the illness its name, is found. With MPA, vascular inflammation is also found, but without the granulomas. A positive finding in histology is often firm evidence of vasculitis. However, even here it might be that an examination remains negative.

Histology is the most certain and best evidence for vasculitis.

Vasculitides such as GPA and MPA used to be feared illnesses, because no effective treatment was available. With today’s knowledge and medical options, although often not fully curable, both illnesses are mostly easily treated and thus manageable.

Most patients will go into remission within one year. Very often, therefore, patients can go on to lead a normal life again; by going back into work, for example. In addition to going into remission, the improvement of the quality of life is also an important objective of therapy for physicians. Since vasculitides can progress very differently in all patients, there is no uniform therapy based on a single scheme.

Treatment is adjusted to the spread, activity and progress of the illness. The therapy for vasculitides is therefore customised therapy for the individual patient. The treatment itself and the regular checking of the progress of the illness should be performed by a specialised physician. Medical specialists of different disciplines collaborate on the diagnosing and treating vasculitis. As mentioned earlier, vasculitides are a rheumatic illness. Since the rheumatologist specialises in autoimmune diseases, the lead for the treatment and checking of the treatment must be taken by the rheumatologist.

The therapy for GPA and MPA can essentially be split into two parts:

  • With so-called remission induction therapy, the initial aim is to initiate remission quickly.
  • In very early stages (locally restricted to the head) of GPA, the antibiotic co-trimoxazole can be prescribed in some cases, which often leads to an improvement.
  • Milder illness progressions, especially those without kidney or other organs affected posing potentially fatality, are mostly treated with methotrexate (MTX) or also azathioprine (AZA) in combination with cortisone. Patients with serious progressions receive cortisone and cyclophosphamide. Cortisone is always required to begin with, since it acts very quickly.
  • Recently, the B cell therapy rituximab has also been available for the remission induction therapy of serious progressions, which is also given in combination with cortisone.
  • If a person goes into remission, the induction therapy can be terminated and subsequent treatment for maintaining remission can be started. As is evident from the wording, this is to maintain the containment of the illness for as long as possible and prevent a repeat flare-up.
  • In patients with limited kidney function, azathioprine is usually prescribed; in rare cases, also mycophenolic acid or leflunomide in the event of intolerance to azathioprine.
  • If the kidney function is normal, MTX can also be given. The question as to how long the treatment of a GPA or MPA lasts in total varies from patient to patient and cannot be answered in a blanket manner.

Please note:
Even if the vasculitis has been completely forced back following successful treatment, regular visits to the physician and checks of your condition and blood are necessary. This way a recurrence of the illness (relapse) can be detected early and treatment can be started again early or the treatment can be adjusted.

The best counsel for your illness is you yourself, to the extent that the physicians treating you are critically dependent on your support. If you are well-informed about your illness, your progress has the potential to be more pleasant. Pay attention to any early warning signals of a repeat flare-up of the illness – for example: new joint pains, skin changes, complaints in the ear, nose and throat region, general feelings of illness, unexplained fever, weight loss and gain, as well as night sweats. See a physician promptly. Then you can start on the right medications immediately and the flare-up and the consequences will perhaps progress less severely.

In addition to their effects, many medicines have undesired side effects (e.g. infections), which are often indistinguishable from a flare-up of the underlying illness. In case of doubt, either you or the physician looking after you should refer to a rheumatologist. Also enquire early on about possible side effects of the medication which you have been prescribed.

Very sensible and important in correctly dealing with your illness without doubt is also patient training, which nowadays is offered by many rheumatology clinics. Here you get to meet other people affected on the one hand, while also learning everything about the various medicines, early warning symptoms and what else you are able to do to get your illness under control on the other. For many people affected, communication in self-help groups is also helpful.

And another tip: as a patient with GPA and MPA, you have a right to a severely disabled person’s pass. In Germany, this is officially referred to as an ‘application under the Disabilities Act’. This brings with it various advantages, in particular special protection against dismissal and tax benefits. Consult the physician taking care of you about this. He or she can provide extensive advice.

Other things you can do:

  • While in therapy with medicines, you should have yourself inoculated regularly. Your physician will be happy to advise you about this.
  • If you have been prescribed cortisone, you should take vitamin D3 to protect your bones. Please also seek the advice of your physician in this regard.
  • Make sure you have a healthy and balanced diet. There is no special ‘rheumatoid diet’.
  • If your health permits it again, do regular exercise.
  • If you previously smoked, you should stop this for your general health.

Possible side effects of medicinal treatment:

With any effective treatment, there is no effect without side effect. The overexuberant immune system is restricted by immunosuppressants. Unfortunately, this restriction also impacts the functioning of the healthy immune system. For this reason, in general infections occur more frequently when taking immunosuppressants. These infections commonly affect the respiratory tract and are usually mostly minor. In rare cases, serious infections may also arise. Therefore, to be on the safe side, please refer to your physician early on in the event of associated symptoms (e.g. fever, coughing, shortness of breath, sputum, etc.).

Infusion-related reactions may occur with medicines that are administered by means of infusion. This involves flu-like symptoms, such as fever, fatigue and chills, which mostly progress mildly. The team in the practice in which you are receiving the infusion are trained on such side effects, however, and can initiate appropriate countermeasures.

MTX can lead to harm to an unborn child. For this reason, while taking MTX and six months after the end of MTX therapy, women must not become pregnant. The same applies to men being treated with MTX: they should not produce any offspring during the MTX therapy and up to six months after the end of the treatment. During MTX therapy, blood tests must also be conducted regularly, and certain side effects may arise. Your physician will tell you about this.

Another side effect of cyclophosphamide is bladder damage. This is why you receive a medicine that protects the bladder mucosa simultaneously with the cyclophosphamide dose. This medicine is called Mesna. Mesna should always be administered in the mornings and also be drunk with a lot of liquid.

The most common side effects of azathioprine are changes to the blood count, infections, nausea and loss of appetite.

Apart from the aforementioned possible infusion reactions, side effects are rare with rituximab therapy. There is a slightly increased risk of infection, especially to the respiratory tract and the urinary tract. You should pay special attention to any indications of an infection lasting longer than normal and then seek your physician immediately. For more detailed information on the possible additional side effects of vasculitides therapy, please consult your physician. You can also find information on the specific medicines on the website of the German Society for Rheumatology [Deutsche Gesellschaft für Rheumatologie (DGRh)]. Deutschen Gesellschaft für Rheumatologie.

Other treatment options: plasmapheresis