What is Granulomatosis With Polyangiitis (Wegener granulomatosis)?
Wegener granulomatosis, now called granulomatosis with polyangiitis, is a disease that causes small to medium blood vessels to become inflamed and damaged. This condition is part of a broader group of disorders known as anti-neutrophil-cytoplasmic-antibody (ANCA) associated vasculitides (AAV). The AAV group includes other conditions like microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA or also known as Churg Strauss syndrome). These categories were established in 2012 during a specialist conference. Granulomatosis with polyangiitis is marked by a type of pneumonia and kidney syndrome, often alongside ear, nose, and throat symptoms.
The first case of this disease was documented back in 1931 by a German medical student named Heinz Klinger. Five years later, in 1936, a pathologist named Friedrich Wegener highlighted three more cases of this unusual inflammation and concluded that the disease was a unique form of blood vessel inflammation. For many years, the disease was known as Wegener’s granulomatosis. However, in 2000, it was discovered that Wegener had connections to the Nazis, which led to a push to rename the disease in the medical field. As a result, the disease is now referred to by its more descriptive name – granulomatosis with polyangiitis.
What Causes Granulomatosis With Polyangiitis (Wegener granulomatosis)?
The exact cause of Granulomatosis with polyangiitis (GPA), a disorder affecting blood vessels, is hard to pin down. It is believed to be related to certain types of antibodies, known as anti-neutrophilic cytoplasmic antibodies (ANCA). These antibodies play a major role in how our immune system responds to threats by helping to control inflammation. ANCA, in particular, seem to react with an enzyme called proteinase 3 (PR3), which is part of a type of white blood cell. Too much of this reaction can increase white blood cells’ stickiness to the lining of vessels, leading to their breakdown and potentially damaging cells.
The excessive production of ANCA happens due to malfunctioning immune responses to threats like infections. This excessive response produces high levels of inflammation-causing substances, which can create an inflammatory lump in the vessels. The ANCA test is 66% accurate in people with GPA and is present in 80%-90% of patients with active disease. In some cases, however, ANCA doesn’t show up in tests.
Aside from these likely causes, some genetic factors might be involved. Certain changes or defects in genes have been linked to GPA, including the gene governing alpha 1 antitrypsin, a protein that protects the body from an enzyme that digests damaged or aged cells and bacteria. Other genes, such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, which activates a type of white blood cell, and the proteinase 3 (PRTN 3) gene, involved in releasing enzymes during inflammation, are also associated.
Another factor that may contribute to the development of GPA is infection. Certain bacteria such as Staphylococcus aureus, as well as several viruses including hepatitis C, cytomegalovirus, Epstein-Barr, and parvovirus, have all been connected to GPA.
Lastly, a range of medications like hydralazine (for high blood pressure), phenytoin (for seizures), anti-thyroid drugs, sulfasalazine (for rheumatoid arthritis and other inflammatory conditions), and allopurinol (for gout) have all been linked to GPA.
Risk Factors and Frequency for Granulomatosis With Polyangiitis (Wegener granulomatosis)
Granulomatosis with polyangiitis (GPA) is the most common type of a group of conditions known as ANCA-associated vasculitides. The number of new cases of GPA reported each year varies worldwide, but it’s estimated at about 10 to 20 cases for every one million people. This number can be higher in colder regions. For example, in the United States, there are about 3 new cases per million people each year. GPA is more common in adults compared to children and tends to peak between the ages of 64 to 75. People of all genders can be affected equally. While it’s often diagnosed in white individuals, any racial and ethnic groups can be affected by GPA.
Signs and Symptoms of Granulomatosis With Polyangiitis (Wegener granulomatosis)
Granulomatosis with polyangiitis is a disease that involves inflammation in various parts of the body. It tends to affect three main areas: the upper and lower respiratory tracts (like the sinuses and lungs), the blood vessels throughout the body, and the kidneys.
General symptoms can include fever, feeling unwell, weight loss, joint pain, and muscle aches. However, this illness can affect specific organs as well, leading to a variety of symptoms.
- Upper respiratory tract: Most patients have problems with their nasal and sinus regions, including pain, stuffiness, discharge, nose bleeds, and ear infections. Severe nasal inflammation can even cause the nose to collapse, creating a “saddle nose” deformity.
- Lower respiratory tract: Symptoms may include a cough, spitting blood, difficult breathing, sometimes chest pain, and occasionally, a blocked windpipe. Almost half of patients have patches appearing in their lungs, and some people have fluid in the space surrounding their lungs. In extreme cases, patients can end up having significant bleeding in the lungs leading to severe illness and possibly death.
- Kidneys: At first, only 10-20% of patients have kidney involvement, but most patients develop a form of kidney inflammation called glomerulonephritis within two years. This can progress to serious kidney disease requiring treatment.
- Eyes: Over half the patients will have symptoms with the eyes, like inflammation of the white part of the eyes or the inside surface of the eyelids. Severe cases could lead to blindness. Some develop obstructions in the tear ducts.
- Ears: People might experience different types of hearing loss and issues with the middle ear, like ear infections.
- Skin: Half to most patients have skin issues, most commonly a type of skin rash called purpura, usually affecting lower legs. Other skin issues include red bumps, skin ulcers, small skin blisters, and hard lumps under the skin.
- Nervous system: Up to 40% of patients could have nerve-related symptoms, typically peripheral neuropathy. Some might experience seizures or inflammation of the membranes surrounding the brain and spinal cord.
- Musculoskeletal: Joint pain and muscle ache occur in most patients but are usually accompanied by other symptoms. Misdiagnosis often happens because of the resemblance to rheumatoid arthritis.
- Cardiac: Heart problems can occur but are less common, and could involve changes in the heart valves, inflammation of the heart’s outer lining, or inflammation of the blood vessels that supply the heart.
Granulomatosis with polyangiitis shows considerable overlap with another disease called microscopic polyangiitis, sharing symptoms such as bleeding in the lungs and a particular type of kidney inflammation. They can be distinguished by certain lab tests and patterns of inflammation in certain body tissues.
Testing for Granulomatosis With Polyangiitis (Wegener granulomatosis)
If your doctor suspects that you might have Granulomatosis with Polyangiitis (GPA), a condition that causes inflammation in your blood vessels and can cause damage to your kidneys and lungs, they will make a detailed evaluation of your condition. This involves a thorough clinical check-up to identify how and where the disease is affecting your body.
As part of this process, your doctor will carry out a series of lab tests. These include a complete blood count, electrolyte levels, renal (kidney) function panel, urinalysis, erythrocyte sedimentation rate (ESR) which is a test that can detect inflammation in your body, and C-reactive protein (CRP) which is a protein that increases in your blood when there is inflammation in your body. They may also check for PR3-ANCA and MPO-ANCA titers – these are antibodies sometimes found in people with GPA.
For a better understanding, they may use imaging studies to look at your sinuses, lungs, trachea (windpipe), and orbits (eye sockets). A chest X-ray and CT (computed tomography) scan can help examine the lungs for any lesions (abnormalities) or bleeding. These images can also help to distinguish between GPA and a similar disease, MPA (Microscopic Polyangiitis).
Additionally, your doctor may suggest biopsies (a procedure where a small sample of tissue is removed for examination) of your kidneys, skin, and lungs to look for signs of vasculitis, which means inflammation of the blood vessels, and immune deposits, which are build-ups of immune system cells. The lung is the most common place to take a biopsy from, and a kidney biopsy can show if there is damage to the kidney.
To diagnose GPA, several different criteria have been proposed:
1. The ACR (American College of Rheumatology) criteria require at least two of the following: evidence of kidney involvement in the urine, abnormal findings on a chest X-ray, symptoms in the mouth or nose such as ulcers or a nasal discharge, or inflammation typical of GPA seen in a biopsy. These criteria have a specificity of 92% and sensitivity of 88%, meaning they are quite accurate in identifying GPA.
2. The ELK criteria proposed by DeRemee, named for the three primary areas affected: ‘E’ for the Ear, nose, and throat, ‘L’ for Lung, and ‘K’ for Kidney. If someone with suspected GPA has symptoms in these areas, combined with a positive c-ANCA (a certain type of antibody) test or a biopsy showing typical signs, this would be enough for a GPA diagnosis.
Treatment Options for Granulomatosis With Polyangiitis (Wegener granulomatosis)
Treatment for patients with Granulomatosis with Polyangiitis (GPA), an uncommon disorder causing inflammation of blood vessels in your nose, sinuses, throat, lungs and kidneys, is determined by the severity of the disease.
If the disease is considered severe, meaning it poses a direct threat to life or critical organs, it would include dangerous symptoms such as kidney inflammation, lung bleeding, inflammation of blood vessels in the brain, serious nerve damage, GI bleeding, inflammation of heart tissues, inflammation or swelling of the eye orbits, or heart muscle inflammation. Less threatening symptoms are classified as limited disease.
For severe cases, a medication called cyclophosphamide is usually recommended. Cyclophosphamide is a powerful medication used to suppress the immune system and control the body’s inflammatory response.
In treating GPA, a variety of drugs that suppress the immune system are used in different combinations. The treatment is divided into two parts: the induction phase, where the process of decreasing the body’s immune response begins, and the maintenance phase, where the decreased immune response is kept steady.
Cyclophosphamide, glucocorticoids, rituximab, azathioprine, methotrexate, and plasmapheresis are common treatments. Plasmapheresis is a procedure used to remove, treat, and return or replace blood plasma or components thereof from the blood circulation.
For severe cases, cyclophosphamide along with glucocorticoids has been found to be an effective treatment. It’s often started after giving pulse steroids for 3 days (a large dose of steroids for a short duration). The decision on which drug to choose depends on patient comfort, doctor’s suggestion and the possible side effects of the drug.
In a study known as the “RAVE trial,” it was concluded that rituximab is just as effective as cyclophosphamide, and it might be even better for disease that keeps coming back. If the disease is less severe and there’s no reason not to use methotrexate, methotrexate combined with glucocorticoids is used.
Plasmapheresis is usually indicated for rapidly declining kidney function, presence of damaging antibodies against kidney basement membrane, or lungs bleeding resulting in respiratory compromise and not responding to glucocorticoids.
Once our body responds to the treatment and the symptoms are in control (usually within 3-6 months), the maintenance therapy is started. This aims to prevent the disease from flaring up again. Methotrexate, azathioprine, and rituximab are typically used for this. Deciding which one to use depends on whether the patient is newly diagnosed or has had relapses before. Other factors include any prior bad reactions to medication or any other medical condition that might increase the risk of a bad reaction to a specific drug. This ongoing treatment usually lasts for 12 to 36 months after the disease is under control. For individuals at high risk of the disease returning, ongoing treatment may continue indefinitely.
Other medications like mycophenolate mofetil, cyclosporine, and intravenous immunoglobulin (IVIG), have also been found effective. A drug combination of trimethoprim-sulfamethoxazole can be used in patients with a limited form of GPA without kidney involvement.
What else can Granulomatosis With Polyangiitis (Wegener granulomatosis) be?
Because of how it affects multiple systems in the body, diagnosing Granulomatosis with Polyangiitis (GPA) can be challenging. There are many conditions that have similar symptoms and must be ruled out before we can determine that it’s actually GPA. These include:
- Other forms of vasculitis related to ANCA antibodies:
- Microscopic polyangiitis
- Churg- Strauss syndrome
- Drug-induced ANCA associated vasculitis
- Renal limited vasculitis
- Mixed cryoglobulinemia
- Polyarteritis nodosa
- Henoch Schonlein purpura
- Goodpasture syndrome
- Other autoimmune disorders:
- Systemic lupus erythematosus
- Sarcoidosis
- Rheumatoid arthritis
- Amyloidosis
- Infections:
- Infective endocarditis
- Sepsis
- Mycobacterial infections
- Disseminated fungal infections
- Disseminated gonococcal infection
- Streptococcal pneumonia with glomerulonephritis
- Types of cancers:
- Lymphomatoid granulomatosis
- Lymphomas
- Castleman’s disease
- Carcinomatosis
- Drug toxicities:
- Intranasal cocaine
- Amphetamines
- Levamisole
- Other various conditions:
- Idiopathic pulmonary alveolar hemorrhage
It’s essential for the doctor to consider these possible conditions and perform the necessary tests to accurately diagnose GPA.
What to expect with Granulomatosis With Polyangiitis (Wegener granulomatosis)
GPA, short for granulomatosis with polyangiitis, a rare disease causing inflammation of blood vessels, can cause significant health problems and increases risk of death. This is due to irreversible damage to organs or side effects from long-term use of medications like glucocorticoids or immunosuppressive agents.
Without any treatment, a patient with GPA has an average life expectancy of 5 months, and less than 30% of patients survive one year. However, with modern treatment options, more than 80% of treated patients live for at least eight to nine years. Thanks to advancements in treatment, patients now have a better long-term survival rate and can live a fairly normal life.
Despite improvements, there are still significant challenges. The disease itself can lead to health problems in 86% of patients, and the side effects of treatment pose problems for 42% of patients. Especially, patients with severe kidney involvement might face a higher risk of death and a less certain prognosis.
Possible Complications When Diagnosed with Granulomatosis With Polyangiitis (Wegener granulomatosis)
The disease itself might lead to several complications:
- Hearing loss
- Permanent loss of eyesight
- Change in nose shape or a hole in the nasal septum
- Sudden severe breathing problems due to widespread bleeding in the lungs
- Long-term kidney disease or advanced kidney disease
- Multiple nerve injuries
Certain complications might also arise due to treatment involving immune system suppression: (Refer to the management of side effects and toxicity)
- Infections
- Cancers like lymphomas and disorders of the bone marrow
- Reactions to medication infusions and death
Preventing Granulomatosis With Polyangiitis (Wegener granulomatosis)
Living with a disease called granulomatosis with polyangiitis can be tough. This condition can cause feelings of tiredness, pain, various health complications, side effects from medications, and emotional stress. These issues can impact daily routine and relationships with people. It can be beneficial to share what you are going through with your doctors, family, and friends. Joining a support group can also provide comfort and understanding. This is a complex disease that affects many different parts of the body, so patients will usually need to see several different health care providers. It’s crucial to stick to the recommended schedule for check-ups. A useful tip can be to maintain a health care journal. This can help you to keep track of the medicines you are taking and when your appointments are scheduled.
