Wegener Granulomatosis

Wegener granulomatosis (WG) is an uncommon disease, caused by inflammation of the blood vessels (vasculitis). The inflammation damages important organs of the body by limiting blood flow to those organs and destroying tissue. Although the disease can involve any organ system, Wegener granulomatosis mainly affects the respiratory tract (sinuses, nose, trachea (windpipe), and lungs) and kidneys. This disorder can affect people at any age and strikes men and women equally. It is more common in Caucasians than in African Americans.

Diagram of a cross section of a vein with valves. Blood flow to the organs can be impeded by the inflammation caused by Wegener granulomatosis. Source: Wikimedia Commons.

Other Names

• Wegener arteritis
• Wegener’s disease.
• Morbus Wegener

Signs and Symptoms

Upper Respiratory Tract

The most common signs of Wegener granulomatosis occur in the upper respiratory tract. Symptoms include sinus pain, discolored or bloody fluid from the nose, and, occasionally, nasal ulcers. A common sign of the disease is almost constant rhinorrhea ("runny nose") or other cold symptoms that do not respond to usual treatment or that become increasingly worse. Rhinorrhea can result from nasal inflammation or sinus drainage and can cause pain. A hole may develop in the cartilage of the nose, which may lead to collapse (called saddle-nose deformity). The eustachian tubes, which are important for normal ear function, may become blocked, causing chronic ear problems and hearing loss. Bacterial infection can cause Wegener-related sinusitis (inflammation of the sinuses) with congestion and chronic sinus pain.

Lungs

The lungs are affected in most people with Wegener granulomatosis, although no symptoms may be present. In those that do have symptoms of lung involvement these include cough, coughing up blood (hemoptysis), shortness of breath, and chest discomfort.

Kidneys

Kidney involvement, which occurs in more than 75% of people with this disorder ^[1], can cause no symptoms or could lead to a rapid loss of kidney function. If detected by blood and urine tests, a nephrologist can start proper treatment, preventing long-term damage to the kidneys. The disease associated with this disease in the kidney is called ANCA associated kidney damage.

Musculoskeletal system

Pain in the muscles and joints or, occasionally, joint swelling affects two thirds of people with Wegener granulomatosis. ^[1] Although joint pain can be very uncomfortable, it does not lead to permanent joint damage or deformities.

Eyes

Wegener granulomatosis can affect the eyes in several ways. Eye complications include the following:

• Inflammation of the conjunctiva, the inner lining of the eyelid (conjunctivitis)
• Inflammation of the scleral layer, the white part of the eyeball (scleritis)
• Inflammation of the episcleral layer, the outer surface of the sclera (episcleritis)
• Mass lesion behind the eye globe

Symptoms in the eye include redness, burning, or pain. Serious eye complications include double vision or a decrease in vision.^[2]

Skin lesions

Nearly half of people with Wegener granulomatosis develop skin lesions. These often have the appearance of small red or purple raised areas or blister-like lesions, ulcers, or nodules that may or may not be painful.

Other symptoms

Some people experience narrowing of the trachea that expresses itself as voice change, hoarseness, shortness of breath, or cough.The nervous system and heart are occasionally affected. Fever and night sweats may occur. Fever also may signal an infection, often of the upper respiratory tract. Pancreas involvement has been described, as the first presentation of Wegener granulomatosis, in the form of acute pancreatitis.^[3]

Causes

Wegner granulomatosis is an autoimmune disease; the autoantibodies associated with this disease are the anti-neutrophil cytoplasmic antibodies (ANCAs). These antibodies are directed at the cytoplasm of the body's neutrophils (a type of white blood cell). The immune response caused by the ANCAs damage the walls of the blood vessels and cause granulomas to form. The exact cause of the production of ANCAs in patients with WG is unknown. There may be a genetic cause, an infectious cause or an effect of medications. The cause is likely a combination of these factors.

Diagnosis

There are two separate classification systems with firm diagnostic criteria for Wegener granulomatosis. They are: the 1990 American College of Rheumatology (ACR) classification criteria and the 1992 Chapel Hill Consensus Conference (CHCC) definitions. ^[4] A full description of the diagnostic criteria can be found in the reference. A new classification system, that unifies the previously mentioned classifications, for all ANCA-associated vasculitides has been proposed by Watts and validated by Liu.^[5][6]

Other diagnostic tools may include:

Exams and Tests

Most blood tests can only suggest that a person has inflammation somewhere in the body. Anemia (low red blood cell count), elevated white blood cell count and platelet count are commonly found in people with Wegener granulomatosis. If the kidneys are involved, red blood cells and structures called red blood cell casts appear in the urine when viewed under a microscope, and the blood tests measuring kidney function may show abnormalities.

X-ray results can be very helpful in diagnosing Wegener granulomatosis (WG). People with lung problems have abnormal chest x-rays. CT (computed tomography) scans in people with sinus problems may show thickening of the sinus lining.

Lung biopsy (either open or thoracoscopic) is often the best way of diagnosing Wegener. The ample amount of tissue obtainable through these procedures usually permits confirmation of the disease. Similarly, although the amount of tissue obtained through a kidney biopsy is usually much smaller, the finding of certain pathologic features in the context of a patient’s overall symptoms, signs, and laboratory tests is frequently diagnostic. If there is presence of blood or protein in the urine or if there is renal function loss, a renal biopsy might be the least invasive way to diagnose Wegner.

The blood of many people with active Wegener granulomatosis have antibodies called antineutrophil cytoplasmic antibodies (ANCA) (an antibody is a disease-fighting protein). These antibodies can be detected by blood tests. Although a positive ANCA test is useful to support a suspected diagnosis of Wegener granulomatosis, in most instances health care providers do not use it by itself to diagnose this disorder. The ANCA test may be negative in some people with active Wegener granulomatosis. Currently, the only clear-cut way to diagnose Wegener granulomatosis is by performing a biopsy (removing a tiny piece of tissue) of an involved organ (usually the sinuses, lung, or kidney). This tissue is examined under a microscope to confirm the presence of inflammation and granulomas (a specific type of inflammation), which together are features of Wegener granulomatosis. A biopsy is very important both to confirm the presence of the disease and also to make sure other disorders that may have similar signs and symptoms are not present.^[7]

Treatment

In most cases, treatment consists of a combination of a steroid and a drug such as cyclophosphamide that kills cells. Although these medicines are helpful in treating Wegener granulomatosis, serious side effects can occur. In many instances these can be minimized or prevented by careful monitoring by both the doctor and patient.

Prednisone

Prednisone is the most common glucocorticoid that doctors use to treat the disorder. Prednisone is similar to cortisol which is the natural glucocorticoid hormone produced by the body. It is chemically different from the anabolic steroids that have been used by athletes and is given in doses much higher than the body normally produces. Doctors usually give prednisone as a single morning dose to try to imitate how the body normally secretes cortisol.When the person's illness improves, the prednisone dose is gradually decreased and converted to an every other day dosing schedule, usually over a period of three to four months. With further improvement in the disease, prednisone is gradually decreased and discontinued completely after approximately 6 to 12 months.

When prednisone is taken by mouth, the body stops making its own natural cortisol. As the glucocorticoid dose is gradually reduced, the body will start making cortisol again. For this reason, the dose of prednisone is reduced gradually and the drug is not discontinued abruptly.

Cyclophosphamide

Cyclophosphamide is the most commonly used cytotoxic (cell killing) drug for the treatment of Wegener granulomatosis. People take cyclophosphamide once a day by mouth and must take the drug all at once in the morning followed by drinking a large amount of liquid. Although the first dose of cyclophosphamide is based on weight and kidney function, dose adjustments are made based on blood counts (the numbers of red blood cells, white blood cells, and platelets), which are monitored closely to be sure that the white blood cell count is maintained at a safe level.

Cyclophosphamide is given until remission (the disappearance of signs and symptoms of the disease). Once remission is achieved, cyclophosphamide is replaced with methotrexate (Trexall), azathioprine (Imuran), or some other medicines.

Methotrexate

Methotrexate has been studied at NIH for the treatment of Wegener granulomatosis since 1990. In people with active, but not immediately life-threatening, Wegener granulomatosis, methotrexate has been used in combination with prednisone to bring about remission. It also is used to maintain remission after a person has initially received cyclophosphamide, and is usually given for one to two years, after which time if people stay in remission, it is decreased and stopped. Methotrexate is given once a week, usually by mouth, but occasionally it is given as an injection under the skin or in the muscle. People taking methotrexate need to have regular blood work to monitor their body's response and to watch for side effects.^[8]

Azathioprine

Azathioprine is used primarily to maintain remission in people who have initially been treated with cyclophosphamide. It is taken once a day by mouth. Similar to methotrexate, it is usually given for one to two years after which time the dosage is lowered until it is stopped.

Rituximab

The use of rituximab has been proven effective in the treatment of limited Wegener granulomatosis and in patients in remission of the disease. ^[9]

Other medicines

During the course of treating Wegener granulomatosis, doctors often give their patients other medicines to prevent medicine-related side effects. These include the following:

• Trimethoprim/sulfamethoxazole (also called bactrim or septra) is given three times a week to prevent Pneumocystis carinii infection.
• A medicine regimen is often given to prevent prednisone-related bone loss (osteoporosis).
• Folic acid or folinic acid (also called leucovorin) are often given to people taking methotrexate.

Clinical Trials

A list of ongoing U.S. government-sponsored clinical trials is available here: Wegener granlomatosis trials.

Research

Recent discoveries

• The presentation and treatment of a case of WG involving primarily the skin is discussed. The study authors recommend consideration of a diagnosis of WG when a patient presents with necrotizing vasculitis of the skin (ususally raised, red or purple nodules on the extremities). ^[10]
• The risk of early death in patients with WG was evaluated using the disease extent index (DEI) and Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) questionnaires. Predictors of early death are: disease duration, hemoglobin concentration, necessity of dialysis and occurrence of cough. Simultaneous renal and respiratory tract involvement is associated with the highest early death risk. ^[11]
• When WG occurs along with another disease called Anti GBM disease, the prognosis is worse.

Current Research

• Rituximab, a drug used to treat certain types of cancer, is being studied as to its effectiveness as a treatment for Wegener granulomatosis in adults. ^[12]
• A study is ongoing to determine whether autologous peripheral blood stem cell transplantation is effective for use in the treatment of patients with life threatening autoimmune diseases, including Wegener granulomatosis. ^[13]
• A comparison between methotrexate and azathioprine for maintenance treatment (after initial treatment with corticosteroids and intravenous cyclophosphamide) of Wegener granulomatosis. ^[14]
• The treatment of Wegener granulomatosis in elderly patients is researched. Older patients tend to have a poorer prognosis when diagnosed over age 65. In this trial, patients will be randomly assigned to receive either low doses of corticosteroids systematically in combination with immunosuppressants (CYC then azathioprine) or usual regimen with corticosteroids combined with immunosuppressants only if factor(s) of poor prognosis is present (this latter regimen relying on previously published therapeutic guidelines). ^[15]

History

Wegener granulomatosis was first described in 1931 by Heinz Klinger, a German medical student. The condition was named for German pathologist Dr. Friedrich Wegener, who described additional cases of WG several years later and recognized the disorder as a form of vasculitis. ^[16]

Expected Outcome

Wegener granulomatosis recurs in approximately half of patients who respond to treatment. ^[17] This occurs most frequently within two years of stopping medicine but can occur at any point either during treatment or after stopping treatment.

Notable Experts

The National Institutes of Health (NIH) has recently awarded a $6.25 million, 5-year grant to establish the Vasculitis Clinical Research Consortium (VCRC). The multicenter VCRC will foster and facilitate clinical investigation in the inflammatory vasculitides, including Wegener granulomatosis.

The VCRC will consist of four major U.S. vasculitis centers:

• Boston University School of Medicine, Massachusetts
• The Cleveland Clinic, Ohio
• The Johns Hopkins Vasculitis Center, Baltimore, Maryland
• The Mayo Clinic College of Medicine, Rochester, Minnesota

References

1. ↑ ^{1.0 1.1} National Institute of Allergy and Infectious Disease web site. Wegener's Granulomatosis
2. ↑ Biswas J, Babu K, Gopal L. Ocular manifestations of Wegener's granulomatosis. Analysis of nine cases. Indian J Ophthalmol. 2003 Sep;51(3):217-23. Abstract Full Text
3. ↑ Abu-Hilal M, Abu-Hilal M, McPhail MJ, Acute pancreatitis as the first presentation of Wegener's granulomatosis. JOP. 2008 May 8;9(3):300-4. Abstract Full Text PDF
4. ↑ Bruce IN, Bell AL. A comparison of two nomenclature systems for primary systemic vasculitis. Br J Rheumatol. 1997 Apr;36(4):453-8. Abstract | Full Text
5. ↑ Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007 Feb;66(2):222-7. Abstract Full text PDF
6. ↑ Liu LJ, Chen M, Yu F, Zhao MH, Wang HY. Evaluation of a new algorithm in classification of systemic vasculitis. Rheumatology (Oxford). 2008 May;47(5):708-12. Abstract
7. ↑ Frankel SK, Cosgrove GP, Fischer A, Meehan RT, Brown KK. Update in the diagnosis and management of pulmonary vasculitis. Chest. 2006 Feb;129(2):452-65. Abstract Full Text PDF
8. ↑ Specks U. Methotrexate for Wegener's granulomatosis: what is the evidence? Arthritis Rheum. 2005 Aug;52(8):2237-42. Full Text PDF
9. ↑ Seo P, Specks U, Keogh KA. Efficacy of Rituximab in Limited Wegener's Granulomatosis with Refractory Granulomatous Manifestations. J Rheumatol. 2008 Aug 1. Abstract
10. ↑ Bramsiepe I, Danz B, Heine R, Taube KM, Holzhausen HJ, Marsch WC, Fiedler E. Primary cutaneous manifestation of Wegener's granulomatosis. Dtsch Med Wochenschr. 2008 Jul;133(27):1429-32. Abstract
11. ↑ Zycinska K, Wardyn KA, Tyszko P, Otto M. Analysis of early death based on the prediction model in Wegener's granulomatosis with pulmonary and renal involvement. J Physiol Pharmacol. 2007 Nov;58 Suppl 5(Pt 2):829-37. Abstract
12. ↑ ClinicalTrials.gov. Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis (RAVE)
13. ↑ ClinicalTrials.gov. Autologous Peripheral Blood Stem Cell Transplantation in Patients With Life Threatening Autoimmune Diseases
14. ↑ ClinicalTrials.gov. WEGENT - Comparison of Methotrexate or Azathioprine as Maintenance Therapy for ANCA-Associated Vasculitides
15. ↑ ClinicalTrials.gov. Treatment of Necrotizing Vasculitides for Patients Older Than 65 Years (CORTAGE)
16. ↑ Socias R, James DG, Pozniak A. Wegener and Wegener's granulomatosis. Thorax. 1987 Dec;42(12):920-1. PDF
17. ↑ Ursea R, Nussenblatt R, Buggage R. American Uveitis Society. Wegener's Granulomatosis: A Patient Education Monograph

External Links

• American Autoimmune Diseases Related Association

• Vasculitis Foundation

• Vasculitis Clinical Research Consortium