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• First Description
• Who gets EGPA (the “typical” patients)?
• Classic symptoms of EGPA
• What causes EGPA?
• How is EGPA diagnosed?
• Treatment and Course of EGPA

First Description

Eosinophilic granulomatosis with polyangiitis (EGP), formerly known as the Churg-Strauss Syndrome , is a systemic vasculitis. This disease was first described in 1951 by Dr. Jacob Churg and Dr. Lotte Strauss as a syndrome consisting of “asthma, eosinophilia [an excessive number of eosinophils in the blood], fever, and accompanying vasculitis of various organ systems”. EGPA shares many of the clinical and pathological features of polyarteritis nodosa (“PAN”, another type of vasculitis) and granulomatosis with polyangiitis (GPA). However, Drs. Churg and Strauss discovered that the presence of granulomas as well as the abundance of eosinophils distinguished this disease from PAN and GPA.

Who gets EGPA (the “typical” patient)?

The typical patient with EGPA is a middle aged individual with a history of new-onset or newly-worsened asthma. The distribution of the disease among males and females is approximately equal.

Classic symptoms and signs of EGPA

Asthma is one of the cardinal features of EGPA. Asthma symptoms may begin long before the onset of vasculitis – e.g., many years before any other symptoms of EGPA arise, and long before the diagnosis of EGPA is made. Other early symptoms/signs include nasal polyps and allergic rhinitis.

The next phase of the disease is often marked by eosinophilia, the finding of an excessive number of eosinophils in the blood or in tissues. An eosinophil is one subtypes of white blood cell. Normally, eosinophils comprise 5% or less of the total white blood cell count. In EGPA, the percentage of eosinophils may reach as high as 60%. In the picture below, the eosinophils are shown by the dark pink stain.

The third phase of the illness is a vasculitis, which involves the skin, lungs, nerves, kidneys, and other organs. Particular mention should be made of the frequent devastating involvement of the nerves (called mononeuritis multiplex), which produces severe tingling, numbess, shooting pains, and severe muscle wasting/power loss in the hands or feet. The list below contains the organs commonly involved by EGPA and the specific disease manifestation(s) in each organ.

• Nose
• Lung
• Skin
• Kidney
• Gastrointestinal
• Heart
• Nerve

Nose

• Sinusitis, including allergic rhinitis
• Nasal polyps

Lung

• Pulmonary infiltrates (only one-third of all patients)
• Bleeding into the lungs (occasionally)
• Diffuse interstitial lung disease (rarely)

Skin

• Rashes
• Palpable purpura
• Nodules (above or below the skin), often at sites of pressure, such as the elbows

Kidney

• Glomerulonephritis (inflammation in the small units of the kidney that filter blood)
• Hypertension

Gastrointestinal

• Lesions (vasculitic) are occasionally found in the GI tract
• Granuloma sometimes found in spleen

Heart

• Vasculitis lesions in heart, can lead to congestive heart failure or a heart attack

Nerve

• Peripheral nerve involvement including pain, numbness, or tingling in extremities (neuropathy/mononeuritis multiplex)

What causes EGPA?

The cause of EGPA is unknown but is probably multi-factorial. Genetics may play a small role in the disease, but EGPA is almost never seen in two members of the same family. Environmental factors such as exposure to industrial solvents may play a role in susceptibility to this disease, but this is largely speculative. Infections may be the inciting event(s), but to date there is no definitive evidence of this.

How is EGPA Diagnosed?

Among all of the vasculitides, asthma is a distinctive feature of EGPA alone. However, not all patients with asthma have vasculitis – only a tiny minority do, in fact. It is the specific combination of symptoms and signs, the pattern of organ involvement, and the presence of certain abnormal blood tests (eosinophilia, in particular) that help the doctor make the diagnosis. In addition to a detailed history and physical examination, blood tests, chest X-rays and other types of imaging studies, nerve conduction tests, and tissue biopsies (e.g., of lung, skin, or nerve) may be performed to help diagnose EGPA.

The following features are consistent with a diagnosis of GPA:

1. asthma
2. eosinophilia [>10% on differential WBC count]
3. mononeuropathy
4. transient pulmonary infiltrates on chest X-rays
5. paranasal sinus abnormalities
6. biopsy containing a blood vessel with extravascular eosinophils.

Treatment and Course of EGPA

EGPA usually responds to prednisone. Initially, high doses of oral prednisone are used in an attempt to get the disease into remission as quickly as possibly (e.g., using oral prednisone 40-60 mg/day). After the first month or so, this high dose of prednisone is gradually tapered down over the ensuing months. Other immunosuppressive drugs, such as azathioprine, cellcept, methotrexate, cyclophosphamide, or rituximab may be used in addition to prednisone. High doses of intravenous steroids (usually methylprednisolone) maybe useful for those patients with severe disease or for those who are unresponsive to the combination of oral prednisone used with other immunosuppressive medications.

Prior to the advent of prednisone, EGPA was often a fatal disease. The majority of patients died from rampant, uncontrolled disease. With present therapy, constitutional symptoms begin to resolve quite quickly, with gradual improvement in cardiac and renal function, as well as improvement in the pain that results from peripheral nerve involvement. The course of therapy can last for 1 to 2 years, although the length and type of treatment depend on the severity of disease and the organs involved. The patient’s response to treatment and the continuation of disease control during lowering of the prednisone dose are the primary determinants of how long therapy is continued. Laboratory monitoring of blood tests is very helpful in gauging the activity of disease. Some of the most useful laboratory tests are the erythrocyte sedimentation rate (ESR) and the eosinophil count.

• First Description
• Who gets Behcet’s Disease (the “typical” patients)?
• Classic symptoms of Behcet’s Disease
• What causes Behcet’s Disease?
• How is Behcet’s Disease diagnosed?
• Treatment and Course of Behcet’s Disease
• What’s new in Behcet’s Disease?

First Description

In the 1930’s, a Turkish dermatologist, Hulusi Behcet, noted the triad of aphthous oral ulcers, genital lesions, and recurrent eye inflammation, and became the first physician to describe the disease in modern times. Another name for Behcet’s Disease is Behcet’s syndrome.

Who gets Behcet’s Disease (the “typical” patient)?

Behcet’s disease is most common along the “Old Silk Route,” which spans the region from Japan and China in the Far East to the Mediterranean Sea, including countries such as Turkey and Iran. Although the disease is rare in the United States, sporadic cases do occur in patients who would not appear to be at risk because of their ethnic backgrounds (e.g., in Caucasians or African–Americans). The disease is not rare in regions along the Old Silk Route, but the disease’s epidemiology is not well understood. In Japan, Behcet’s disease ranks as a leading cause of blindness. Below is a magnetic resonance image (MRI) study of a Behcet’s patient demonstrating central nervous system involvement (white matter changes in the pons).

Classic symptoms and signs of Behcet’s Disease

Behcet’s disease is virtually unparalleled among the vasculitides in its ability to involve blood vessels of nearly all sizes and types, ranging from small arteries to large ones, and involving veins too. Because of the diversity of blood vessels it affects, manifestations of Behcet’s may occur at many sites throughout the body. However, the disease has a predilection for certain organs and tissues; these are described below.

• Eye
• Mouth
• Skin
• Lungs
• Joints
• Brain
• Genitals
• Gastrointestinal Tract

Eye

• Behcet’s may cause either anterior uveitis (inflammation in the front of the eye) or posterior uveitis (inflammation in the back of the eye), and sometimes causes both at the same time.
• Anterior uveitis results in pain, blurry vision, light sensitivity, tearing, or redness of the eye.
• Posterior uveitis may be more dangerous and vision–threatening because it often causes fewer symptoms while damaging a crucial part of the eye — the retina.

(top of section)

Mouth

• Painful sores in the mouth called “aphthous ulcers”(pictured below). These are very similar in appearance to ulcers that frequently occur in the general population, usually as a result of minor trauma. In Behcet’s, however, the lesions are more numerous, more frequent, and often larger and more painful. Aphthous ulcers can be found on the lips, tongue, and inside of the cheek. Aphthous ulcers may occur singly or in clusters, but occur in virtually all patients with Behcet’s.

Skin

• Pustular skin lesions that resemble acne, but can occur nearly anywhere on the body. This rash is sometimes called “folliculitis”.
• Skin lesions called erythema nodosum: red, tender nodules that usually occur on the legs and ankles but also appear sometimes on the face, neck, or arms. Unlike erythema nodosum associated with other diseases (which heal without scars), the lesions of Behcet’s disease frequently ulcerate.

Lungs

• Aneurysms (outpouchings of blood vessel walls, caused by inflammation) of arteries in the lung, rupture of which may lead to massive lung hemorrhage.

Joints

• Arthritis or “arthralgias” (pain in the joints not accompanied by joint swelling).

Brain

• Central nervous system involvement is one of the most dangerous manifestations of Behcet’s. The disease tends to involve the “white matter” portion of the brain and brainstem, and may lead to headaches, confusion, strokes, personality changes, and (rarely) dementia. Behcet’s may also involve the protective layers around the brain (the meninges), leading to meningitis. Because the meningitis of Behcet’s disease is not associated with any known infection, it is often referred to as “aseptic” meningitis.

Genitals

• Male — painful genital lesions that form on the scrotum, similar to oral lesions, but deeper.
• Female — painful genital ulcers that develop on the vulva.

Gastrointestinal

• Ulcerations may occur anywhere in the gastrointestinal tract from the mouth to the anus. The terminal ileum and cecum are common sites. Involvement of the GI tract by Behcet’s may be difficult to distinguish from inflammatory bowel disease (such as Crohn’s disease).

Blood Vessels

• Clots can occur in veins in any site, most often including veins in the lower extremity (superficial or deep venous thrombosis).
• Inflammation in arteries can occur as well, such as the pulmonary or abdominal arteries, sometimes causing obstruction of the vessel (thrombosis).

What causes Behcet’s Disease?

Behcet’s is one of the few forms of vasculitis in which there is a known genetic predisposition. The presence of the gene HLA–B51 is a risk factor for this disease. However, it must be emphasized that presence of the gene in and of itself is not enough to cause Behcet’s: many people possess the gene, but relatively few develop Behcet’s. Despite the predisposition to Behcet’s conferred by HLA–B51, familial cases are not the rule, constituting only about 5% of cases. Thus, it is believed that other factors (perhaps more than one) play a role. Possibilities include infections and other environmental exposures.

How is Behcet’s Disease Diagnosed?

There is not one specific test to diagnose Behcet’s. Rather the diagnosis is based on the occurrence of symptoms and signs that are compatible with the disease. The presence of certain features that are particularly characteristic (e.g., oral or genital ulcerations), elimination of other possible causes of the patient’s symptoms, and if possible, proof of vasculitis by biopsy of an involved organ would together support a diagnosis of Behcet’s.

A positive pathergy test can be supportive of the diagnosis of Behcet’s but is not diagnostic by itself of the condition. A pathergy test is a simple test in which the forearm is pricked with a small, sterile needle. Occurrence of a small red bump or pustule at the site of needle insertion constitutes a positive test. Please note, that although a positive pathergy test is helpful in the diagnosis of Behcet’s, only a minority of Behcet’s patients demonstrate the pathergy phenomenon (i.e., have positive tests). Patients from the Mediterranean region are more likely to demonstrate pathergy. In addition, other conditions can occasionally result in positive pathergy tests, so the test is not 100% specific.

Pictured below is an example of the pathergy test; 1) taken at the time when the patient was “stuck” with the sterile needle; 2) shows the area immediately after the stick; 3) & 4) show the area one day and two days after the needle stick, respectively.

Treatment and Course of Behcet’s Disease

For disease that is confined to mucocutaneous regions (mouth, genitals, and skin), topical steroids and non–immunosuppressive medications such as colchicine or dapsone may be effective. Apremilast (Otezla) is now FDA-approved for treatment of oral ulcers in Behcet’s. Moderate doses of systemic corticosteroids are also frequently required for disease exacerbations. Some patients require chronic, low doses of prednisone or conventional immunosuppressives such as (azathioprine) to keep the disease under control.

In the event of serious end–organ involvement such as eye or central nervous system disease, both high doses of prednisone and some other form of immunosuppressive treatment are usually necessary. Immunosuppressive agents used in the treatment of Behcet’s include azathioprine, cyclosporine, cyclophosphamide, and TNF-alpha inhibitors (infliximab, adalimumuab). Cyclophosphamide is generally used in life-threatening disease, such as central nervous system involvement. Blood clots can be another manifestation of Behcet’s, and in some scenarios blood thinners may be used in treatment.

 

Prednisone is a corticosteroid with potent anti-inflammatory effects. Corticosteroids are a cornerstone of treating most types of vasculitis, and are often used in combination with other immunosuppressive medications. Prednisone works very quickly, and is therefore used (often at high doses) at the time of initial diagnosis to bring vasculitis under control. Then, prednisone is gradually reduced (“tapered”) while another immunosuppressive drug is started for long term treatment. Over time, the “steroid-sparing” immunosuppressive drug is used to control vasculitis, and prednisone is eventually stopped.

Side Effects

Corticosteroids cause a long list of side effects, making it dangerous to use these drugs at significant doses for long term treatment. The side effects of prednisone are related to: 1) the amount of steroid a patient takes in his/her daily dose, and 2) the length of time the patient remains on the medication. We emphasize that not all side effects occur in all patients.

Despite the numerous potential side effects of corticosteroids listed below, their introduction into patient care more than 50 years ago revolutionized the treatment of many diseases, including vasculitis. When used properly, these drugs save lives and avert threats to the function of important organs.

Common Side Effects of Steroids:

• Increased Susceptibility to Infections
• Weight Gain
• Glucose Intolerance
• Hypertension
• Bone Thinning
• Avascular Necrosis of bone
• Easy Bruising
• Abdominal Striae
• Hirsutism
• Acne
• Mood Swings/Insomnia
• Cataracts

Increased Susceptibility to Infections

Patients are at increased risk for many types of infections, from minor fungal infections in the mouth (“thrush”, caused by Candida) to life–threatening infections such as Pneumocystis carinii pneumonia. The higher the steroid dose and the longer the duration of therapy, the greater the risk of infection. The risk is also increased when patients receive combinations of immunosuppressive medications, such as cyclophosphamide (cytoxan) and prednisone. The risk of some infections can be greatly reduced by taking specific types of antibiotics prophylactically (such as Bactrim).

Pictured below is woman under treatment with prednisone and methotrexate for vasculitis and a concurrent neurologic condition (myasthenia gravis) developed painful vesicles in her mouth. The vesicles were confirmed by culture to be caused by reactivation of a Herpes simplex infection, and responded to treatment with acyclovir.

Weight Gain

Weight gain is usually the most dreaded side–effects of steroids, incurred to some degree by nearly all patients who take them. The amount of weight gain varies from individual to individual. In addition to causing weight gain, prednisone leads to a redistribution of body fat to places that are undesirable, particularly the face, back of the neck, and abdomen. Pictured below is an example of redistribution of body fat to the back of the neck. Accumulation of fat in this area is sometimes referred to as a “buffalo hump”.

Another example of this “redistribution” is pictured below. Supraclavical “fat pads” are collections of fat at the base of the neck, just above the collarbones, which are common in patients on steroids. They sometimes cause concern among patients if mistaken for lymph nodes or other causes for worry, but will gradually subside as the prednisone dose is tapered to below 10 milligrams/day.

In addition to this redistribution of fat, many patients undergo loss of muscle strength (muscle atrophy) while taking steroids. Regular physical exercise is key to avoiding this type of deconditioning that often occurs with prednisone treatment.

Glucose Intolerance

High blood sugar, or steroid–induced diabetes. Patients who are “pre-diabetic” can develop diabetes and the need for insulin while taking steroids. This usually resolves when the steroids are decreased or discontinued, but can be worsened by weight gain.

Hypertension

High blood pressure. This usually improves as the corticosteroid dose is reduced.

Bone Thinning (Osteoporosis)

Prednisone may cause thinning of the bones even in people who are not usually at high risk for osteoporosis (for example: males, young people). In people susceptible to osteoporosis, prednisone may accelerate the process of bone loss. Fortunately, in the past few years, excellent treatments and preventive measures have become available for osteoporosis. All patients on prednisone for prolonged periods are candidates for these medicines. Patients should be aware of their daily intake of calcium and Vitamin D while on steroids. Bone density measurement is commonly done using DEXA scans.

Avascular Necrosis of Bone

For reasons that are not known, high dose prednisone (for example, greater than 20 milligrams a day) predisposes some patients to joint damage, most often of the hips. In avascular necrosis (or osteonecrosis, meaning “bone death”) of the hip, the part of the leg bone that inserts into the pelvis dies, resulting in pain with weight–bearing and some loss of joint function. Many patients with avascular necrosis require joint replacements.

Easy Bruising

Prednisone also causes “thin skin”. Patients on moderate to high doses of prednisone often notice that they bruise easily, even with only slight trauma. Pictured below is a patient with giant cell arteritis who suffered a skin laceration after she struck her leg against a chair.

Abdominal Striae

Abdominal striae (“stripes”), as pictured below, frequently occur in patients who take high doses of steroids for long periods of time.

Hirsutism

Hirsutism is excessive growth of body hair. Patients vary in the degree to which this side effect of steroids occurs. Although some patients experience minimal hirsutism, the patient depicted below developed this side effect after taking 10 milligrams of prednisone for a few months.

Acne

High dose prednisone predisposes some patients to acne, especially facial acne, as pictured below. The facial acne developed after several weeks of high steroid doses.

Mood Swings/Insomnia

Many patients find it difficult to fall asleep when taking high doses of steroids. Many also find that they are more irritable or anxious than usual. Steroids sometimes even induce depression or psychosis, which usually improves when the drug is decreased or discontinued.

Cataracts

Long–term steroid use may lead to cataract development in the eyes, which frequently require surgical removal.

Vasculitis Center Doctors

Collaborators

Vasculitis can involve virtually any organ system within the body. Hence, our Vasculitis Center maintains close collaborative relationships with experts from other specialties. The Vasculitis Center includes collaborators from several medical disciplines who help provide the highest level of care for our patients. They have extensive experience managing vasculitis within their subspecialty and work closely with the Physicians in the Vasculitis Center to provide comprehensive care for our patients:

Otolaryngology (ENT):

Our ENT team includes specialists in inflammatory sinus disease, sensorineural hearing loss, and chronic middle ear disease. We are pleased to also have a Doctor of Audiology, Dr. Dinkes, who specializes in inflammatory process on our team as well.

• Dr. Jean Kim (sinus disease, middle ear manifestations)
• Dr. Alexander Hiller (upper airway disease)
• Dr. Roni Dinkes (audiology)

Neuro-ophthalmology:

• Dr. Andrew Carey

Endocrinology / Osteoporosis:

• Dr. Han Na Kim

• First Description
• Who gets Buerger’s Disease (the “typical” patients)?
• Classic symptoms of Buerger’s Disease
• What causes Buerger’s Disease?
• How is Buerger’s Disease diagnosed?
• Treatment and Course of Buerger’s Disease

First Description

This disease was first reported by Buerger in 1908, who described a disease in which the characteristic pathologic findings — acute inflammation and thrombosis (clotting) of arteries and veins — affected the hands and feet. Another name for Buerger’s Disease is thromboangiitis obliterans.

Who gets Buerger’s Disease (the “typical” patient)?

The classic Buerger’s Disease patient is a young male (e.g., 20–40 years old) who is a heavy cigarette smoker. More recently, however, a higher percentage of women and people over the age of 50 have been recognized to have this disease. Buerger’s disease is most common in the Orient, Southeast Asia, India and the Middle East, but appears to be rare among African–Americans.

Classic symptoms and signs of Buerger’s Disease

The initial symptoms of Buerger’s Disease often include claudication (pain induced by insufficient blood flow during exercise) in the feet and/or hands, or pain in these areas at rest. The pain typically begins in the extremities but may radiate to other (more central) parts of the body. Other signs and symptoms of this disease may include numbness and/or tingling in the limbs and Raynaud’s phenomenon (a condition in which the distal extremities — fingers, toes, hands, feet — turn white upon exposure to cold). Skin ulcerations and gangrene (pictured below) of the digits (fingers and toes) are common in Buerger’s disease. Pain may be very intense in the affected regions.

An angiogram demonstrating lack of blood flow to vessels of the hand (figure below). This decreased blood flow (“ischemia”) led to ulcers of the fingers and severe pain.

An abnormal result from an angiogram of the hand (figure below).

Despite the severity of ischemia (lack of blood flow) to the distal extremities that occurs in Buerger’s, the disease does not involve other organs, unlike many other forms of vasculitis. Even as ulcers and gangrene develop in the digits, organs such as the lung, kidneys, brain, and gastrointestinal (GI) tract remain unaffected. The reasons for the confinement to the extremities and sparing of other organs are not known.

What Causes Buerger’s Disease?

The association of Buerger’s Disease with tobacco use, particularly cigarette smoking, cannot be overemphasized. Most patients with Buerger’s are heavy smokers, but some cases occur in patients who smoke “moderately”; others have been reported in users of smokeless tobacco. It has been postulated that Buerger’s Disease is an “autoimmune” reaction (one in which the body’s immune system attacks the body’s own tissues) triggered by some constituent of tobacco.

Pictured below, are a patient’s fingertips that have developed gangrene. This is a very painful condition which sometimes requires amputation of the affected area.

How is Buerger’s diagnosed?

Buerger’s disease can be mimicked by a wide variety of other diseases that cause diminished blood flow to the extremities. These other disorders must be ruled out with an aggressive evaluation, because their treatments differ substantially from that of Buerger’s Disease (for Buerger’s, there is only one treatment known to be effective: complete smoking cessation — see below).

Diseases with which Buerger’s Disease may be confused include atherosclerosis (build–up of cholesterol plaques in the arteries), endocarditis (an infection of the lining of the heart), other types of vasculitis, severe Raynaud’s phenomenon associated with connective tissue disorders (e.g., lupus or scleroderma), clotting disorders of the blood, and others.

It should be noted that other substances, such as marijuana, have also been associated with a vasculitis similar to Buerger’s or polyarteritis nodosa that should be considered in the differential diagnosis.

Angiograms of the upper and lower extremities can be helpful in making the diagnosis of Buerger’s disease. In the proper clinical setting, certain angiographic findings are diagnostic of Buerger’s. These findings include a “corkscrew” appearance of arteries that result from vascular damage, particularly the arteries in the region of the wrists and ankles. Angiograms may also show occlusions (blockages) or stenoses (narrowings) in multiple areas of both the arms and legs.

Pictured below on the left is a normal angiogram. On the right, is an abnormal angiogram of an arm demonstrating the classic “corkscrew” appearance of arteries to the hand. The changes are particularly apparent in the blood vessels in the lower right hand portion of the picture (the ulnar artery distribution).

In order to rule out other forms of vasculitis (by excluding involvement of vascular regions atypical for Buerger’s), it is sometimes necessary to perform angiograms of other body regions (e.g., a mesenteric angiogram).

Skin biopsies of affected extremities are rarely performed because of the frequent concern that a biopsy site near an area poorly perfused with blood will not heal well.

Treatment and Course of Buerger’s

It is essential that patients with Buerger’s disease stop smoking immediately and completely. This is the only treatment known to be effective in Buerger’s disease. Patients who continue to smoke are generally the ones who require amputation of fingers and toes.

Despite the clear presence of inflammation in this disorder, anti-inflammatory agents such as steroids have not been shown to be beneficial. Similarly, strategies of anticoagulation (thinning of the blood with aspirin or other agents to prevent clots) have not proven effective. The only way to prevent the progression of the disease is to abstain from all tobacco products.