Wegener's Granulomatosis Support Group Of Australia Inc.

 

What's W.G.

 

Wegener’s Granulomatosis (WG) is a rare form of Vasculitis; that is a disease characterized by inflammation of the walls of the blood vessels.  This inflammation results in a reduction of oxygen in the blood and damages vital organs of the body by restricting blood flow to those organs and destroying normal tissue.  WG primarily affects the respiratory tract (sinuses, nose, trachea [windpipe] and lungs) and the kidneys.  WG that does not affect the kidneys is referred to as Limited Wegener’s Granulomatosis.  This disorder can occur at any age, usually during middle age, strikes men and women equally, and is extremely rare in people of Negroid origin.  The cause of Wegener’s Granulomatosis is unknown but much research is being done.  As of this time no single genetic marker, environmental agent, micro-organism, or other factor can be identified as initiating this syndrome.  WG is not contagious and there is no evidence that it is hereditary.
Before the 1960’s, Wegener’s Granulomatosis was almost uniformly fatal (generally between 6 and 12 months), and renal failure was the main course of death.  Corticosteroids (Prednisolone) therapy resulted in improvement in some cases, but the overall mortality was not altered appreciably.  With the use of cytoxic drugs for the treatment of WG, the course of the disease has been altered favorably.  Cyclophosphamide, Azathioprine (Imuran), Methotrexate and Cyclosporin have all been used with Cyclophosphamide being the most effective form of cytoxic treatment.  Azathioprine may be used in maintenance therapy in those patients who have had an adverse reaction to Cyclophosphamide.  Some patients with limited Wegener’s Granulomatosis and milder exacerbation of disease have been reported to be controlled with the antibiotic Trimethoprim-Sulfamethxazole (Bactrim, Septrim).


 
History of Wegener’s Granulomatosis

In 1931, Heinz Klinger at the University of Berlin first reported two patients who died having prolonged sepsis with inflammation of the blood vessels scattered throughout the body.  Five years later, Friederic Wegener in Bresllau described a distinct syndrome in three patients.  These patients were found to have necrotizing (gradually degenerating) granulomas involving the upper and lower respiratory tract.  In 1954 seven more patients were described.  This resulted in the establishment of a definite criteria for the diagnosis of the disease by Wegener.  Dr Friederic Wegener died in July of 1990 at the age of 83.

Symptoms

The initial symptoms of Wegener’s Granulomatosis are often vague or nonspecific and frequently include upper respiratory tract symptoms, joint pains, weakness and fatigue.

Upper respiratory tract. The most common sign of Wegener’s Granulomatosis is involvement of the upper respiratory tract, which occurs in nearly all patients.  Symptoms include sinus pain, discolored or bloody nasal drainage and, occasionally, nasal ulceration. A common manifestation of the disease is persistent rhinorrhea (runny nose) or other cold symptoms that do not respond to standard treatment or that become progressively worse.  Rhinorrhea can result from nasal inflammation or sinus drainage and can cause pain.  A hole or perforation of the nasal septum may develop, and collapse of the nasal bridge (called saddle nose deformity) may occur in some individuals.  Blockage of the eustachian tubes, which are important for normal ear function, may cause chronic ear problems and hearing loss  A secondary bacterial infection can cause Wegener’s related sinusitis (inflammation of the sinus) with congestion and chronic sinus pain.

Lungs.  The lungs are affected in most patients with Wegener’s Granulomatosis, although no symptoms may be present.  If symptoms are present, they include cough, hemoptysis (coughing up of blood), shortness of breath, and chest discomfort.

Kidneys.    Kidney involvement, which occurs in more than three fourths of patients, usually does not cause symptoms.  If detected by blood tests, proper treatment can be started, preventing long term damage to the kidneys.
Musculoskeletol system.  Pain in the muscles and joints such as the knees, or, occasionally, joint swelling affect two thirds of patients with Wegener’s Granulomatosis. Although joint pain can be very uncomfortable, it does not lead to permanent joint damage or deformities.

Eyes.  Wegener’s Granulomatosis can affect the eyes in several ways.  Patients may develop conjunctivitis (inflammation of the conjunctiva, the inner lining of the eyelid), scleritis (inflammation of the scleral layer, the white part of the eyeball), episcleritis (inflammation of the episcleral layer, the outer surface of the sclera), or as an orbital mass lesion (sore behind the eye globe).  The symptoms of eye involvement include redness, burning or pain in the eye or one becoming more prominent than the other.  Double vision or a decrease in vision are serious symptoms requiring immediate medical attention.

Skin lesions.  Nearly half of people with Wegener’s Granulomatosis develop skin lesions.  These small red or purple raised areas or blister-like lesions, ulcers, or nodules may or may not be painful.

Other symptoms.  Some patients experience narrowing of the trachea (subglottic stenosis).  The symptoms can include voice change, hoarseness, shortness of breath, or cough.

The nervous system and heart occasionally may be affected.  Fever and night sweats also may occur.  However, fever also may signal an underlying infection, often of the upper respiratory tract.

Diagnosis

To treat people with Wegener’s Granulomatosis most effectively, doctors must diagnose the disease early in its course.  There are no blood tests that a doctor can use to diagnose Wegener’s Granulomatosis, but blood tests are important to rule out other causes of illness and to determine which organ sites may be affected.  Most blood tests are nonspecific and can only suggest that a person has an inflammatory process.  Anemia (low red blood cell count),. elevated white blood cell count and platelet count are commonly found in people with Wegener’s Granulomatosis. Measuring the erythrocyte sedimentation rate (ESR) and C reactive protein (C RP) can indicate how active the disease is. If the kidneys are involved, red blood cells and structures called red blood cell casts are visible in the urine when viewed under a microscope, and the blood tests measuring kidney function (creatinine and urea) may show abnormalities.

X-ray results can be very helpful in diagnosing Wegener’s Granulomatosis.  People with lung involvement will have abnormal chest x-rays, which may show one or many fluffy infiltrates, solid nodules, or cavities.  Sinus x-rays or computed tomography (CT) scans in people with sinus involvement may show thickening of the sinus lining.

Many patients with active Wegener’s Granulomatosis have a blood test that reveals the presence of a specific type of antibody called antineutrophil cytoplasmic antibodies (ANCA) (an antibody is a disease-fighting protein).  Although a positive ANCA test (C-ANCA is characteristic, measuring Proteinase-3 antibodies) is useful in supporting a suspected diagnosis of Wegener’s Granulomatosis, in most instances it is not used by itself to make a diagnosis of this disorder. If the patients Wegener’s disease is active an ANCA test should be taken approximately every six weeks whilst if the patient is in remission every six months.  The ANCA test may be negative in some patients with active Wegener’s Granulomatosis. Antibodies act not only as disease fighting proteins (as with bacterial infections) but there is increasing evidence that they may also cause  autoimmune diseases such as WG.

It takes 5-15 months on average to make a diagnosis of WG. Forty per cent of all diagnosis are made within less than three months, ten per cent within 5-15 years. The demonstration of ANCA has proved enormously helpful in the diagnosis of small Vasculitis disease.  While it is still not clear that ANCA actually contributes to the origin and development of the disease, there is increasing evidence that this is so.

Currently, the only definite way to diagnose Wegener’s Granulomatosis is by performing a biopsy of an involved organ site (usually the sinuses, lung or kidney).  The tissue is examined under the microscope to confirm the presence of Vasculitis and granulomas (a specific type of inflammation), which together are diagnostic feature of the disease.  A biopsy is very important both to confirm the presence of Wegener’s Granulomatosis and also to assure the absence of other disorders that may have similar signs and symptoms.

Treatment

With the appropriate treatment, the outlook is good for patients with Wegener’s Granulomatosis. 

In most cases, standard therapy consists of a combination of Corticosteroids (such as Prednisone) that reduces inflammation and a cytotoxic drug (Cyclophosphamide) that interferes with the abnormal growth of cells.

Prednisone is the most common corticosteriod that is used. 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.  Prednisone is usually administered as a single morning dose in an attempt to imitate how the body normally secretes hydrocortisone. 
When the person’s illness improves, the prednisone dose is gradually decreased, usually over a period of 3 to 4 months.  With further improvement in the disease, the prednisone is very gradually decreased and discontinued completely after approximately 6 to 12 months.  When prednisone is taken by mouth, the body stops making its own natural hydrocortisone.  As the prednisone dose is gradually reduced the body will resume making hydrocortisone again.  It is extremely important that prednisone never be stopped suddenly because the body requires prednisone (or hydrocortisone) for its function and may not be able to immediately make what it needs.

Cyclophosphamide (Cytoxan O) is the most commonly used cytotoxic drug. Cyclophosphamide acts principally by destroying the cells that produce antibodies. That is one reason why doctors think ANCA antibodies might contribute to the development of WG.  Cyclophosphamide is taken once a day by mouth.  It is important for a patient to take the drug all at once in the morning followed by drinking a large amount of fluid.  Although the initial dose of Cyclophosphamide is based on the patient’s weight and kidney function, the doctor may adjust the dosage based on the blood counts, which are monitored closely to be sure that the white blood cell count is maintained at a safe level.  Cyclophosphamide may be, but is not always, continued for a full year beyond that point at which the disease has become quiet (is in remission). Current therapy, if possible, is to use Cyclophosphamide for shorter and shorter periods so that it is still effective but will not have the side effects that it is capable of. The dose of Cyclophosphamide is then decreased gradually and eventually discontinued.

Cyclophosphamide and prednisone are both powerful drugs that suppress the immune system.  Although these medications are beneficial in treating Wegener’s Granulomatosis, patients and their doctors should be aware that the drugs potentially have serious side effects.  Careful monitoring by the doctor is very important.  Because these drugs suppress the immune system, they can affect the body’s ability to fight off infection.  Patients should report immediately any symptoms of infection and, specifically, any fever to their doctors.  Prednisone can cause weight gain, cataracts, brittle bones, diabetes, and alterations in mood and personality.  Cyclophosphamide can cause bone marrow suppression (lowering of blood counts), sterility, hemorrhagic cystitis (bleeding from the bladder) as well as other serious side effects.

Despite its life saving effects in patients with Wegener’s Granulomatosis, Cyclophosphamide cannot be tolerated by certain patients, such as those that develop severe neutropenia (abnormally low number of white blood cells) at low doses of the drug or those who develop severe cystitis or bladder cancer.  In those patients alternative treatment regimens should be initiated.

 Azathioprine has proven effective in some patients particularly in maintaining remission in those in whom remission was induced by Cyclophosphamide.  The drug should be administered together with a corticosteriod regimen.  There have been reports of therapeutic success with less frequent and severe toxic side effects using intermittent doses of intravenous Cyclophosphamide in place of the daily oral doses.

Although certain reports have indicated that trimethothoprim-sulfamethooxazole (Bactrim) may be of benefit in the treatment of Wegener’s Granulomatosis there are no firm data to substantiate this, particularly in patients with serious renal and pulmonary disease.

Data support the use of weekly Methotrexate in the induction phase and to maintain remission in patients with limited Wegener’s Granulomatosis. However there appears to be a high level of relapse when the dosage was dropped. Furthermore some patients who were treated with methotrexate developed renal disease.

Other treatments that have recently been  tried are cyclosporin (an immunosupressant) which together with Prednisolone can induce remission even in patients with renal disease and may also prevent relapses.  Mycophenolate mofetil causes ANCA levels to fall and may maintain remission. Patients a with life threatening disease may respond to immune ablation and peripheral blood stem rescue.  However, in general, controlled prospective studies are lacking, and clinical efficacy has been unproved.

Approximately half of people with Wegener’s Granulomatosis may experience a return (relapse) of their disease.  This occurs most frequently within two years of stopping medication, but potentially can occur at any point both during treatment or after stopping treatment.  Thus, it is extremely important that patients continue to see their physicians regularly, both while they are on these medications, as well as after the medications have been stopped.  Even while on medication, many patients are able to lead relatively normal lives and will remain in remission after therapy has been stopped completely.


Side Effects of Medications

Azathioprine (Imuran)-Can cause skin cancers in people who go out in the sun and cancer of the cervix. Hypersensitivity reactions such as general malaise, headache, dizziness, vomiting, fever, rigors, muscular pains and disturbed liver function. Depression of bone marrow function, increase in red cell haemoglobin content, reduction in white blood cells, and susceptibility to infection. Nausea, vomiting and gastrointestinal discomfort may occur during the first few months.

Co-Trimoxazole (Bactrim)-Nausea, with or without vomiting and skin rashes. Haematological (blood) changes have been reported, the majority being mild and reversible when treatment was stopped. May also cause low white blood cell counts. There can also be gastro-intestinal effects, respiratory, metabolic and Musculoskeletal effects.

Cyclophosphamide-Falling white blood count, haematuria (blood in the urine), bladder cancer in the long term, acute leukemia, anorexia, nausea, vomiting, mucosal ulceration, hair loss, and fluid retention. Other side effects include pigmentation of the fingernails and skin, inflammation of the lung and interstitial (between) pulmonary fibrosis.

Methotrexate-The most common adverse reactions include ulcerative stomatitis (inflammation of the mouth), leucopoenia (abnormal decrease of white blood corpuscles), nausea and abdominal distress.
Adverse reactions are generally classified into three groups, acute, sub acute and chronic.

1)    Acute-Chemical arachnoiditis (inflammation of the thin, delicate membranes of the meninges) manifested by headache, back or shoulder pain, rigidity in the nape of the neck, and fever.
2)    Sub acute-May include paresis (muscle weakness)-usually transient, paraplegia, nerve palsies, and cerebella dysfunction.
3)    Chronic-This is a leukoencephalopathy (widespread destruction of normal healthy myelin sheaths of the brain and brain stem) manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma and rarely death.


Prednisolone

a)    Gastro-intestinal-Dyspepsia, peptic ulceration with perforation and haemorrhage, abdominal distension, esophageal ulceration, esophageal candidiasis, acute pancreatitis.
b)    Musculo-skeletal-proximal myopathy (striated muscle), osteoporosis, vertebral and long bone fractures, avascular osteonecrosis death of a segment of bone), tendon rupture.
c)    Fluid and electrolyte disturbance-Sodium and water retention, hypertension, hypokalaemic alkalosis (potassium depletion with increase in alkalinity of the blood).
d)    Dermatological-Impaired healing, skin atrophy bruising, striae (a band of skin differing in colour), telengiectasia (skin lesions), acne.
e)    Endocrine/metabolic-Suppression of the hypothalamo-pituitary adrenal axis, growth suppression in childhood and adolescence, menstrual irregularity and amenorrhoea. Moon face, hirsutism (hairiness), weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, negative nitrogen and calcium balance, and increased appetite.
f)    Neuropsychiatric-Euphoria, psychological dependence, depression, insomnia, pressure on the nerve to the eye, aggravation epilepsy and schizophrenia.
g)    Ophthalmic-Increased intra-ocular pressure, glaucoma, pressure on the nerve to the eye, posterior subcapsular cataracts, corneal or scleral thinning, worsening of viral or fungal infections of the eye.
h)    Anti-inflammatory and immunosuppressive effects-Increased susceptibility to and severity of, infections with suppression of clinical symptoms and signs, opportunistic infections, recurrence of dormant TB.
i)    General-Increased number of white blood cells (leucocytosis), hypersensitivity including allergies, thrombosis, nausea, malaise. Can cause difficulties in sleeping.

As corticosteriod therapy becomes prolonged and as the dose is increased, the incidence of disabling side effects increases.

Too rapid a reduction of corticosteriod dosage following ptolonged treatment can lead to acute adrenal insufficiency, hypotension but rarely/never causes death. A ‘withdrawal syndrome’ may also occur including fever, myalgia pain in the muscles), arthralgia (pain in a joint), rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight, feelings of tiredness, washed out and feeling dizzy when standing up.



Anti-Neutrohilic Cytoplasmic Antibodies (ANCA) in Wegener’s Granulomatosis

Author:  Nabih I. Abdou, M.D., Ph.D., F.A.C.P

The ANCA blood test has been shown to be very valuable in the diagnosis and follow-up of patients with Wegener’s Granulomatosis.  It is a very helpful test in early cases in which the diagnosis is not very clear, and in patients who already have been diagnosed with Wegener’s and have a flare, to know if the flare is due to concurrent infection or due to a flare of the disease itself.  It is a very helpful guide to determine the treatment and whether the disease is improving and is in remission or not.  Every Wegener’s patient should have the test done to confirm the diagnosis and follow the disease process.

The ANCA test is done by obtaining serum from the Wegener’s patient and adding that to a glass slide with a preparation of white blood cells.  If the Wegener’s patient has antibodies against the cytoplasm, that is, the non-nuclear part of the white cell, it will attach itself to the cytoplasm and then this could be detected by a technique called immunofluorescence that is read by the fluorescent microscope and will show bright colors.  Another test for ANCA is by a technique called ELSIA in which the component of the cytoplasm of the white cell is attached to plastic plates and then the patient’s serum is added.  The binding of the patient’s serum to the plates is detected by certain enzyme markers and read automatically by certain machines to detect the binding of the antibody of the serum to the plates.

There are two kinds of ANCA – one called cytoplasmic and abbreviated as C-ANCA; and the other called perinuclear, abbreviated P-ANCA.  This has been very helpful to differentiate between Wegener’s Granulomatosis in which the type of the test is C-ANCA and another related disease called microscopic polyarteritis in which there is inflammation of the blood vessels (small ones, particularly in the kidneys) in which the test is P-ANCA.

In rare situations the ANCA test could by positive in other diseases, and this is currently under investigation.

The positive ANCA test in Wegener’s has been studied carefully by many investigators to find out what is in the white blood cell that makes the serum of the Wegener’s patient bind to it.  It was found that there are certain enzymes in the white cell, which are the targets for the antibody that is present in the serum of the Wegener’s patient.  One of these antibodies is called proteinase which is contained in granules inside the cytoplasm of normal white cells called neutrophils.  The granules inside the white cells are called primary or azurophilic granules or alpha granules.  The P-ANCA is due to antibodies in the serum of the patient with arteritis and is directed to another enzyme in the white blood cell called myeloperoxidase, abbreviated MPO.

The big question now in the research of causes of Wegener’s is why patients have antibodies in their serum that are directed against the enzymes of the white blood cells.  Do these antibodies have any role in the disease process of Wegener’s, or are they just secondary to the disease process itself?  Understanding all basic pieces of information will open the doors for finding out the causes and what is happening in the body or immune system of the Wegener’s patient.  There are no definite answers to these questions at the present time and all these issues are under investigation by several research labs all over the world.

The sensitivity of the ANCA test in Wegener’s Granulomatosis is 95% or higher in patients who have active disease that is disseminated, that means affecting many parts of the body, including the kidneys.  In patients who have limited Wegener’s, that means the disease is not affecting the kidneys, the sensitivity of the test is 60-70%.  Sensitivity means the percentage of positive tests in all Wegener’s patients who have a certain part of the disease.  Seventy percent means if we take 100 Wegener'’ patients with limited disease we find 70 of the 100 patients have a positive test.  The levels of the positive tests are also important; this fluctuates with disease activity and may decrease or disappear after treatment.  The test is very valuable in patients who are doing well and all of a sudden have more symptoms, to assist the physician in distinguishing if the relapse is due to the disease process itself or due to a concurrent infection.  There is new data to indicate that the ANCA test will go up and increase immediately before the disease flares.  Moreover, there is data to indicate that the ANCA test will go down and disappear if the disease is responding well to the appropriate treatment.  Moreover, there are several data to indicate that very high levels of ANCA are bad prognostic signs and indicate the disease is spreading and probably affecting the kidneys with multiple organ involvement.  A cutoff point that indicated very active disease is an ANCA titer at a level greater than 1/80.

They physician not only looks at the ANCA blood test to make decisions but also examines the patient to dine out if the patient has, on; physical examination, evidence of disease activity.

In summary, the ANCA test is very valuable for the diagnosis, follow-up, and prognosis of Wegener’s patients.  The test, if done accurately in a reputable lab, should be of great value in the management of the patient.


Living With a Chronic Illness

A chronic illness often begins gradually and may have several causes. Rarely is a chronic illness cured. Usually it persists for an indefinite time.
Many factors can affect the course of a chronic illness. As a result it is difficult to predict how you may feel from day to day.
Living well with a chronic illness begins with understanding your illness. What you know about your condition can make a difference in how you approach each day.
Living with a chronic illness often involves in making adjustments. One of the first things to consider is how you pace yourself. Adapting a moderate pace, keeping a regular schedule and getting adequate rest and exercise can help you better manage your illness. Be wary of over-extending yourself. Learn how to say “no”. It is especially important to pace yourself on days when you feel energetic and may be tempted to overdo things.
Take medications regularly. Carefully follow your doctor’s instructions on how and when to take your medication. Be aware of how your symptoms are affected by your medications and what side effects you may experience.
Eat properly. Depending on your illness and the medications you take, you may need to avoid some types of food and incorporate others into your diet. In addition talk with your doctor about determining a healthful weight and ways to reach that goal.
Exercise is a vital tool in managing chronic illness. Regular exercise can improve strength and energy levels, as well as self-confidence. It also plays a role in lessening anxiety and depression, which can be associated with chronic conditions.
Living with a chronic illness can be a roller coaster of emotions. There are several ways you can help even out the ups and downs-maintaining normal daily activities as best as you can, stay connected with family and friends, continue to pursue hobbies you enjoy and are able to do, social networks-the company you keep can keep you healthy.
Keep in mind that your physical health can directly impact on your mental health. Denial, anger and frustration are not uncommon when you learn life has dealt you something painful and unexpected.
Sometimes a support group is the best answer. Does sharing common problems help you manage your illness better.
In addition many chronic illnesses are associated with an increased risk of depression. This isn’t a “failure to cope” but may indicate a disruption in the body’s neuro-chemistry that can be helped with appropriate medical treatment.

Living With Someone who is Chronically Ill.

With longer life expectancy and smaller families, chances are greater than ever that you or an immediate family member will help care for someone who is chronically ill.
The role has its ups and downs, but there are many things that you can do as a caregiver to help make your role more manageable.
Accept that the chronic illness may not go away.
Focus on aspects of well being such as activities and the person’s feelings rather than just physical health.
Be available and listen, focusing on positive changes.
Get involved together in productive, fun activities to distract from the illness.
Encourage independence while maintaining as normal a family life as possible.
Take care of yourself, and seek help when needed. If necessary look for organisations that offer support for caregivers

Finally

The uncommon nature of this disease leaves patients feeling isolated, freakish, in a strange kind of way separated from those around them.
Sadly the average GP and, perhaps, even the local hospital will never have heard of the illness. The patient gets shut in and only has the specialist at the clinic to talk to. It is essential for the WG patient to have support from family and friends, as his/her body goes through physical and emotional turmoil. Support groups can also play an important part at this most difficult time. Hence the need for publicity.
If there is anything you can do to spread the word concerning this most dreadful disease it will improve the possibility of earlier diagnosis and treatment for those who will inevitably contract Wegener’s Granulomatosis, and therefore fewer will die as a consequence.

References.

1)    Antineutrophil cytoplasmic antibodies and associated diseases:A review of the clinical and laboratory features: (July 1999)
Judy   Savige, David Davies, Ronald J Falk, J Charles Jennette and  Allan Wilk                                            .

2)    Anti Neutrophilic Cytoplasmic Antibodies (ANCA) in Wegener’s Granulomatosis. (July 1992) – Nabih Abdou. M.D., Ph.D., F.A.C.P.

3)    The Merck Medical Manual.(2001)

4)    Oxford Textbook of Medicine: Third Edition, Volume 2.

5)    Taber’s Cyclopedic Medical Dictionary: 18th Edtion

6)  UK WG Support Group web site: www.btinternet.com/~wegeners.uk

7)  USA WG Support Group web site: www.wgsg.org

8) American National Institute of Allergy and Infectious Diseases Fact
Sheet. (August 1999


Edited by Prof. Judy Savige.