Granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis, is a systemic
disorder that involves both granulomatosis and polyangiitis.
It is a form of vasculitis that affects small- and medium-size vessels in many organs.
Damage to the lungs and kidneys can be fatal.
It requires long-term immunosuppression.
When referred to as Wegener's granulomatosis, it is named after Friedrich Wegener, who described
the disease in 1936.
Because of Wegener's association with the German Nazi party, professional bodies and
journals have replaced his name with a descriptive name.Granulomatosis with polyangiitis is part
of a larger group of vasculitic syndromes called systemic vasculitides or necrotizing
vasculopathies, all of which feature an autoimmune attack by an abnormal type of circulating
antibody termed ANCAs against small and medium-size blood vessels.
Apart from GPA, this category includes Churg–Strauss syndrome and microscopic polyangiitis.
Although GPA affects small- and medium-size vessels, it is formally classified as one
of the small vessel vasculitides in the Chapel Hill system.
Signs and symptoms Initial signs are extremely variable, and
diagnosis can be severely delayed due to the nonspecific nature of the symptoms.
In general, rhinitis is the first sign in most people.
Kidney: rapidly progressive glomerulonephritis, leading to chronic kidney failure
Upper airway, eye and ear disease: Nose: pain, stuffiness, nosebleeds, rhinitis,
crusting, saddle-nose deformity due to a perforated septum
Ears: conductive hearing loss due to auditory tube dysfunction, sensorineural hearing loss
Oral cavity: strawberry gingivitis, underlying bone destruction with loosening of teeth,
non-specific ulcerations throughout oral mucosa Eyes: pseudotumours, scleritis, conjunctivitis,
uveitis, episcleritis Trachea: subglottal stenosis
Lungs: pulmonary nodules, infiltrates, cavitary lesions, pulmonary haemorrhage causing haemoptysis,
and rarely bronchial stenosis.
Arthritis: Pain or swelling, often initially diagnosed as rheumatoid arthritis
Skin: nodules on the elbow, purpura, various others
Nervous system: occasionally sensory neuropathy and rarely mononeuritis multiplex
Heart, gastrointestinal tract, brain, other organs: rarely affected.Causes
Its causes are unknown, although microbes, such as bacteria and viruses, as well as genetics
have been implicated in its pathogenesis.
Pathophysiology Inflammation with granuloma formation against
a nonspecific inflammatory background is the classical tissue abnormality in all organs
affected by GPA.It is now widely presumed that the anti-neutrophil cytoplasmic antibodies
are responsible for the inflammation in GPA.
The typical ANCAs in GPA are those that react with proteinase 3, an enzyme prevalent in
neutrophil granulocytes.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.
Diagnosis
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 can aid in the diagnosis, but positivity
is not conclusive and negative ANCAs are not sufficient to reject the diagnosis.
Cytoplasmic-staining ANCAs that react with the enzyme proteinase 3 in neutrophils are
associated with GPA.If the person has renal failure 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 on microscopy.
These granulomas are the main reason for the appellation of "Wegener's granulomatosis",
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.
Criteria In 1990, the American College of Rheumatology
accepted classification criteria for GPA.
These criteria were not intended for diagnosis, but for inclusion in randomised controlled
trials.
Two or more positive criteria have a sensitivity of 88.2% and a specificity of 92.0% of describing
GPA.
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:
microhematuria or red cell casts
Biopsy: granulomatous inflammation within the arterial wall or
in the perivascular areaAccording to the Chapel Hill Consensus Conference on the nomenclature
of systemic vasculitis, establishing the diagnosis of GPA demands:
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.
Treatment The standard treatment for GPA is cyclophosphamide
and high dose corticosteroids for remission induction and less toxic immunosuppressants
like azathioprine, leflunomide, methotrexate or mycophenolate mofetil.
Trimethoprim/sulfamethoxazole may also help prevent relapse.
Rituximab may be substituted for cyclophosphamide in inducing remission.
A systematic review of 84 trials examined the evidence for various treatments in GPA.
Many trials include data on pooled groups of people with GPA and microscopic polyangiitis.
In this review, cases are divided between localised disease, non-organ threatening,
generalized organ-threatening disease and severe renal vasculitis and immediately life-threatening
disease.
In generalised non-organ-threatening disease, remission can be induced with methotrexate
and steroids, where the steroid dose is reduced after a remission has been achieved and methotrexate
used as maintenance.
In case of organ-threatening disease, pulsed intravenous cyclophosphamide with steroids
is recommended.
Once remission has been achieved, azathioprine and steroids can be used to maintain remission.
In severe renal vasculitis, the same regimen is used but with the addition of plasma exchange.
In pulmonary haemorrhage, high doses of cyclophosphamide with pulsed methylprednisolone may be used,
or alternatively CYC, steroids, and plasma exchange.Prognosis
Today, with corticosteroids and cyclophosphamide, 5-year survival is over 80%.
Long-term complications are common, mainly chronic renal failure, hearing loss and deafness.Before
modern treatments, the 2-year mortality was over 90% and average survival five months.
Death usually resulted from uraemia or respiratory failure.
Epidemiology The incidence is 10-20 cases per million per
year.
It is exceedingly rare in Japan and African Americans.
History Scottish otolaryngologist Peter McBride first
described the condition in 1897 in a BMJ article entitled "Photographs of a case of rapid destruction
of the nose and face".
Heinz Karl Ernst Klinger would add information on the anatomical pathology, but the full
picture was presented by Friedrich Wegener, a German pathologist, in two reports in 1936
and 1939.An earlier name for the disease was pathergic granulomatosis.
The disease is still sometimes confused with lethal midline granuloma and lymphomatoid
granulomatosis, both malignant lymphomas.In 2006, Alexander Woywodt and Eric Matteson
investigated Wegener's past, and discovered that he was, at least at some point of his
career, a follower of the Nazi regime.
In addition, their data indicate that Wegener was wanted by Polish authorities and that
his files were forwarded to the United Nations War Crimes Commission.
Furthermore, Wegener worked in close proximity to the genocide machinery in Łódź.
Their data raise serious concerns about Wegener's professional conduct.
They suggest that the eponym be abandoned and propose "ANCA-associated granulomatous
vasculitis."
The authors have since campaigned for other medical eponyms to be abandoned, too.
In 2011, the American College of Rheumatology, the American Society of Nephrology and the
European League Against Rheumatism resolved to change the name to granulomatosis with
polyangiitis.
References
External links Classification criteria by the American College
of Rheumatology Largest Wegener's Granulomatosis/GPA patient
support group