Granulomatosis with polyangiitis

Typical saddle nose damage due to granulomatosis with polyangiitis.

Initial signs are highly variable, and diagnosis can be severely delayed due to the nonspecific nature of the symptoms. In general, irritation and inflammation of the nose is the first sign in most people.[11][12] Involvement of the upper respiratory tract, such as the nose and sinuses, is seen in nearly all people with GPA.[13] Typical signs and symptoms of nose or sinus involvement include crusting around the nose, stuffiness, nosebleeds, runny nose, and saddle-nose deformity due to a hole in the septum of the nose.[7][13] Inflammation of the outer layers of the eye (scleritis and episcleritis[14]) and conjunctivitis are the most common signs of GPA in the eye; involvement of the eyes is common and occurs in slightly more than half of people with the disease.[6]

• Kidney: rapidly progressive glomerulonephritis (75%), leading to chronic kidney disease
• Upper airway, eye and ear disease:
  • Ears: conductive hearing loss due to auditory tube dysfunction, sensorineural hearing loss (unclear mechanism)
  • Oral cavity: strawberry gingivitis, underlying bone destruction with loosening of teeth, non-specific ulcerations throughout the lining of the mouth[15]
• Trachea: subglottal stenosis
• Lungs: pulmonary nodules (referred to as "coin lesions"), infiltrates (often interpreted as pneumonia), cavitary lesions, bleeding in the lungs causing a person to cough up blood, and rarely bronchial stenosis.
• Arthritis: Pain or swelling (60%), often initially diagnosed as rheumatoid arthritis
• Skin: subcutaneous nodules (granulomas) on the elbow, purpura, various others (see cutaneous vasculitis)
• Nervous system: occasionally sensory neuropathy (10%) and rarely mononeuritis multiplex
• Heart, gastrointestinal tract, brain, other organs: rarely affected.

The cause of GPA is unknown, although microbes, such as bacteria and viruses, as well as genetics have been implicated in its pathogenesis.[12][16]

Classic microscopic features of GPA include inflammation of blood vessels associated with poorly formed granulomas, necrosis, and many giant cells.[17] Bacterial colonization with Staphylococcus aureus has been hypothesized as an initiating factor of the autoimmunity seen in people with GPA.[8] Several genes involved in the immune system including PTPN22, CTLA4, and human leukocyte antigen genes may influence the risk of developing GPA.[7]

It is now widely presumed that the anti-neutrophil cytoplasmic antibodies (ANCAs) are responsible for the inflammation in GPA.[11] The typical ANCAs in GPA are those that react with proteinase 3, an enzyme prevalent in neutrophil granulocytes.[7] In vitro studies have found that ANCAs can activate neutrophils, increase their adherence to endothelium, and induce their degranulation that can damage endothelial cells. In theory, this phenomenon could cause extensive damage to the vessel wall, in particular of arterioles.[11]

Immunofluorescence pattern produced by binding of ANCA to ethanol-fixed neutrophils, from a person with GPA

Granulomatosis with polyangiitis is usually suspected only when a person has had unexplained symptoms for a long period of time. Determination of anti-neutrophil cytoplasmic antibodies (ANCAs) can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis. More than 90% of people who have GPA test positive for ANCA.[17] Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 (cANCA) in neutrophils (a type of white blood cell) are associated with GPA.[11] Involvement of the ears, nose, and throat is more common in granulomatosis with polyangiitis than in the similar condition microscopic polyangiitis.[7]

If the person has signs of kidney involvement or cutaneous vasculitis, a biopsy is obtained from the kidneys. On rare occasions, thoracoscopic lung biopsy is required. On histopathological examination, a biopsy will show leukocytoclastic vasculitis with necrotic changes and granulomatous inflammation (clumps of typically arranged white blood cells) on microscopy. These granulomas are the main reason for the name granulomatosis with polyangiitis, although it is not an essential feature. Nevertheless, necrotizing granulomas are a hallmark of this disease. However, many biopsies can be nonspecific and 50% provide too little information for the diagnosis of GPA.[11]

Criteria

In 1990, the American College of Rheumatology accepted classification criteria for GPA. These criteria were not intended for diagnosis, but for inclusion in randomized controlled trials. Two or more positive criteria have a sensitivity of 88.2% and a specificity of 92.0% of describing GPA.[13][19]

The left apical region is opacified in a case of granulomatosis with polyangiitis.

• Nasal or oral inflammation:
  • painful or painless oral ulcers or
  • purulent or bloody nasal discharge
• Lungs: abnormal chest X-ray with:
  • nodules,
  • infiltrates or
  • cavities
• Kidneys: urinary sediment with:
  • microscopic hematuria or
  • red cell casts
• Biopsy: granulomatous inflammation
  • 

    Photo showing the sclerokeratitis associated with GPA
    within the arterial wall or
  • in the perivascular area

According to the Chapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of GPA demands:[20]

• a granulomatous inflammation involving the respiratory tract, and
• a vasculitis of small to medium-size vessels.

Several investigators have compared the ACR and Chapel Hill criteria.[21]

GPA treatment depends on its severity and whether it has caused organ damage.[8]

Before modern treatments, the 2-year survival was under 10% and average survival five months.[12][25] Death usually resulted from uremia or respiratory failure.[12] The revised Five-factor score is associated with 5-year mortality from GPA and is based on the following criteria: age greater than 65 years, cardiac symptoms, gastrointestinal involvement, chronic kidney disease, and the absence of ears, nose, and throat symptoms.[7]

With corticosteroids and cyclophosphamide, 5-year survival is over 80%.[12] Long-term complications are common (86%), mainly chronic kidney failure, hearing loss, and deafness.[11] The risk of relapse is increased in people with GPA who test positive for anti-PR3 ANCA antibodies and is higher than the relapse risk for microscopic polyangiitis.[7]

Today, medication toxicity is managed more carefully and long-term remissions are possible. Some affected individuals are able to lead relatively normal lives and remain in remission for 20+ years after treatment.[26]

The incidence is 10–20 cases per million per year.[27][28] It is exceedingly rare in Japan and in African Americans.[28]

Scottish otolaryngologist Peter McBride (1854–1946) first described the condition in 1897 in a BMJ article entitled "Photographs of a case of rapid destruction of the nose and face".[29] Heinz Karl Ernst Klinger (born 1907) added information on the anatomical pathology. An early name for the disease was pathergic granulomatosis.[30] The disease is still sometimes confused with lethal midline granuloma and lymphomatoid granulomatosis, both malignant lymphomas.[31]

The full clinical picture was first presented by Friedrich Wegener (1907–1990), a German pathologist, in two reports in 1936 and 1939, leading to the eponymous name Wegener's granulomatosis or Wegener granulomatosis (English: /ˈvɛɡənər/).[10] In 2011, the American College of Rheumatology (ACR), the American Society of Nephrology (ASN) and the European League Against Rheumatism (EULAR) resolved to change the name to granulomatosis with polyangiitis, given Wegener's association with the Nazi Party.[32]

• List of medical eponyms with Nazi associations