Predominately Small Vessel

Granulomatosis with polyangiitis (GPA)

  • Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis (WG), is a form of vasculitis that mainly affects small blood vessels in the upper (nose and sinuses) and lower (lungs) respiratory system of the body. It is a part of a group of pediatric conditions known as ANCA-associated vasculitides (AAV). This group of conditions involves patients who are found to display the presence of ANCA (anti-neutrophil cytoplasmic antibodies). Additionally, though primarily affecting the respiratory system at first, over a longer period of time, patients frequently show renal (kidney) involvement. Other organ systems have also been known to be affected, but far less frequently than the respiratory system and kidneys. Furthermore, GPA is often depicted as necrotizing, which describes the death of tissues. GPA without kidney (renal) involvement is known as the Non-severe ANCA-associated vasculitis. and is present in one fourth of all cases. However, it is important to note that 80% these less severe cases can still develop the severe form of GPA or another severe condition.
  • In the term GPA, “granulomatosis” describes the formation of granulomas and “polyangiitis” describes inflammation (swelling) of multiple vessels. A granuloma is an organized collection of immune cells (histiocytes) that form after the body’s immune system attempts to attack substances that it believes are foreign. This immune system attack, along with the role of ANCAs, leads to the formation of granulomas and to the inflammation of the blood vessel walls in the lungs. As in other forms of vasculitis, this narrowing then limits the amount of blood supply to other parts of the body.
  • Though the causes of GPA are unknown, previous infections, specifically streptococcal infections (involving bacteria causing strep throat and pneumonia), have been implicated in GPA. Also, the presence of ANCAs play a role in causing blood vessel inflammation by activating immune cells, but the origin of ANCAs is still unknown.
  • GPA is a rare disease, presenting 1 new patient for every 1 million children each year. Some studies have found that pediatric patients with GPA are more commonly females, and 90% of patients are Caucasians. The median age of being diagnosed with GPA is around 14 years.
  • According to the EULAR/PRINTO/PRES framework, a patient must present 3 out of the 6 features to be classified as having GPA.
    • Click here for more detailed information on classifying and diagnosing GPA.
  • Often times, induction therapy comprised of a combination of corticosteroids and cyclophosphamide (common chemotherapy drug) is used in treating patients with GPA. After the disease settles, a combination of different drugs is used as a form of maintenance therapy.
    • Click here for more detailed information on suggested treatment protocols.
  • According to the 2010 EULAR, PRINTO and PRES criteria for classification of GPA, a patient must present with at least 3 of the following 6 features:
    1. Renal involvement (hematuria, proteinuria, or red blood cell casts, or necrotizing pauci-immune glomerulonephritis)
    2. Upper airway involvement(chronic/recurrent purulent or bloody nasal discharge or crusting, or recurrent epistaxis)
    3. Laryngotracheobronchial stenosis
    4. Pulmonary involvement (chest radiograph, CT showing nodules, cavities, or fixed infiltrates)
    5. ANCA positivity (PR3 ANCA or cANCA staining)
  • In order to reach a diagnosis, it is important to consider a combination of clinical features, laboratory tests, along with a biopsy. For more details view the diagnostic algorithm for GPA.
  • Below is a table of symptoms of GPA patients in various studies. The most common symptoms displayed by GPA patients include constitutional, ear/nose/throat, pulmonary/respiratory and renal symptoms.
    • It is important to note that not all of the symptoms mentioned below are displayed by every patient.

Patients with GPA can experience some or all of the following:

Type of Symptom Symptoms
Constitutional/General Malaise
fatigue
Fever
Weight loss
Cutaneous Palpable purpura/petechiae
Eye Nonspecific red eye
Conjunctivitis
Scleritis
Keratitis
blepharitis
Renal Abnormal urianalysis results
Biopsy-proven GN
Elevated serum creatinine
Ears, Nose, Throat Nasal involvement
Sinusitis
Otitis/mastoiditis
Subglottic involvement
Hearing loss
Oral ulcers
Saddle nose
Nasal septal perforation
Pulmonary/Respiratory Shortness of breath
Chronic cough
Hemoptysis/alveolar hemorrhage
Nodules
Abnormal pulmonary function test results
Fixed pulmonary infiltrates
Oxygen dependency
Pleurisy
Gastrointestinal Nonspecific abdominal pain
Chronic nausea
Musculoskeletal Muscle pain/tenderness
Arthritis
Arthralgia/myalgia
Nervous System Severe headache
Dizziness
Cardiovascular Venous thrombosis
Venous thombotic event Deep vein thrombosis
Pulmonary embolus
  • Inflammatory markers
    • Erythrocyte sedimentation rate (ESR) has been found to be elevated in 95.8% of pediatric patients with GPA in a previous study.
  • Complete blood count
    • Hemoglobin levels have commonly been found to be low at the presentation of GPA in pediatric patients. For example, in a study of pediatric patients with GPA, 88% were found to be anemic.
  • Autoantibodies
    • In many studies focusing on GPA, a large proportion of pediatric patients are found to be positive for ANCA (antineutrophil cytoplasmic antibodies). A majority of these ANCA-positive patients are found to have PR3-ANCA, which reflects specificity for proteinase 3 (PR3).
  • A renal (kidney) biopsy is an important technique in diagnosing GPA. In a majority of pediatric patients with GPA, renal biopsy results report This is one of the defining characteristics of GPA in children and is often very helpful in making a more accurate diagnosis.

Figure 1: Axial CT image of a patient with GPA Retrieved from:  http://pubs.rsna.org/doi/full/10.1148/rg.2015140076

Figure 2: Axial abdominal CT scan of a patient with GPA.  This image shows the swollen kidneys of a 17-year-old boy with GPA.  Retrieved from:  http://pubs.rsna.org/doi/full/10.1148/rg.2015140076

 

In this image, you can see the diagnostic algorithm for GPA by following the diagram from the “INDICATIONS FOR TESTING” box (at the top) to the bottom-right box for “Granulomatosis with polyangiitis…”

Retrieved from: https://arupconsult.com/content/takayasu-arteritis/?tab=tab_item-1This is the website for ARUP Consult, whose disclaimer and policies outline that the “content at this website may be freely downloaded and used for non-commercial purposes.” 

Steroids

  • Corticosteroids
    • Glucocorticoids (ex. prednisone) are usually used in the treatment of GPA in order to suppress the systemic symptoms and arrest the progression of GPA. More specifically, these medications suppress the immune system and help reduce the amount of inflammation of the blood vessels.

Immunosuppressants

  • Cyclophosphamide (CYC)
  • Methotrexate (MTX)
  • Azathioprine (AZA)
  • Mycophenolate mofetil (MMF)

Immunosupressants are often used in combination with steroids. It is important to note that different combinations of medications are used at different phases in the treatment of GPA. For example, initially, corticosteroids and cyclophosphamide are used together to begin treatment (induction therapy). Later on, maintenance therapy is composed of drugs such as mycophenolate mofetil or azathioprine. Also note that in milder cases of GPA, methotrexate is used in conjunction with corticosteroids instead of cyclophosphamide.

Surgery

Biological Therapy

  • Infliximab
  • Rituximab

Refractory diseases, which do not respond to medications such as steroids and immunosupressants, can be treated using biological therapies.

Figure 3: Flowchart outlining the treatment protocol of Granulomatosis with polyangiitis

 

(Please note that the treatment protocol for GPA, provided by Dr. Benseler, will be added to this page)

 


Akikusa, J. D., Schneider, R., Harvey, E. A., Hebert, D., Thorner, P. S., Laxer, R. M. and Silverman, E. D. (2007), Clinical features and outcome of pediatric Wegener’s granulomatosis. Arthritis & Rheumatism, 57: 837–844. doi: 10.1002/art.22774
Bohm et al.: Clinical features of childhood granulomatosis with polyangiitis (wegener’s granulomatosis). Pediatric Rheumatology 2014 12:18.

Cabral, D. A., Uribe, A. G., Benseler, S., O’Neil, K. M., Hashkes, P. J., Higgins, G., Zeft, A. S., Lovell, D. J., Kingsbury, D. J., Stevens, A., McCurdy, D., Chira, P., Abramson, L., Arkachaisri, T., Campillo, S., Eberhard, A., Hersh, A. O., Huber, A. M.,

Kim, S., Klein-Gitelman, M., Levy, D. M., Li, S. C., Mason, T., DeWitt, E. M., Muscal, E., Nassi, L., Reiff, A., Schikler, K., Singer, N. G., Wahezi, D. and Woodward, A. (2009), Classification, presentation, and initial treatment of Wegener’s granulomatosis in childhood. Arthritis & Rheumatism, 60: 3413–3424. doi: 10.1002/art.24876
Khanna, G., Sargar, K., Baszis, K. W., (2015), Pediatric vasculitis: recognizing multisystemic manifestations at body imaging. RadioGraphics, 35(3), 849-865. doi: 10.1148/rg.2015140076
Stone, J. H. (2003), Limited versus severe Wegener’s granulomatosis: Baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis & Rheumatism, 48: 2299–2309. doi: 10.1002/art.11075

Twilt M, Benseler S, Cabral D. Granulomatosis with polyangiitis in childhood. Curr Rheumatol Rep 2012; 14: 107-15.

Weiss, P. F. (2012). Pediatric Vasculitis. Pediatric Clinics of North America,59(2), 407–423.

 

Notes:

  • Granulomatous
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
  • Granulomatosis with polyangiitis (Wegener’s)
  • Nongranulomatous
  • Microscopic polyangiitis
  • Henoch-Schönlein purpura (IgA vasculitis)
  • Isolated cutaneous leukocytoclastic vasculitis
  • Hypocomplementemic urticarial vasculitis