Johns Hopkins Vasculitis Center

Home / Search for "search.html/treatments/methotrexate.html"

Search Results for: search.html/treatments/methotrexate.html

Rheumatoid Vasculitis

First Description

Rheumatoid Vasculitis (RV) is an unusual complication of longstanding, severe rheumatoid arthritis. The active vasculitis associated with rheumatoid disease occurs in about 1% of this patient population.

RV is a manifestation of “extra-articular” (beyond the joint)rheumatoid arthritis and involves the small and medium-sized arteries in the body. In many of its disease features, RV resembles polyarteritis nodosa.

Other common extra-articular manifestations of rheumatoid arthritis, such as inflammation in the sac surrounding the heart (pericarditis), inflammation in the lining of the lungs (pleuritis), and interstitial lung disease (resulting in fibrosis or scarring of the lungs).

Who gets Rheumatoid Vasculitis? A typical patient

RV can affect a person from any ethnic background, either gender, and from any age group. However, more often than not, the typical patient has long-standing rheumatoid arthritis with severe joint deformities from the underlying arthritis. Although the arthritis has usually led to significant joint damage, at the onset of RV the joint disease is paradoxically quiet.

Figure: Patient with joint damage from rheumatoid arthritis. Note the bulbous swelling of some knuckles and lateral (ulnar) deviation of the fingers.

Classic symptoms of Rheumatoid Vasculitis

RV has many potential signs and symptoms. The manifestations of RV can involve many of the body’s different organ systems, including but not limited to the skin, peripheral nervous system (nerves to the hands and feet) , arteries of the fingers and toes causing digital ischemia, and eyes with scleritis. Scleritis (inflammation of the white part of the eye) commonly occurs in the setting of RV. This ocular complication requires urgent treatment with immunosuppressive medications.

Figure: Digital ischemia – this image shows a blood flow deficiency in the tip of the finger caused by an obstruction of the digital artery.

Figure: Scleritis – Inflammation of the sclera (the white of the eye) causing redness, light sensitivity and pain.

In addition, generalized symptoms such as fever and weight loss are common.

As is true with other forms of vasculitis that involve the skin, cutaneous lesions can erupt on various areas of the body in RV, with a predilection for the lower extremities. Typical findings include ulcers concentrated near the ankles.

Figure: Cutaneous ulcer – an open skin sore caused by an obstruction of the small blood vessels in the superficial ulcers or obstruction of medium vessels in a deeper ulcer.

Small nail fold infarcts (small spots around fingernail) can

occur in rheumatoid arthritis

but these do not necessarily signify the presence of systemic vasculitis and do not necessitate a change in rheumatoid arthritis treatment.

Nerve damage can cause foot or wrist drop, known in medical terminology as “mononeuritis multiplex”. The images below show a patient with a right wrist drop and a patient with right foot drop. This condition, which may be significantly disabling, is often preceded by a change in sensation in the same area (numbness, tingling, burning, or pain). These abnormal sensations can progress to muscle weakness, focal paralysis, and eventually to muscle wasting. Recovery from this condition, caused by nerve infarction, can take months. In some cases, recoveries from mononeuritis multiplex are incomplete.

Figures of drop wrist and drop foot (courtesy of the University of North Carolina)

(Video of drop foot viewable on our Microscopic Polyangiitis page under classic symptoms.)

Laboratory Tests

Most laboratory findings in RV – for example, elevations in the erythrocyte sedimentation rate or C-reactive protein – are non-specific, and reflect the presence of a generalized inflammatory state. Hypocomplementemia, anti-nuclear antibodies (ANA), and atypical anti-neutrophil cytoplasmic antibodies (ANCA) are common. Rheumatoid factor levels are usually extremely elevated. However, there is no definitive laboratory test for RV short of a tissue biopsy. The diagnosis must usually be made using a combination of history, physical examination, pertinent laboratory investigations, specialized testing (e.g., nerve conduction studies), and sometimes a tissue biopsy.

Because the treatment implications for RV are major, any diagnostic uncertainty must be met with definitive approaches to establishing the diagnosis. This usually involves biopsy of an involved organ. Deep skin biopsies (full-thickness biopsies that include some subcutaneous fat) taken from the edge of ulcers are very useful in detecting medium-vessel vasculitis. Nerve conduction studies help identify involved nerves for biopsy. Muscle biopsies (e.g., of the gastrocnemius muscle) should be performed at the same time as nerve biopsies, to increase the chance of finding changes characteristic of vasculitis. Imaging studies have no consistent role in the evaluation of RV, although sometimes angiography of the gastrointestinal tract is useful.

What Causes Rheumatoid Vasculitis?

The cause of RV is unknown, but given the prominence of immune components and the pathologic changes in involved blood vessels, an auto-immune process is suggested.

How is Rheumatoid Vasculitis diagnosed?

Most laboratory findings in RV – for example, elevations in the erythrocyte sedimentation rate or C-reactive protein are non-specific, and reflect the presence of a generalized inflammatory state. Hypocomplementemia, anti-nuclear antibodies (ANAs), and atypical anti-neutrophil cytoplasmic antibodies (atypical ANCAs) are common. Rheumatoid factor levels are extremely elevated, as a rule. However, there is no definitive laboratory test for RV short of a tissue biopsy. The diagnosis must usually be made by the combination of history, physical examination, pertinent lab work, other specialized testing (e.g., nerve conduction studies), and sometimes even a tissue biopsy is required.

The diagnosis of RV should be considered in any rheumatoid arthritis patient who develops new constitutional symptoms, skin ulcerations, decreased blood flow to the fingers or toes, symptoms of a sensory or motor nerve dysfunction (numbness, tingling, focal weakness); or any inflammation of the lining around the heart or lungs (pericarditis or pleurisy/pleuritis).

Patients with a history of joint-destructive rheumatoid arthritis are at an increased risk for infection. Therefore, when a rheumatoid arthritis patient presents with a new onset of non-specific systemic complaints an infection must first be eliminated. Patients with rheumatoid arthritis typically have immune systems that are disordered from previous immunosuppression and underlying disease (e.g., joint damage). This patient population, therefore, is at higher risk of infection.

The differential diagnosis of RV includes:

  • Cholesterol embolization syndromes, in which a piece of cholesterol breaks off of a plaque, may cause digital ischemia (blood flow obstruction to a finger or toe), and a host of other symptoms that mimic vasculitis.
  • Diabetes mellitus is another major cause of mononeuritis multiplex, but multiple mononeuropathies occurring over a short period of time are unusual in diabetes.
  • Many clinical features of RV mimic those of polyarteritis nodosa, cryoglobulinemia, and other forms of necrotizing vasculitis. Therefore they too should be considered in this setting.

Because the treatment implications for RV are major, any diagnostic uncertainty must be met with a definitive approach to establishing the diagnosis. As alluded to earlier, this usually involves the biopsy of an involved organ. Deep skin biopsies (full-thickness biopsies that include some subcutaneous fat) taken from the edge of ulcers are very useful in detecting medium-vessel vasculitis. Nerve conduction studies help identify involved nerves for biopsy. Muscle biopsies (e.g., of the gastrocnemius muscle) should be performed at the same time as nerve biopsies, to increase the chance of finding changes characteristic of vasculitis. Imaging studies have no consistent role in the evaluation of RV, although sometimes angiography of the gastrointestinal tract is useful.

Normally, the cells of the blood vessel wall would be fewer in number (less thick) and the lumen (larger red area) would be larger. The arrow points (Figure 6, left) to an inflamed blood vessel found on a muscle biopsy. The globular pink areas are muscle fibers.

Treatment and Course of Rheumatoid Vasculitis

Therapy should reflect the severity of organ involvement. Prednisone or other steroid therapies are often the first line of treatment. Optimizing treatment of the underlying rheumatoid arthritis is also essential, therefore medications such as methotrexate or tumor necrosis factor inhibitors may be employed. In the setting of impending damage to major organs such as the eyes, a peripheral nerve, the gastrointestinal tract, or of a severe skin ulceration, cyclophosphamide is usually warranted.

What’s New in Rheumatoid Vasculitis?

Compared to other forms of vasculitis, there has been relatively little research in recent years on the specific entity of RV. The lack of similarity in available reports on RV and discrepancies in case definitions have created challenge to building standard approaches to the diagnosis and treatment of this condition. There is some evidence that the incidence of RV has decreased over the past several decades, perhaps because of better treatment of the underlying rheumatoid arthritis.

Supplemental Immunoglobulin (IVIG/SCIG)

What is IVIG/SCIG?

Intravenous immunoglobulin (IVIG) is a therapy consisting of pooled antibodies (immunoglobulin) obtained from healthy donors that is given as an infusion by vein. This same therapy can also be given as a subcutaneous injection (SCIG) rather than an intravenous one.

How does it work?

IVIG and SCIG are often used to treat patients with immunodeficiency syndromes, which are genetic or acquired conditions that lead to low immunoglobulin levels. For these patients, IVIG/SCIG provide the protective effect of antibodies that they otherwise lack.

In treating vasculitis, we sometimes encounter the need for IVIG/SCIG due to the use of Rituximab – a drug that targets B cells. In some patients, the long-term use of rituximab may lead to an acquired deficiency of immunoglobulins. By combining IVIG/SCIG with rituximab, we are able to continue to provide patients with the immunosuppressive benefit of rituximab, while compensating for the increased risk of infection by giving IVIG/SCIG.

How is IVIG/SCIG given?

IVIG is often given as a home infusion. SCIG is given as a subcutaneous injection. These treatments are generally given once per month.

Side effects:

These treatments carry a risk of blood clot, renal injury, and headaches. IVIG constitutes a large fluid challenge, and therefore may not be appropriate for patients with heart or kidney failure.

Polyarteritis Nodosa

First Description

The first description of this disease dates back to 1866 when Kussmaul and Maier identified a condition that consisted of “focal, inflammatory, arterial nodules”. They termed this disorder “periarteritis nodosa” because of the inflammation they observed around the blood vessel wall. The name was changed to polyarteritis nodosa (PAN) to underscore the fact that inflammation throughout the entire arterial wall – not just around the wall – is a major disease feature. Polyarteritis nodosa is sometimes termed “systemic necrotizing vasculitis”, but this term is non-specific as other forms of vasculitis also have systemic and necrotizing features.

Who gets Polyarteritis Nodosa (the “typical” patient)?

Most cases of PAN occur in the 4th or 5th decade, although it can occur at any age. Men are twice as likely to be affected than women. A minority of patients with PAN have an active hepatitis B infection. In the rest of the cases, the cause(s) is presently unknown, and the disease is said to be “idiopathic” in nature.

Classic symptoms and signs of Polyarteritis Nodosa

PAN is a multisystem disease that may present with fever, sweats, weight loss, and severe muscle and joint aches/pains. PAN may develop in a subacute fashion, over several weeks or months. Patients may have nonspecific complaints such as fever, malaise, weight loss, anorexia, and abdominal pain. The disease can affect nearly any site in the body, but it has a predisposition for organs such as the skin, kidney, nerves, and gastrointestinal tract. Many patients with PAN have high blood pressure and elevated erythrocyte sedimentation rates (ESR). The presentation of PAN may also include skin abnormalities (rash, ulcers) and peripheral neuropathy (pain, the sensations of burning, tingling, or numbness, or weakness in a hand or foot). However, the disease has a predilection for certain organs and tissues; these are described below.

Nerve

  • Peripheral neuropathies are very common (50 to 70%). This includes tingling, numbness and/or pain in the hands, arms, feet, and legs.
  • Central nervous system (CNS) lesions may occur 2 to 3 years after the onset of PAN and may lead to cognitive dysfunction, decreased alertness, seizures and neurologic deficits.

Skin

  • Skin abnormalities are very common in PAN and may include purpura, livedo reticularis, ulcers, nodules or gangrene.
  • Skin involvement occurs most often on the legs and is very painful.

Kidney

  • Renal artery vasculitis may lead to protein in the urine, impaired kidney function, and hypertension.
  • Small percentage of patients go on to require dialysis.

Gastrointestinal Tract

  • Abdominal pain, gastrointestinal bleeding (occasionally is mistaken for inflammatory bowel disease)
  • Hemorrhage, bowel infarction, and perforation are rare, but very serious

Heart

  • Clinical involvement of the heart does not usually cause symptoms.
  • However, some patients develop myocardial infarctions (heart attacks) or congestive heart failure.

Eye

  • Scleritis or inflammation in the sclera (white part of the eye)

Genitals

  • Testicular infarction

What causes Polyarteritis Nodosa?

Hepatitis B causes a minority of cases of PAN. With the availability of hepatitis B vaccine now, cases of PAN caused by hepatitis B are now rare in the developed world. It is possible that other infections contribute to other cases of PAN, but links between other infections and this disease remain conjectural at the present time.

How is Polyarteritis Nodosa Diagnosed?

Routine laboratory tests may provide important clues to PAN, but there is no single blood test that is diagnostic of this disease. Most patients with PAN have elevated ESRs. Proteinuria (protein in the urine) is common among those with kidney involvement.

If there is skin or muscle/nerve involvement, a skin or muscle/nerve biopsy can be extremely helpful in coming to a definite diagnosis of PAN. Nerve conduction studies are a non-invasive way of identifying nerves that are involved by the inflammation. (These nerves can then be biopsied to confirm the diagnosis). The diagnosis is confirmed by a biopsy showing pathologic changes in medium-sized arteries. The biopsy site may vary. Most biopsies are taken from skin, symptomatic nerve, or muscle. An angiogram of the abdominal blood vessels may also be very helpful in diagnosing PAN. Aneurysms most often affect the arteries leading to the kidneys, liver or gastrointestinal tract.

The American College of Rheumatology (ACR) has established criteria that should be fulfilled if a patient is to be included in a research study of PAN. The criteria are designed to differentiate PAN from other forms of vasculitis. Not all patients have all criterion. Some, in fact, may have only 2 or 3 criteria, yet their physicians are still comfortable classifying their disease as PAN. A committee of ACR physicians selected 10 disease features (criteria) as being those that best distinguish PAN from other vasculitides. In order to be classified as a PAN patient – for the purpose of research studies – a patient should have at least 3 of the 10 ACR criteria.

The American College of Rheumatology 1990 criteria for the classification of Polyarteritis Nodosa

  1. Weight loss of > 4 kg since beginning of illness
  2. Livedo reticularis
  3. Testicular pain or tenderness
  4. Myalgias, weakness, or leg tenderness
  5. Mononeuropathy or polyneuropathy
  6. Development of hypertension
  7. Elevated BUN or creatinine unrelated to dehydration or obstruction
  8. Presence of hepatitis B surface antigen or antibody in serum
  9. Arteriogram demonstrating aneurysms or occlusions of the visceral arteries
  10. Biopsy of small or medium-sized artery containing granulocytes

Treatment and Course of Polyarteritis Nodosa

Treatment of PAN has improved dramatically in the past couple of decades. Before the availability of effective therapy, untreated PAN was usually fatal within weeks to months. Most deaths occurred as a result of kidney failure, heart or gastrointestinal complications. However, effective treatment is now available for PAN. After diagnosis, patients are treated with high doses of corticosteroids. Other immunosuppressive drugs are also added for patients who are especially ill. In most cases of PAN now, if diagnosed early enough the disease can be controlled, and often cured.

In medical terms, by David Hellmann, M.D.

A discussion of Polyarteritis Nodosa written in medical terms by David Hellmann, M.D. (F.A.C.P.), for the Rheumatology Section of the Medical Knowledge Self–Assessment Program published and copyrighted by the American College of Physicians (Edition 11, 1998). The American College of Physicians has given us permission to make this information available to patients contacting our Website.

Polyarteritis nodosa is a small– and medium–sized arteritis affecting multiple organs, especially the skin, peripheral nerve, gut, kidney, and heart. The age of onset ranges from childhood to late adulthood but averages 40 years. Polyarteritis nodosa has been associated with active hepatitis B, hepatitis C, or both; therefore, the disease is more common in injection drug users.

Polyarteritis nodosa is probably mediated by deposition of immune complexes. Evidence includes the observation that patients with polyarteritis nodosa associated with hepatitis B or hepatitis C have immune complexes consisting of immunoglobulin and viral antigens circulating in the blood and deposited in inflamed vessels. Moreover, antiviral therapy can remit the vasculitis in some of these patients.

The onset is gradual over weeks to months, and the initial symptoms are often nonspecific. The earliest clues that the patient has vasculitis come usually from the skin (where vasculitis may appear as palpable purpura, livedo reticularis, digital gangrene, or tender nodules), or the peripheral nervous system (where infarction of one mixed motor and sensory nerve after another results in mononeuritis multiplex, one of the most specific clues that a patient has vasculitis). Renal involvement eventually develops in most and is accompanied by hypertension in half of patients, whereas Granulomatosis with Polyangiitis
rarely elevates the blood pressure. Polyarteritis nodosa also commonly involves the gut (abdominal angina, hemorrhage, perforation), heart (myocarditis, myocardial infarction), or eye (scleritis). Rupture of renal or mesenteric micoaneurysms can simulate an acute abdomen.

Confirming the diagnosis requires either biopsy specimen showing small– or medium–sized arteries, or mesenteric arteriography showing microaneurysms or alternating areas of stenosis and dilation. Biopsy of a symptomatic nerve or a symptomatic muscle is 65% sensitive, whereas biopsy of an asymptomatic site is less than 30% sensitive. Because mesenteric angiography is 60% sensitive, it should be done when there is not a symptomatic site to biopsy. Renal biopsy should be avoided unless angiography rules out microaneurysms susceptible to rupture.

Without treatment, almost all affected patients die within 2 to 5 years. Treatment with prednisone (starting at 1 mg/kg daily) and cyclophosphamide (2 mg/kg daily) appeared to revolutionize the outcome of polyarteritis nodosa by achieving 70% 10–year survivals and established this combination of agents as the standard therapy. However, newer studies suggest that prednisone alone may achieve the same high survival as prednisone and cyclophosphamide, although flares were less frequent in patients taking cyclophosphamide. Other studies indicate that the traditional therapy with prednisone and cyclophosphamide should be abandoned in patients with polyarteritis nodosa associated with hepatitis B. Patients treated with the traditional combination respond, but almost all survivors become chronic carriers of hepatitis B and may die later of cirrhosis or variceal bleeding. The newly propsed regimen consists of 2 weeks of prednisone to control the vasculitis, followed by plasmapheresis to remove immune complexes, and accompanied by antiviral therapy with lamivudine to rid the patient of the hepatitis B infection. The long–term value of anti–viral therapy for polyarteritis nodosa associated with hepatitis C is not established.

Giant Cell Arteritis

Description

Giant cell arteritis (GCA) is the most common form of vasculitis that occurs in adults. Almost all patients who develop giant cell arteritis are over the age of 50. GCA commonly causes headaches, joint pain, facial pain, fever, and difficulties with vision, and sometimes permanent visual loss in one or both eyes. Because the disease is relatively uncommon and because the disease can cause so many different symptoms, the diagnosis of GCA can be difficult to make. With appropriate therapy, GCA is an eminently treatable, controllable, and often curable disease. The disease used to be called “temporal arteritis” because the temporal arteries, which course along the sides of the head just in front of the ears (to the temples) can become inflamed. However, we also know that other blood vessels, namely the aorta and its branches, can also become inflammed. The term “giant cell arteritis” is often used because when one looks at biopsies of inflamed temporal arteries under a microscope, one often sees large or “giant” cells.

Who gets Giant Cell Arteritis?

GCA is a disease of older people. The average age at onset is 72, and almost all people with the disease are over the age of 50. Women are afflicted with the disease 2 to 3 times more commonly than men. The disease can occur in every racial group but is most common in people of Scandinavian descent.

Classic Symptoms of Giant Cell Arteritis

The most common symptoms of GCA are headache, pain in the shoulders and hips (called polymyalgia rheumatica), pain in the jaw after chewing (called jaw claudication), fever, and blurred vision. Other symptoms can include tenderness of scalp (it hurts to comb the hair), cough, throat pain, tongue pain, weight loss, depression, stroke, or pain in the arms during exercise. Some patients have many of these symptoms; others have only a few. Blindness — the most feared complication — can develop if the disease is not treated in a timely fashion.

What Causes Giant Cell Arteritis?

We do not know. We do know that aging has something to do with the disease. And we know that the body’s immune system attacks and inflames the arteries. But we do not know why the immune system attack occurs when and where it does.

How is Giant Cell Arteritis Diagnosed?

The diagnosis is made by doing a biopsy of the temporal artery. Using a local numbing medication (the same one used by a dentist), the doctor can remove a small part of the temporal artery from under the scalp and look at it under the microscope for evidence of inflammation. A temporal artery biopsy is almost always safe, causes very little pain, and often leaves little or no scar. An example of this is pictured below

There are blood tests that help the doctor decide who is likely to have GCA. Almost everyone with the condition has an elevated erythrocyte sedimentation rate (also called “sed rate”). The sed rate measures how fast a patient’s red blood cells settle when placed in a small tube. In inflammatory conditions, red blood cells settle more quickly than in non–inflammatory states. In addition, most patients with GCA have a slight–anemia, or low red blood cell count. Other conditions can also cause a high sed rate or anemia, so the final diagnosis depends on a temporal artery biopsy.

A few patients with GCA do not have positive biopsies. We now know that GCA does not affect every part of every temporal artery but can “skip” around. When one biopsy is negative, biopsying the temporal artery on the other side can lead to the diagnosis.

Treatment and Course of Giant Cell Arteritis

GCA requires treatment with prednisone, a type of corticosteroid. Typically, treatment begins with 40–60 mg of prednisone, taken by mouth each day. Most patients improve rapidly and dramatically on this dose, with improvement of most symptoms in 1–3 days. Unfortunately, if blindness has occurred as a symptom it is usually irreversible, which only emphasizes the importance of early detection and treatment.

Almost all patients experience side effects from prednisone. After the patient improves, the doctor gradually reduces the prednisone dose. The rate of tapering prednisone depends on how the patient feels, what the doctor finds on exam, and the results of blood tests, including the sedimentation rate. Although virtually all patients are able to reduce their prednisone dose, most require some amount of prednisone for 1–2 years. Longer treatment periods are not uncommon.

In medical terms, by David Hellmann, M.D.

A discussion of Giant Cell Arteritis written in medical terms by David Hellmann, M.D. (F.A.C.P.), Co-Director of the Johns Hopkins Vasculitis Center, for the Rheumatology Section of the Medical Knowledge Self-Assessment Program published and copyrighted by the American College of Physicians (Edition 11, 1998). The American College of Physicians has given us permission to make this information available to patients contacting our Website.

Giant cell arteritis is vasculitis of unknown cause that affects the elderly and is characterized by panarteritis of medium- to large-sized arteries, especially in the extracranial branches of the carotid artery. The average age of onset is 72 years, and women are affected two times as often as men. Irreversible blindness, the most commonly feared complication, results from necrosis of the posterior ciliary branch of the ophthalmic artery and is usually preventable by early diagnosis and corticosteroid treatment.

Giant cell arteritis can begin suddenly or gradually with nonspecific symptoms such as malaise, weight loss, depression, and fatigue or with the classic symptoms of headache, scalp tenderness, jaw claudication, visual changes, or polymyalgia rheumatica. Polymyalgia rheumatica which can occur with or without giant cell arteritis, is characterized by pain and stiffness of the hips and shoulders that worsens in the morning. About one third of patients resemble the preceding patient and present with atypical manifestations such as fever of unknown origin, respiratory symptoms (dry cough is most common), large vessel disease (causing Raynaud’s phenomenon, claudication, or thoracic aortic aneurysm), mononeuritis mutiplex, glossitis, or profound anemia. Although giant cell arteritis accounts for only 2% of all fever of unknown origin, it accounts for 16% of fever of unknown origin in patients over age 65 years and is often associated with rigors and sweats. Only half of patients have enlarged, nodular, or nonpulsatile temporal arteries: normal temporal arteries on physical examination do not exclude the diagnosis. Subclavian bruits, diminished pulses, aoritic regurgitation, or Raynaud’s phenomenon are found in patients with large vessel disease. Fundoscopic examination is normal in the first day or two after blindness develops. Almost all patients have a markedly elevated ESR, averaging about 100 mm/h. Very rarely, the ESR may be normal, especially in patients who are already taking prednisone for allergic or respiratory diseases. MOst patients have mild normochromic normocytic anemia, and 20% to 30% resemble the preceding patient in having mildly elevated serum alkaline phosphatase. The leukocyte count at presentation is usually normal, a point favoring giant cell arteritis over infection or malignancy.

Because blindness from giant cell arteritis is almost irreversible, treatment with 40 to 60 mg of prednisone should be started as soon as the diagnosis is suspected. Although immediate temporal artery biopsy has been preferred, one study suggests that biopsy remains positive within at least the first 2 weeks of corticosteroid therapy. Therapy should not be held pending biopsy. In patients with giant cell arteritis, arterial involvement is patchy: therfore, maximizing the chance of diagnosis requires obtaining a long (3 to 4 cm) segment and examining multiple sections. Positive biopsy specimens show infiltration of the vessel wall with mononuclear inflammatory cells and giant cells, intimal proliferation, and thrombosis. Unilateral biopsy specimens are positive in approximately 85% of patients, and bilateral biopsy specimens are positive in 95%. Patients dramatically improve within 24 to 72 hours of beginning therapy, and the ESR usually normalizes within 1 month. Thereafter, prednisone can be tapered slowly, although most patients require some prednisone for at least 9 months and often longer.

Treatment decisions should probably be based on the patient’s symptoms, the hemoglobin, the ESR: ESR alone should not dictate therapy. Because compression fractures develop in one third of patients, prevention and treatment of osteoporosis should be part of initail management. Methotrexate, azathioprine, and cyclophosphamide have been used in rare patients who do not respond to adequate prednisone. Long–term follow–up is required to detect late recurrences (including the late onset of thoracic aortic aneurysms with aortic regurgitation, congestive heart failure, and aortic dissection). Patients with polymyalgia rheumatica but no symptoms of giant cell arteritis above the neck (such as jaw claudication, headache and visual symptoms) do not need temporal artery biopsy and respond to low–dose prednisone (10 to 20 mg/d orally). Because polymyalgia rheumatica is a clinical diagnosis, other conditions such as hypothyroidism, amyloidosis, rheumatoid arthritis, and malignancy should be considered in the initial evaluation and reconsidered if the patient does not improve rapidly on prednisone.

Eosinophilic Granulomatosis with Polyangiitis, formerly Churg-Strauss Syndrome (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

  • 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.

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.