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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.

Diagnosing Vasculitis

How do we diagnose Vasculitis?

Patients with vasculitis learn that making the diagnosis is sometimes quite difficult. Many endure numerous doctors’ visits, tests, and hospitalizations before the pieces of the puzzle are assembled. The diagnosis of vasculitis usually requires a biopsy of an involved organ (skin, kidney, lung, nerve, temporal artery). This allows us to ‘see’ the vasculitis by looking under a microscope to see the inflammatory immune cells in the wall of the blood vessel. Although, making a diagnosis of vasculitis can be quite involved, this is very important for two main reasons:

# ONE:  Vasculitis has many MIMICKERS (other diseases that have similar features but require different treatments). It is important to rule out other causes of vascular inflammation, other than a primary autoimmune condition as the management could be different.

# TWO:  The treatments for vasculitis itself involve substantial risk. No physician should prescribe such treatment without making every effort to secure a firm diagnosis.

Blood tests, X–rays, and other studies may suggest the diagnosis of vasculitis, but often the only way to clinch the diagnosis is to biopsy  involved tissue, examine the tissue under the microscope in consultation with a pathologist (ideally one experienced at examining biopsies in vasculitis), and find the pathologic hallmarks of the disease.

If a patient’s symptoms, physical examination, and diagnostic testing suggest involvement of a particular organ, one of the procedures below may be used to confirm (or exclude) the diagnosis of vasculitis:

1. Skin Biopsy: One of the least invasive ways of making the diagnosis. A minor procedure performed under local anesthesia. The wound is closed with 1–2 stitches that are removed 7–10 days later.

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An abnormal skin biopsy showing leukocytoclastic vasculitis. The white oval shapes are subcutaneous fat cells beneath the dermis.

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An example of an inadequate skin biopsy.

The correct diagnosis of PAN (polyarteritis nodosa) was not confirmed by this biopsy because the biopsy was not deep enough. The biopsy specimen contains only the epidermis and superficial dermis. PAN classically affects medium–sized arteries located in the deep dermis.

In contrast to the biopsy above, the skin biopsy below was deep enough to include the deep dermis as well as some subcutaneous fat.

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The white, oval–shaped areas are fat lobules. Just superficial to the subcutaneous fat, within the deep dermis, an inflamed medium–sized vessel is evident.

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A closer view of the vessel is provided in the next figure which provides a high power view of the vasculitic artery lying at the junction of the dermis and subcutaneous fat.

2. Kidney Biopsy: A kidney biopsy will be performed if there is evidence of kidney involvement by vasculitis (red blood cells or protein in the urine, for example). This procedure is done under local anesthesia while the kidney is visualized by ultrasound. Because of the small but significant risk of bleeding after this procedure, patients are usually monitored in the hospital for 24 hours after the biopsy.

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This biopsy shows a “crescent” in a glomerulus, a feature of glomerulonephritis which can be seen in ANCA-associated vasculitis (GPA or MPA).

3. Sural Nerve Biopsy: The sural nerve is a sensory nerve over the lateral aspect of the foot. Under local anesthesia in an operating room, a surgeon removes a small piece of the nerve, usually along with a piece of the adjacent muscle (the gastrocnemius). Because the sural nerve does not innervate muscles (remember: it is a sensory nerve, not a motor nerve), the patient does not lose any strength on the side of the foot and lower leg. There maybe, however, some residual numbness on the side of the foot. Patients generally tolerate this numbness well (if the vasculitis has involved the nerve severely enough, some patients already have numbness in that region).

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Below is the surgical site of a sural nerve and gastrocnemius muscle biopsy one week after the procedure: a few sutures and a thin, well–healing scar.

4. Temporal Artery Biopsy: Performed to diagnose Giant Cell Arteritis, also known as Temporal Arteritis, because the temporal artery is often involved. The temporal artery courses up the temples, just in front of the ears. The biopsy, done under local anesthesia, is performed by making a small incision just above the hairline (sometimes shaving a small area of hair is required). The procedure is extremely well–tolerated by patients. Within several weeks, there is usually little or no sign that a biopsy was done. Complications of temporal artery biopsies are extremely rare. Sometimes, to increase the diagnostic yield, both temporal arteries (i.e., the ones on each side of the head) are biopsied.

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5. Lung Biopsy : Often the best way to make a diagnosis of vasculitis that involves the lungs, such as granulomatosis with polyangiitis (GPA). A lung biopsy may be performed in one of two ways: 1) open lung biopsy, a sizable surgical procedure; or 2) thoracoscopic lung biopsy, a less invasive but still significant procedure. Even a thoracoscopic biopsy usually requires at least 48 hours in the hospital and the temporary placement of a chest tube to permit the lung to re–expand.

6. Brain Biopsy: Often necessary to confirm the diagnosis of Central Nervous System (CNS) Vasculitis. This is usually performed on the non–dominant side of the patient’s brain (that is, if the patient is right–handed — and therefore “left–brained” — the biopsy is performed on the right side of the brain). Biopsy of the brain’s covering, the meninges, is usually performed at the same time.

7. Angiogram / angiography: Angiography is helpful in the diagnosis of Polyarteritis Nodosa (PAN). Similar to a heart catheterization,  after inserting a catheter into a large artery in the leg and advancing the catheter into the aorta, radiographic dye is injected into blood vessels supplying the gastrointestinal tract. In the proper clinical setting, the detection of aneurysms (small outpouchings of blood vessel walls) is diagnostic of PAN. This gives an accurate picture of the luminal (inside) anatomy of blood vessels.

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8. Central nervous system angiogram Frequently part of the “work–up” of CNS vasculitis. The procedure is identical to an abdominal angiogram, except the catheter is advanced all the way up to the large vessels supplying the head and neck (for example, the carotid arteries). On angiography, CNS vasculitis is characterized by “beading” (dilated areas alternating with narrowing of the blood vessels). A strikingly abnormal angiogram may eliminate the need for a brain biopsy.

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The angiogram pictured shows prominent dilations of arteries visible at several sites in the intra–cerebral region.

9. Other Useful Tests: There are many other tests that are helpful in the diagnosis of vasculitis, or in evaluating the activity of the disease:

Erythrocyte sedimentation rate (ESR):  Also known as the “sed rate”, for short. This is an old but useful test first employed by the ancient Greeks as a test for pregnancy. It is important to note that there are several influences on the ESR such as anemia and hypergammaglobulinemia which may have nothing to do with an inflammatory state.

C–reactive protein (CRP): CRP is a protein produced by the liver in response to inflammation within the body.

Urinalysis: Many forms of vasculitis affect the kidneys. A simple way of determining whether or not the kidneys are involved is to perform a urinalysis. By performing checks for several indicators of inflammation in a patient’s urine, the physician may determine if inflammation is present within the kidneys. These indicators include:

  • Protein (“proteinuria”)
  • Red blood cells (“hematuria”)
  • Clumps of red blood cells (“casts”)

Pictured below is a urine specimen from a patient with Wegener’s granulomatosis and glomerulonephritis (inflammation in the kidneys).

This is a view of the specimen examined under the microscope, showing cylindrical “casts” comprised of red blood cells. This finding strongly indicates vasculitis in the kidney.

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From another Wegener’s granulomatosis patient’s urinalysis, “blebs” (identified by white arrows) protrude from the surface of the red blood cells that have been damaged in transit through the kidney.

Because inflamed kidneys leak blood, red blood cells — dismorphic as these are — appear in the urine.

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CT Scan (a CAT scan, or computed tomography) — A type of radiology test that permits a non-invasive, cross–sectional view of a patient’s anatomy. On the illustration below (a chest CT scan from a patient with GPA), the view is up (looking toward the patient’s head, from his or her feet). The heart is the white, rounded object in the upper center of the picture. The black regions are the patient’s lungs. The large spot in the left lung (corresponding to the patient’s right lung) is a nodule caused by GPA. Other smaller nodules are also evident.

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MRI / MRA: MRI is another imaging modality that can be useful for diagnosing and following systemic vasculitis; particularly large vessel vasculitis. MRI allows for visualization of the vessel wall. In vasculitis, the vessel wall may be thickened or edematous.

ANCA tests — ANCA is an abbreviation (acronym) for anti–neutrophil cytoplasmic antibodies. These antibodies are found in the blood of patients with several different types of vasculitis, including Wegener’s Granulomatosis, Microscopic Polyangiitis, and the Churg–Strauss Syndrome. ANCAs and their association with vasculitis were recognized in the mid–1980s, and their use has become increasingly widespread since the 1990s. ANCAs are detected by a simple blood test. These antibodies are directed against the cytoplasm (the non–nucleus part) of white blood cells. Their precise role in the disease process remains uncertain but is a topic of considerable research interest. ANCAs come in two primary forms: 1) the C–ANCA [C stands for cytoplasmic] and, 2) the P–ANCA [P stands for perinuclear]. C–ANCAs have a particularly strong connection to Wegener’s Granulomatosis (up to 80% of patients – and possibly more of those with active disease – have these antibodies). When C–ANCAs are present in the blood of a patient with symptoms or signs suggesting Wegener’s, the likelihood of the diagnosis increases considerably. Because of the long list of other conditions that are sometimes associated with ANCAs, however, in most cases it is still VERY IMPORTANT to biopsy an organ involved by vasculitis to verify the diagnosis.

 

All information contained within the Johns Hopkins Vasculitis Center website is intended for educational purposes only. Visitors are encouraged to consult other sources and confirm the information contained within this site. Consumers should never disregard medical advice or delay in seeking it because of something they may have read on this website.

Causes of Vasculitis

There are many different types of vasculitis, some with different causes than others.

Certain forms of vasculitis that can be due to infection where the microbe directly invades the vessel wall. Syphilis is one example of vasculitis that can be caused by infection in the blood vessel. Treating the infection is the main goal in managing this sort of vasculitis, which is not an autoimmune disease, but rather an infection.

Other infections can provoke the immune system into causing damage in blood vessels. Here, the infection is the trigger, but the immune system is the cause of the vascular damage. Viral hepatitis (B and C) are examples of this sort: some patients with Hepatitis B may develop polyarteritis nodosa, while some patients with Hepatitis C may develop cryoglobulinemic vasculitis.

Other types of vasculitis may be due to an ‘allergic‘-type reaction to medications. For example, certain blood pressure medications (hydralazine) or thyroid medications (propylthiouracil) can trigger ANCA associated vasculitis in some patients. Cocaine is an illicit drug that is linked to vasculitis and vascular damage.

However, the causes of most vasculitides are currently unknown. While we can identify some risk factors (such as older age in giant cell arteritis), we do not know the specific causes of these diseases. These forms of vasculitis of unknown cause are considered autoimmune diseases.

Under normal circumstances, our immune system serves to defend us from infection and other threats, such as cancers. In autoimmune diseases, the immune system generates a response not against a foreign threat, but against normal “self” tissues. This abnormal immune response against “self” tissues can result in a wide array of autoimmune diseases, including relatively common diseases (such as psoriasis or thyroid disease) as well as rare conditions (such as vasculitis).

In most cases, autoimmune diseases are believed to be due to an abnormal immune response that is generated in a susceptible person, and eventually leads to a cycle of ongoing inflammation in otherwise normal tissues where no infection or other identifiable threat is present. Some interaction between the immune system and the environment is thought necessary for this to occur, and a person’s genetic background likely places some individuals at higher risk than others.

A better understanding of the specific causes of these diseases would lead to improved means of diagnosing, treating, and even preventing these conditions. Uncovering the causes of vasculitis is a major goal of vasculitis research.

While we may not know the specific causes of the vasculitidies, we do have a basic understanding of the way that the immune system causes organ damage in these conditions. In all forms of vasculitis, activation of the immune system leads to the deposition of inflammatory cells and proteins in the walls of blood vessels. As this inflammation in blood vessels continues, the vessels become damaged and no longer serve their normal function of delivering blood to the organs that they supply. Consequently, the tissues downstream of these inflamed vessels are starved of oxygen and nutrients needed for normal function. At a basic level, this is a process similar to what occurs in a heart attack or a stroke – but instead of the cholesterol plaque that blocks a coronary artery in a heart attack, the immune system is responsible for blockage of blood vessels in vasculitis.

All information contained within the Johns Hopkins Vasculitis Center website is intended for educational purposes only. Visitors are encouraged to consult other sources and confirm the information contained within this site. Consumers should never disregard medical advice or delay in seeking it because of something they may have read on this website.

Linda’s Loop

contributed by Brenda Shilling

I have always known that chronic and life-threatening diseases can have a devastating effect on people’s lives. I’ve seen it happen to friends’ families and heard of it happening to friends of friends. But until 2002, the realities of such challenges were quite remote to me, as I had never felt a loved one struggle with a serious condition.

Linda Gray and her twin sister, Brenda Shilling.

In the spring of 2002, my identical twin, Linda, was diagnosed with neuropsychiatry lupus and central nervous system vasculitis. It was a scary time for all of us, particularly for Linda and her family. Like many lupus patients, Linda had been ill often and had many problems in the years leading up to her diagnosis. We were extremely thankful that The Johns Hopkins Vasculitis Center quickly identified what was wrong and started Linda on a treatment program.

In the months that followed, I watched my sister experience a multitude of emotions, including devastation over her diagnosis, fear for her future, and relief that she had finally found help. Although I know that not all lupus patients fare well, I learned that the treatment of lupus has come a long way over the years and I prayed that Linda would benefit from these advances. Her treatment was extremely challenging. However, during the hard realities of chemotherapy and steroids on Linda’s body, her spirit was amazing.

Despite knowing that family is extremely important during times like this and that frequent calls, letters, and visits to Linda were supportive, I slowly began to feel helpless. This was an unexpected emotion. I wanted to do more. I needed to do more. My sister was going through the most difficult time of her life, and I had do something more.

One morning in the late spring of 2003 I considered coordinating a bicycle ride to raise funds for The Johns Hopkins Vasculitis Center. Our sister, Liz, thought it was wonderful idea and wanted to help. We were driven by love for our sister and that was all the motivation we needed!

Linda Gray and her sister, Liz Adams.

We decided on a 50-mile ride – short enough to manage but long enough to sound good! We then mailed over 200 letters to friends and family asking for a financial gift to The Johns Hopkins Vasculitis Center in honor of our sister and others with her disease. We also distributed the letter to social and religious groups in which we are involved. Four of our friends asked if they could join us on the bike ride in a generous gesture of support. We even had t-shirts made!

Linda's Loop Participants

Participants in Linda’s Loop:

Left to Right: (Front Row, kneeling) Georgann Pattillo, Jan Rowe, Bill Schilling ; (Middle Row) Kevin Adams, Linda Moore, Liz Adams, Sue Schilling, Brenda Schilling, Betty Lamey, Patrick Pattillo, Leroy Lamey ; (Back Row) Chandler Burroughs, Steven Rowe, and Bill Schilling, Sr.

The night before the ride, we finished packing up drinks, snacks, and lunches and then headed home to get some sleep. Liz told me that she didn’t sleep a wink that night – neither did I! We were too excited.

The day finally arrived and everything went so well. It was such a wonderful day that I simply didn’t want it to end! Our family and friends came out to cheer us along. It felt great to have them there. But wow! The miles were more difficult than I expected. Although three riders finished far ahead, the remaining three of us dragged ourselves over the finish line some time later. We were quite the motley crew!

Hot, sweaty, hungry, but happy!

Response to our effort was overwhelming. My husband Bill teases that this was the only time I actually picked up the mail! Liz and I were moved by all the contributions. Some were from people who don’t know Linda but had read about the ride in the local paper. When we started planning we weren’t sure how much money we could raise. It was wonderful to have received just over $8,600 in contributions to vasculitis research!

Linda told me how much love she felt because of what we did for The Johns Hopkins Vasculitis Center. What more could I have asked of myself? We wanted to show Linda how proud we were of all she accomplished during her difficult treatment. We also wanted to say thank you to The Johns Hopkins Vasculitis Center for the wonderful work they do in caring for their patients everyday.

Hopefully we accomplished both.

All information contained within the Johns Hopkins Vasculitis Center website is intended for educational purposes only. Visitors are encouraged to consult other sources and confirm the information contained within this site. Consumers should never disregard medical advice or delay in seeking it because of something they may have read on this website.

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.

Granulomatosis with Polyangiitis

Who gets Granulomatosis with Polyangiitis?

Granulomatosis with Polyangiitis is nearly equally distributed between the sexes, with a slight male predominance. Granulomatosis with Polyangiitis typically occurs in middle age, but is found in people of all ages. Although it is unusual for Granulomatosis with Polyangiitis to occur in childhood, it is not unusual for a Granulomatosis with Polyangiitis patient to be in his/her 70s or even 80s at the time of diagnosis.

Pictured below is a chest x–ray showing bilateral lung nodules in a 27 year old Indian man with Granulomatosis with Polyangiitis.

Pictured below is a CT scan from the same patient. The view is a cross–section through the patient’s lungs. The CT scan not only permits a better appreciation of the lesions’ size, it also detects more lesions.

Granulomatosis with Polyangiitis can affect virtually any site in the body, but it has a predisposition for certain organs. The classic organs involved in Granulomatosis with Polyangiitis are the upper respiratory tract (sinuses, nose, ears, and trachea [the “windpipe”]), the lungs, and the kidneys. Listed below are the organs commonly involved in Granulomatosis with Polyangiitis and the specific disease manifestation(s) in each organ.

Ear

Ear infections that are slow to resolve. Recurrent otitis media. Decrease in hearing.

Eye

Inflammation can occur in different parts of the eye. Inflammation in the white part of the eye is known as the sclera (“scleritis”). “Uveitis” is inflammation within the eye. Inflammation behind the eye is known as an “orbital pseudotumor”. An orbital pseudotumor such as those caused by Granulomatosis with Polyangiitis can cause “proptosis”, or protrusion of one eye.

Pictured below is a computed tomography (CAT) scan of the eyes in a patient with a retro–orbital mass (a mass behind the eye) in a man with Granulomatosis with Polyangiitis. Masses such as these sometimes cause an abrupt loss of vision through stretching or compression of the optic nerve, which enters the back of the eye.

Nose

Nasal crusting and frequent nosebleeds can occur. Erosion and perforation of the nasal septum. The bridge of the nose can collapse resulting in a “saddle–nose deformity”. Pictured below is an example of this deformity before and after cosmetic surgery. This resulted from the collapse of the nasal septum caused by cartilage inflammation. This patient has Granulomatosis with Polyangiitis, but an identical lesion may occur in Relapsing Polychondritis.

Sinuses

Chronic sinus inflammation that sometimes leads to a destructive process of tissues around the sinuses.

Trachea

A characteristic respiratory tract complication of Granulomatosis with Polyangiitis: narrowing of the “windpipe” just below the vocal cords, a condition called “subglottic stenosis”. This narrowing, caused by inflammation and scarring, causes difficulty breathing and may, after a subacute progression, necessitate emergency tracheostomy. Pictured below are two figures that show subglottic stenosis before (left) and after (right) surgery, performed by an Ear, Nose, & Throat specialist. The surgery provided dramatic improvement in the patient’s breathing.

Lungs

A pneumonia–like syndrome, with lung “infiltrates“ can be seen on chest x–ray. Bleeding from the lungs can occur.

Kidney

Inflammation can occur in the kidney, leading to small (or rarely, large) amounts of blood and protein in the urine. This condition is called glomerulonephritis. If not treated aggressively, Granulomatosis with Polyangiitis’s involvement of the kidneys can lead to kidney failure. Renal masses can occur, but are very unusual in this disease.

The image below is from a urinalysis of a patient with kidney inflammation. When Granulomatosis with Polyangiitis is active, red blood cells will form a clump or “cast” (bracketed in white) within the tubules of inflamed kidneys. These “casts” pass through the renal system and may be viewed under the microscope in a patient’s urine.

Skin

Granulomatosis with Polyangiitis can cause many kinds of skin rashes. The most common rash occurs in the form of small purple or red dots on the lower extremities (known as “palpable purpura”). Inadequate blood flow to fingers and toes can lead to Raynaud’s phenomenon (extreme sensitivity of the fingers to cold) and even infarctions of the tips of fingers and toes, with the development of gangrene.

Joints

Arthritis can occur, with joint swelling and pain.

Nerves

Peripheral nerve involvement leads to numbness, tingling, shooting pains in the extremities, and sometimes to weakness in a foot, hand, arm, or leg.

Miscellaneous

Granulomatosis with Polyangiitis involvement of nearly all organs has been described, including the meninges (the layers of protective tissue around the brain and spinal cord), the prostate gland, and the genito–urinary tract. In addition to involving specific organs, Granulomatosis with Polyangiitis also commonly results in generalized symptoms of fatigue, low–grade fever, and weight loss.

The cause of Granulomatosis with Polyangiitis is not known. Compared to diseases with obvious genetic predispositions, genetics appear to play a relatively small role in the etiology of Granulomatosis with Polyangiitis . It is very unusual for Granulomatosis with Polyangiitis to occur in two people in the same family. (It is possible, however, that less obvious genetic risk factors exist, e.g. genes that might pre-–dispose a patient to infection with an etiologic organism). For some time, an infection has been suspected of causing (or at least contributing to) Granulomatosis with Polyangiitis , but no specific infection (bacterial, viral, fungal, or other) has been identified.

How is Granulomatosis with Polyangiitis Diagnosed?

Whenever possible, it is important to confirm the diagnosis of Granulomatosis with Polyangiitis by biopsying an involved organ and finding the pathologic features of this disease under the microscope. Because many diseases may mimic Granulomatosis with Polyangiitis (and vice versa), before starting a treatment regimen it is essential to be as certain of the diagnosis as possible. We discuss some of the specific biopsy procedures used to diagnose Granulomatosis with Polyangiitis in the section of this Websie entitled What is Vasculitis: Diagnosis?.

Because Granulomatosis with Polyangiitis so often involves the upper respiratory tract (sinuses, nose, ears, and trachea [“windpipe”]) and because biopsy of these tissues is a relatively non–invasive procedure, these sites are frequently biopsied in patients suspected of Granulomatosis with Polyangiitis . Unfortunately, the yield of biopsies from these sites is rather low: probably less than 50%. Therefore, sometimes more invasive procedures are required to make the diagnosis.

Lung biopsy (either open or thoracoscopic) is often the best way of diagnosing Granulomatosis with Polyangiitis . The ample amount of tissue obtainable through these procedures usually permits confirmation of the Granulomatosis with Polyangiitis diagnosis. Similarly, although the amount of tissue obtained through a kidney biopsy is usually much smaller, the finding of certain pathologic features in the context of a patient’s overall symptoms, signs, and laboratory tests is frequently diagnostic.

Since 1982, when ANCAs (anti–neutrophil cytoplasmic antibodies) were first described, the role of these antibodies in the diagnosis of Granulomatosis with Polyangiitis has grown. ANCA testing, which involves the performance of a simple blood test, has achieved wide availability during the 1990s. This is both good and bad: use of ANCA tests has led to earlier diagnoses and more rapid institution of appropriate treatment in many cases, but has also resulted in misdiagnosis and incorrect treatment when the tests are not performed or interpreted correctly.

As their name implies, ANCAs are directed against the cytoplasm (the non-nucleus part) of white blood cells. Their precise role in the disease process remains uncertain but is a topic of considerable research interest. ANCAs come in two primary forms: 1) the C–ANCA [C stands for cytoplasmic] and, 2) the P–ANCA [P stands for perinuclear]. C–ANCAs have a particularly strong connection to Granulomatosis with Polyangiitis (up to 80% of patients — and possibly more of those with active disease — have these antibodies). When C–ANCAs are present in the blood of a patient whose symptoms or signs suggest Granulomatosis with Polyangiitis , the likelihood of the diagnosis increases considerably. In most cases, however, it is still VERY IMPORTANT to biopsy an involved organ to verify the diagnosis.

Treatment and Course of Granulomatosis with Polyangiitis

Until the 1970s, Granulomatosis with Polyangiitis was nearly always a fatal condition. The use of prednisone and other steroids helped prolong patients’ lives, but most patients eventually succumbed to the disease within a few months or years. The first use of cyclophosphamide in the late 1960s began to change the terrible prognosis of this disease. Using the combination of cyclophosphamide and prednisone, more than 90% of patients with severe disease respond to treatment, and 75% are able to achieve disease remissions. Unfortunately, Granulomatosis with Polyangiitis is a disease in which relapses frequently occur. Approximately half of all patients who achieve disease remissions eventually suffer recurrences (“flares”). Flares of Granulomatosis with Polyangiitis are usually responsive to the same treatment that induced remission, but sometimes intensification of treatment (for example, changing to a more powerful medication) is required.

During the 1990s, physicians have increasingly used the combination of methotrexate and prednisone rather than cyclophosphamide and prednisone for Granulomatosis with Polyangiitis patients who do not have immediately life-threatening disease (particularly disease that does not involve the kidneys severely), because of the frequency of severe side-effects associated with the latter regimen.

Bactrim (or Septra), a combination of two antibiotics (trimethoprim and sulfamethoxazole) may also be helpful in the treatment of Granulomatosis with Polyangiitis , particularly in patients whose disease is limited primarily to the upper respiratory tract. A large, multi-center study demonstrated that Bactrim is useful in preventing flares of Granulomatosis with Polyangiitis in the upper respiratory tract.

What’s New in Granulomatosis with Polyangiitis?

In the past few years, significant advances have been made in understanding Granulomatosis with Polyangiitis , although many important questions remain. In addition to an improved understanding of how to use the currently available medicines for Granulomatosis with Polyangiitis , it is likely that the next few years will witness the development of new medicines for this disease. Scientific breakthroughs may lead to the design of more specific modulators of the immune system that are of great benefit to patients with Granulomatosis with Polyangiitis .

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

A discussion of Granulomatosis with Polyangiitis written in medical terms by David Hellmann, M.D. (F.A.C.P.), 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

Granulomatosis with Polyangiitis is a disease involving granulomatous inflammation, necrosis and vasculitis that most frequently targets the upper respiratory tract, lower respiratory tract, and kidneys. Although Granulomatosis with Polyangiitis can begin at any age, the average age of onset is about 40 years. Other organs frequently affected by Granulomatosis with Polyangiitis granulomatosis include the eye (proptosis and double-vision from retro-orbital pseudotumor, scleritis), skin (ulcers, purpura). or peripheral nerve (mononeuritis multiplex). Granulomatosis with Polyangiitis may be limited to one site for many months or years before disseminating. Systemic symptoms (fever, fatigue, weight loss) are also common. Anemia, mild leukocytosis, and elevated Erythrocyte sedimentation rate (ESR) are nonspecific laboratory findings. Chest radiographs often show infiltrates, nodules, masses, or cavities; only hilar adenopathy is incompatible with the diagnosis of Granulomatosis with Polyangiitis. CT of the chest is more sensitive than chest radiography and can be abnormal when the chest radiograph is negative. Glomerulonephritis causes hematuria, erythrocyte casts, and proteinuria.

A novel group of autoantibodies, ANCAs, helps support the diagnosis of Granulomatosis with Polyangiitis and related forms of vasculitis and gives insight into the pathogenesis of these diseases. ANCAs are directed against enzymes cantained in primary granules of neutrophils and monocytes. Two main types of ANCAs are recognized. The C-ANCAs are directed against serine proteinase 3 and are relatively sensitive and highly specific for Granulomatosis with Polyangiitis. The P-ANCAs are directed against myeloperoxidase and other antigens and are not specific for any single form of vasculitis, but have been seen in some patients with Granulomatosis with Polyangiitis, polyarteritis nodosa, Churg-Strauss vasculitis, and some forms of pauci-immune glomerulonephritis (referred to as microscopic polyarteritis nodosa). Some patients with pulmonary-renal syndromes that may not fit the critieria for Granulomatosis with Polyangiitis are also seropositive for ANCAs. Some patients with inflammatory bowel disease, rheumatoid arthritis, or SLE may have atypical P-ANCA test results, based on the autoantibodies directed against other neutrophil constituents such as lactoferrin.

ANCAs may be not only markers for Granulomatosis with Polyangiitis and related disorders, but they may also be actors in pathogenesis. Studies show that when neutrophils are exposed to cytokines such as tumor necrosis factor, small amounts of serine proteinase and myeloperoxidase, the targets for ANCAs, are expressed on the surface of neutrophils. Adding ANCAs to these cytokine-primed neutrophils causes them to generate oxygen radicals and release enzymes capable of damaging blood vessels.

The diagnosis of Granulomatosis with Polyangiitis is established most securely by biopsy specimens showing the triad of vasculitis, granulomata, and large areas of necrosis (known as geographic necrosis) admixed with acute and chronic inflammatory cells. Only large sections of lung tissue obtained via thoracoscopic or open lung biopsy are likely to show all of the histologic features. However, more easily obtained biopsy specimens of the nose, or sinuses may show several of the changes that are highly suggestive of Granulomatosis with Polyangiitis. Such a biopsy specimen combined with a compatible clinical picture and seropositivity for C-ANCAs should suffice to secure the diagnosis. Seropositivity for C-ANCAs alone is not specific enough to establish the diagnosis of Granulomatosis with Polyangiitis.

Untreated Granulomatosis with Polyangiitis is fatal. Prednisone may slow progression of the disease but by itself is insufficient to arrest the disease. Respiratory tract disease usually progresses slowly, but renal disease can progress rapidly and therefore warrants urgent evaluation and treatment. With the traditional treatment of prednisone (initiated at 1 mg/kg daily for 1 to 2 months. then tapered) and cyclophosphamide (2mg/kg daily for at least 12 months), more than 90% of patients improve and 75% remit. However, 50% of the patients who later remit also relapse, and oral daily cyclophosphamide causes serious toxicity. Short-term toxicity includes cytopenia, infection, and hemorrhagic cystitis. Long-term use of cyclophosphamide in patients with Granulomatosis with Polyangiitis more than doubles the risk of cancer overall, increases the risk of bladder cancer 33-fold and the risk of lymphoma 11-fold. Monthly intravenous cyclophosphamide appears less toxic but also less effective. Weekly, methotrexate appears to be an effective alternative for Granulomatosis with Polyangiitis that is not immediately life-threatening, and it also appears to be beneficial in maintaining remission. The role of trimethoprim-sulfamethoxazole in treating active disease is controversial, with some finding it effective for Granulomatosis with Polyangiitis limited to the respiratory tract, and others not. In patients who have achieved remission, trimethoprim-sulfamethoxazole reduces the relapse rate.