Wegener's granulomatosis
Encyclopedia
Wegener's granulomatosis (WG), more recently granulomatosis with polyangiitis (Wegener's) (GPA), is an incurable form of vasculitis
(inflammation of blood vessels) that affects the nose
, lung
s, kidney
s and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression
. Five-year survival is up to 87%, with some of the mortality due to toxicity of treatment. It is named after Dr. Friedrich Wegener
, who described the disease in 1936. In 2011, three professional bodies proposed a more descriptive name.
Wegener's granulomatosis is part of a larger group of vasculitic syndromes, all of which feature an autoimmune attack by an abnormal type of circulating antibody
termed ANCAs (antineutrophil cytoplasmic antibodies) against small and medium-size blood vessel
s. Apart from Wegener's, this category includes Churg-Strauss syndrome
and microscopic polyangiitis
. Although Wegener's granulomatosis affects small and medium-sized vessels, it is formally classified as one of the small vessel vasculitides in the Chapel Hill system.
s. Rhinitis
is generally the first sign in most patients.
(cANCA) in neutrophils
(a type of white blood cell
) are associated with Wegener's.
If the patient has renal failure
or cutaneous vasculitis, these are the most logical organs to obtain a biopsy
from. Rarely, thoracoscopic
lung biopsy is required. On histopathological
examination, a biopsy will show leukocytoclastic vasculitis with necrotic
changes and granuloma
tous inflammation
(clumps of typically arranged white blood cells) on microscopy. These granulomas are the main reason for the appellation of "Wegener's granulomatosis", although it is not an essential feature. Unfortunately, many biopsies can be nonspecific and 50% provide too little information for the diagnosis of Wegener's.
Differential diagnosis
(alternative possible diagnoses) can be extensive. ANCAs can be positive after the use of certain drugs and other forms of vasculitis
can present with very similar symptoms. The saddle-nose deformity may also be seen in relapsing polychondritis, cocaine
abuse and in congenital syphilis
.
accepted classification criteria for Wegener's. 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 Wegener's.
According to the Chapel Hill Consensus Conference (CHCC) on the nomenclature of systemic vasculitis (1992), establishing the diagnosis of Wegener's granulomatosis demands:
Several investigators have compared the ACR and Chapel Hill criteria.
with granuloma
formation against a nonspecific inflammatory background is the classical tissue abnormality in all organs affected by Wegener's granulomatosis.
It is now widely presumed that the anti-neutrophil cytoplasmic antibodies
(ANCAs) are responsible for the inflammation in Wegener's. The typical ANCAs in Wegener's are those that react with proteinase 3
, an enzyme prevalent in neutrophil granulocyte
s. This type of ANCA is also known as cANCA, with the c indicating cytoplasm
ic (in contrast to pANCA, which is perinuclear).
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, particularly of arteriole
s. However, the presence of ANCA bound to circulating neutrophils has never been found, the activation status of neutrophils from patients with high ANCA titer does not differ from normal individuals and the presence of ANCA is not always associated with development of vasculitis.
The exact cause for the production of ANCAs is unknown, although some drugs
have been implicated in secondary forms of Wegener's. As with many autoimmune disorders, the cause is probably genetic predisposition combined with molecular mimicry
caused by a virus
or bacterium.
(CYC) in the 1970s was a major breakthrough. Five-year survival is now 87%.
Initial treatment is generally with corticosteroids and oral CYC, 1 mg/kg/day and 2 mg/kg/day, respectively. Occasionally CYC is given in monthly intravenous (IV) doses. Monitoring of the white blood count
is essential during CYC therapy. Once remission is attained (normally 3 to 6 months), treatment is frequently changed to azathioprine
or methotrexate
, which are less toxic drugs. Total duration of therapy should be at least one year, or longer in high risk patients. Corticosteroids are tapered to a low maintenance dose, 5–10 mg/day. Plasmapheresis
may be beneficial in severe disease or pulmonary hemorrhage
. Experience with other treatment agents is very limited.
A systematic review
of 84 trials examined the evidence for various treatments in Wegener's granulomatosis. Many trials include data on pooled groups of patients with Wegener's and microscopic polyangiitis. In this review, cases are divided between localized disease, non-organ threatening, generalized organ-threatening disease and severe renal vasculitis and immediately life-threatening disease.
In severe disease not responsive to previously mentioned treatment, the review is positive about mycophenolate mofetil
, 15-deoxyspergualin, anti-thymocyte globulin
, rituximab
and infliximab
; data was less favourable for intravenous immunoglobulin
(IVIG) and etanercept
.
In some patients with severe subglottic stenosis, tracheotomy
is required to maintain an airway.
Follow-up: general well-being and laboratory organ markers are checked on a regular basis to ascertain the patient has remained in remission.
On 19 April 2011, the FDA announced its approval of rituximab
in combination with glucocorticoid
s to treat this condition.
is 10 cases per million per year. 90% of the patients are white. While it mainly occurs in the middle-aged, it has been reported in much younger and older patients.
, tracheal stenosis) may require surgery in a small proportion. Relapses can be long and troublesome.
Long-term complications are very common (86%): mainly chronic renal failure
, hearing loss and deafness.
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". Heinz Karl Ernst Klinger (born 1907) would add information on the anatomical pathology
, but the full picture was presented by Friedrich Wegener
(1907–1990), a German
pathologist, in two reports in 1936 and 1939.
An earlier name for the disease was pathergic granulomatososis. The disease is still sometimes confused with lethal midline granuloma
and lymphomatoid granulomatosis
, both malignant lymphomas.
In 2006, Dr. Alexander Woywodt (Preston
, United Kingdom) and Dr. Eric Matteson (Mayo Clinic
, USA) investigated Dr. 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 Dr. Wegener was wanted by Polish authorities and that his files were forwarded to the United Nations War Crimes Commission. Finally, Dr. Wegener worked in close proximity to the genocide machinery in Lodz. Their data raise serious concerns about Dr. 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
(ACR), the American Society of Nephrology
(ASN) and the European League Against Rheumatism
(EULAR) resolved to change the name to granulomatosis with polyangiitis.
Vasculitis
Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis...
(inflammation of blood vessels) that affects the nose
Nose
Anatomically, a nose is a protuberance in vertebrates that houses the nostrils, or nares, which admit and expel air for respiration in conjunction with the mouth. Behind the nose are the olfactory mucosa and the sinuses. Behind the nasal cavity, air next passes through the pharynx, shared with the...
, lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
. Five-year survival is up to 87%, with some of the mortality due to toxicity of treatment. It is named after Dr. Friedrich Wegener
Friedrich Wegener
Friedrich Wegener was a German pathologist who is notable for his description of a rare disease... Although this disease was known before Wegener's description, since the 1950s it has been called by the name Wegener's granulomatosis.Wegener joined the Nazi Party in 1932...
, who described the disease in 1936. In 2011, three professional bodies proposed a more descriptive name.
Wegener's granulomatosis is part of a larger group of vasculitic syndromes, all of which feature an autoimmune attack by an abnormal type of circulating antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
termed ANCAs (antineutrophil cytoplasmic antibodies) against small and medium-size blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s. Apart from Wegener's, this category includes Churg-Strauss syndrome
Churg-Strauss syndrome
Churg–Strauss syndrome is a medium and small vessel autoimmune vasculitis, leading to necrosis. It involves mainly the blood vessels of the lungs , gastrointestinal system, and peripheral nerves, but also affects the heart, skin and kidneys. It is a rare disease that is non-inheritable and...
and microscopic polyangiitis
Microscopic polyangiitis
Microscopic polyangiitis is an ill-defined autoimmune disease characterized by pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of necrotizing granulomatous inflammation.-Presentation:Because many different organ systems may be involved, a wide range of...
. Although Wegener's granulomatosis affects small and medium-sized 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 symptomSymptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s. Rhinitis
Rhinitis
Rhinitis , commonly known as a stuffy nose, is the medical term describing irritation and inflammation of some internal areas of the nose. The primary symptom of rhinitis is nasal dripping. It is caused by chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria or...
is generally the first sign in most patients.
- KidneyKidneyThe kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
: rapidly progressive glomerulonephritisRapidly progressive glomerulonephritisRapidly progressive glomerulonephritis is a syndrome of the kidney that is characterized by a rapid loss of renal function, with glomerular crescent formation seen in at least 50% or 75% of glomeruli seen on kidney biopsies...
(75%), leading to chronic renal failureChronic renal failureChronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite... - Upper airwayRespiratory tractIn humans the respiratory tract is the part of the anatomy involved with the process of respiration.The respiratory tract is divided into 3 segments:*Upper respiratory tract: nose and nasal passages, paranasal sinuses, and throat or pharynx...
, eyeHuman eyeThe human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
and earEarThe ear is the organ that detects sound. It not only receives sound, but also aids in balance and body position. The ear is part of the auditory system....
disease:- Nose: pain, stuffiness, nosebleedNosebleedEpistaxis or a nosebleed is the relatively common occurrence of hemorrhage from the nose, usually noticed when the blood drains out through the nostrils...
s, rhinitis, crusting, saddle-nose deformity due to a perforated septumPerforated septumA nasal septum perforation is a medical condition in which the nasal septum, the cartilaginous membrane dividing the nostrils, develops a hole or fissure.... - 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 oral mucosa
- Eyes: pseudotumours, scleritisScleritisScleritis is a serious inflammatory disease that affects the white outer coating of the eye, known as the sclera. The disease is often contracted through association with other diseases of the body, such as Wegener's granulomatosis or rheumatoid arthritis; it can also be attained through disorders...
, conjunctivitisConjunctivitisConjunctivitis refers to inflammation of the conjunctiva...
, uveitisUveitisUveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....
, episcleritis
- Nose: pain, stuffiness, nosebleed
- TracheaVertebrate tracheaIn tetrapod anatomy the trachea, or windpipe, is a tube that connects the pharynx or larynx to the lungs, allowing the passage of air. It is lined with pseudostratified ciliated columnar epithelium cells with goblet cells that produce mucus...
: subglottal stenosisStenosisA stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a stricture .... - LungLungThe lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s: pulmonary nodules (referred to as "coin lesions"), infiltrates (often interpreted as pneumoniaPneumoniaPneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
), cavitary lesions, pulmonary hemorrhagePulmonary hemorrhagePulmonary hemorrhage is an acute bleeding from the lung, especially in the upper respiratory tract and the endotracheal tube. When evident clinically, the condition is usually massive, associated with bleeding in other sites as well as more than one third of the lungs...
causing hemoptysisHemoptysisHemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
, and rarely bronchial stenosis. - ArthritisArthritisArthritis is a form of joint disorder that involves inflammation of one or more joints....
: Pain or swelling (60%), often initially diagnosed as rheumatoid arthritisRheumatoid arthritisRheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development... - SkinHuman skinThe human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...
: nodules on the elbow, purpuraPurpuraPurpura is the appearance of red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin...
, various others (see cutaneous vasculitis) - Nervous systemNervous systemThe nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
: occasionally sensory neuropathy (10%) and rarely mononeuritis multiplex - HeartHuman heartThe human heart is a muscular organ that provides a continuous blood circulation through the cardiac cycle and is one of the most vital organs in the human body...
, gastrointestinal tractGastrointestinal tractThe human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, brainHuman brainThe human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
, other organs: rarely affected.
Diagnosis
Wegener's granulomatosis is usually suspected only when a patient has had unexplained symptoms for a long period of time. Determination of ANCAs 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 3Proteinase 3
Proteinase 3 also known as PRTN3 is an enzyme which in humans is encoded by the PRTN3 gene.- Function :PRTN3 is a serine protease enzyme expressed mainly in neutrophil granulocytes. Its exact role in the function of the neutrophil is unknown but in human neutrophils proteinase 3 contributes to the...
(cANCA) in neutrophils
Neutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...
(a type of white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
) are associated with Wegener's.
If the patient has renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
or cutaneous vasculitis, these are the most logical organs to obtain a biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
from. Rarely, thoracoscopic
Thoracoscopy
Thoracoscopy is a medical procedure involving internal examination, biopsy, and/or resection of disease or masses within the pleural cavity and thoracic cavity...
lung biopsy is required. On histopathological
Histopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
examination, a biopsy will show leukocytoclastic vasculitis with necrotic
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
changes and granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...
tous inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
(clumps of typically arranged white blood cells) on microscopy. These granulomas are the main reason for the appellation of "Wegener's granulomatosis", although it is not an essential feature. Unfortunately, many biopsies can be nonspecific and 50% provide too little information for the diagnosis of Wegener's.
Differential diagnosis
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
(alternative possible diagnoses) can be extensive. ANCAs can be positive after the use of certain drugs and other forms of vasculitis
Vasculitis
Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis...
can present with very similar symptoms. The saddle-nose deformity may also be seen in relapsing polychondritis, cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
abuse and in congenital syphilis
Congenital syphilis
Congenital syphilis is syphilis present in utero and at birth, and occurs when a child is born to a mother with secondary syphilis. Untreated syphilis results in a high risk of a bad outcome of pregnancy, including mulberry molars in the fetus. Syphilis can cause miscarriages, premature births,...
.
Criteria
In 1990, the American College of RheumatologyAmerican College of Rheumatology
The American College of Rheumatology is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with arthritis and rheumatic and...
accepted classification criteria for Wegener's. 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%
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of describing Wegener's.
- 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 castsUrinary castsUrinary casts are cylindrical structures produced by the kidney and present in the urine in certain disease states. They form in the distal convoluted tubule and collecting ducts of nephrons, then dislodge and pass into the urine, where they can be detected by microscopy.They form via precipitation...
- Biopsy: granulomatous inflammation
- 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 Wegener's granulomatosis demands:
- a granulomatous inflammation involving the respiratory tract, and
- a vasculitisVasculitisVasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis...
of small to medium-size vessels.
Several investigators have compared the ACR and Chapel Hill criteria.
Pathophysiology
InflammationInflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
with granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...
formation against a nonspecific inflammatory background is the classical tissue abnormality in all organs affected by Wegener's granulomatosis.
It is now widely presumed that the anti-neutrophil cytoplasmic antibodies
Anti-neutrophil cytoplasmic antibody
Anti-neutrophil cytoplasmic antibodies are a group of autoantibodies, mainly of the IgG type, against antigens in the cytoplasm of neutrophil granulocytes and monocytes...
(ANCAs) are responsible for the inflammation in Wegener's. The typical ANCAs in Wegener's are those that react with proteinase 3
Proteinase 3
Proteinase 3 also known as PRTN3 is an enzyme which in humans is encoded by the PRTN3 gene.- Function :PRTN3 is a serine protease enzyme expressed mainly in neutrophil granulocytes. Its exact role in the function of the neutrophil is unknown but in human neutrophils proteinase 3 contributes to the...
, an enzyme prevalent in neutrophil granulocyte
Neutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...
s. This type of ANCA is also known as cANCA, with the c indicating cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic (in contrast to pANCA, which is perinuclear).
In vitro studies have found that ANCAs can activate neutrophils, increase their adherence to endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, and induce their degranulation that can damage endothelial cells. In theory, this phenomenon could cause extensive damage to the vessel wall, particularly of arteriole
Arteriole
An arteriole is a small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.Arterioles have muscular walls and are the primary site of vascular resistance...
s. However, the presence of ANCA bound to circulating neutrophils has never been found, the activation status of neutrophils from patients with high ANCA titer does not differ from normal individuals and the presence of ANCA is not always associated with development of vasculitis.
The exact cause for the production of ANCAs is unknown, although some drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
have been implicated in secondary forms of Wegener's. As with many autoimmune disorders, the cause is probably genetic predisposition combined with molecular mimicry
Molecular mimicry
Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides...
caused by a virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
or bacterium.
Treatment
Before steroid treatment became available, mortality within one year was over 90%, with average survival being 5 months. Steroids prolonged average survival to 8 months. The introduction of cyclophosphamideCyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
(CYC) in the 1970s was a major breakthrough. Five-year survival is now 87%.
Initial treatment is generally with corticosteroids and oral CYC, 1 mg/kg/day and 2 mg/kg/day, respectively. Occasionally CYC is given in monthly intravenous (IV) doses. Monitoring of the white blood count
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
is essential during CYC therapy. Once remission is attained (normally 3 to 6 months), treatment is frequently changed to azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
or methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
, which are less toxic drugs. Total duration of therapy should be at least one year, or longer in high risk patients. Corticosteroids are tapered to a low maintenance dose, 5–10 mg/day. Plasmapheresis
Plasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
may be beneficial in severe disease or pulmonary hemorrhage
Pulmonary hemorrhage
Pulmonary hemorrhage is an acute bleeding from the lung, especially in the upper respiratory tract and the endotracheal tube. When evident clinically, the condition is usually massive, associated with bleeding in other sites as well as more than one third of the lungs...
. Experience with other treatment agents is very limited.
A systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
of 84 trials examined the evidence for various treatments in Wegener's granulomatosis. Many trials include data on pooled groups of patients with Wegener's and microscopic polyangiitis. In this review, cases are divided between localized disease, non-organ threatening, generalized organ-threatening disease and severe renal vasculitis and immediately life-threatening disease.
- In localized disease, treatment with the antibiotic co-trimoxazoleCo-trimoxazoleTrimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
is recommended, with steroids in case of treatment failure. - In generalized non-organ threatening disease, remission can be induced with methotrexateMethotrexateMethotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. 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, azathioprineAzathioprineAzathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
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 hemorrhagePulmonary hemorrhagePulmonary hemorrhage is an acute bleeding from the lung, especially in the upper respiratory tract and the endotracheal tube. When evident clinically, the condition is usually massive, associated with bleeding in other sites as well as more than one third of the lungs...
, high doses of cyclophosphamide with pulsed methylprednisoloneMethylprednisoloneMethylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is marketed in the USA and Canada under the brand names Medrol and Solu-Medrol. It is also available as a generic drug....
may be used, or alternatively CYC, steroids, and plasma exchange.
In severe disease not responsive to previously mentioned treatment, the review is positive about mycophenolate mofetil
Mycophenolate mofetil
Mycophenolate mofetil is an immunosuppressant and prodrug of mycophenolic acid, used extensively in transplant medicine. It is a reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis, which is necessary for the growth of T cells and B cells...
, 15-deoxyspergualin, anti-thymocyte globulin
Anti-thymocyte globulin
Anti-thymocyte globulin is an infusion of horse or rabbit-derived antibodies against human T cells which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia.-Uses:...
, rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
and infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
; data was less favourable for intravenous immunoglobulin
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...
(IVIG) and etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
.
In some patients with severe subglottic stenosis, tracheotomy
Tracheotomy
Among the oldest described surgical procedures, tracheotomy consists of making an incision on the anterior aspect of the neck and opening a direct airway through an incision in the trachea...
is required to maintain an airway.
Follow-up: general well-being and laboratory organ markers are checked on a regular basis to ascertain the patient has remained in remission.
On 19 April 2011, the FDA announced its approval of rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
in combination with glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s to treat this condition.
Epidemiology
The incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
is 10 cases per million per year. 90% of the patients are white. While it mainly occurs in the middle-aged, it has been reported in much younger and older patients.
Prognosis
25 to 40% of patients suffer from flare-ups, but a majority respond well to treatment. Anatomical problems (sinusitisSinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...
, tracheal stenosis) may require surgery in a small proportion. Relapses can be long and troublesome.
Long-term complications are very common (86%): mainly chronic renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
, hearing loss and deafness.
History
ScottishScottish people
The Scottish people , or Scots, are a nation and ethnic group native to Scotland. Historically they emerged from an amalgamation of the Picts and Gaels, incorporating neighbouring Britons to the south as well as invading Germanic peoples such as the Anglo-Saxons and the Norse.In modern use,...
otolaryngologist
Otolaryngology
Otolaryngology or ENT is the branch of medicine and surgery that specializes in the diagnosis and treatment of ear, nose, throat, and head and neck disorders....
Peter McBride (1854–1946) first described the condition in 1897 in a BMJ
British Medical Journal
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
article entitled "Photographs of a case of rapid destruction of the nose and face". Heinz Karl Ernst Klinger (born 1907) would add information on the anatomical pathology
Anatomical pathology
Anatomical pathology or Anatomic pathology is a medical specialty that is concerned with the diagnosis of disease based on the gross, microscopic, chemical, immunologic and molecular examination of organs, tissues, and whole bodies...
, but the full picture was presented by Friedrich Wegener
Friedrich Wegener
Friedrich Wegener was a German pathologist who is notable for his description of a rare disease... Although this disease was known before Wegener's description, since the 1950s it has been called by the name Wegener's granulomatosis.Wegener joined the Nazi Party in 1932...
(1907–1990), a German
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
pathologist, in two reports in 1936 and 1939.
An earlier name for the disease was pathergic granulomatososis. The disease is still sometimes confused with lethal midline granuloma
Lethal midline granuloma
Lethal midline granuloma is a condition affecting the nose and palate. The preferred modern term is ulcerating midline lymphoma, as it is by no means always lethal when treated in time.It has been suggested that the term is confusing and obsolete....
and lymphomatoid granulomatosis
Lymphomatoid granulomatosis
Lymphomatoid granulomatosis is a neoplastic disease.It is a lymphoproliferative disorder . The word granulomatosis denotes one of its microscopic character, polymorphic lymphoid infiltrates and focal necrosis within it....
, both malignant lymphomas.
In 2006, Dr. Alexander Woywodt (Preston
Lancashire Teaching Hospitals NHS Foundation Trust
Lancashire Teaching Hospitals NHS Foundation Trust is one of the United Kingdom's thirty-two NHS Foundation Trusts. It provides healthcare for people in the Preston area and surrounding area in northwest England...
, United Kingdom) and Dr. Eric Matteson (Mayo Clinic
Mayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...
, USA) investigated Dr. 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 Dr. Wegener was wanted by Polish authorities and that his files were forwarded to the United Nations War Crimes Commission. Finally, Dr. Wegener worked in close proximity to the genocide machinery in Lodz. Their data raise serious concerns about Dr. 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
American College of Rheumatology
The American College of Rheumatology is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with arthritis and rheumatic and...
(ACR), the American Society of Nephrology
American Society of Nephrology
Founded in 1966, the American Society of Nephrology is the world’s largest professional society devoted to the study of kidney disease. Composed of 11,000 physicians and scientists, ASN promotes expert patient care, advances medical research, and educates the renal community...
(ASN) and the European League Against Rheumatism
European League Against Rheumatism
The is an international organisation in the field of rheumatology. The society publishes a medical journal, the Annals of the Rheumatic Diseases, and organises an annual scientific meeting, the Annual European Congress of Rheumatology....
(EULAR) resolved to change the name to granulomatosis with polyangiitis.
External links
- Classification criteria by the American College of Rheumatology