Vasculitis Causes, Symptoms, Treatment

Cutaneous Leukocytoclastic Angiitis

Small-vessel vasculitis may be confined to the skin. The characteristic acute lesion is leukocytoclastic angiitis involving dermal postcapillary venules. This lesion is histologically identical to dermal lesions occurring as a component of systemic small-vessel vasculitis. Therefore, the onus is on the physician to rule out systemic disease.

• Drug-induced vasculitis should be considered in any patient with small-vessel vasculitis and will be substantiated most often in patients with vasculitis confined to the skin. Drugs cause approximately 10 percent of vasculitic skin lesions. Drug-induced vasculitis usually develops within 7 to 21 days after treatment begins.
• Drugs that have been implicated include penicillins, aminopenicillins, sulfonamides, allopurinol, thiazides, pyrazolones, retinoids, quinolones, hydantoins, and propylthiouracil. Some drugs, such as penicillins, cause vasculitis by conjugating to serum proteins and mediating immune-complex vasculitis that is similar to serum-sickness vasculitis. Other vasculitis-inducing drugs that cause immune-complex formation are foreign proteins, such as streptokinase, cytokines, and monoclonal antibodies. In addition, such drugs as propylthiouracil and hydralazine appear to cause vasculitis by inducing ANCA, although a cause-and-effect relationship has not been proved.
• Most patients with cutaneous leukocytoclastic angiitis have a single episode that resolves spontaneously within several weeks or a few months. Approximately 10 percent will have the recurrent disease at intervals of months to years. In the absence of systemic disease, management is usually symptomatic. Drugs that could cause the disease should be stopped. Antihistamines and nonsteroidal antiinflammatory drugs help alleviate cutaneous discomfort and reduce associated arthralgias and myalgias. The severe cutaneous disease may warrant oral corticosteroid therapy. If signs or symptoms of systemic vasculitis develop, treatment should be based on the type of systemic vasculitis the patient has.

Cryoglobulinemic Vasculitis

Cryoglobulinemic vasculitis is caused by the localization of mixed cryoglobulins in vessel walls, which incites acute inflammation. Venules, capillaries, and arterioles are preferentially involved.

• Patients with this disease have an average age of approximately 50 years. The most frequent manifestations are purpura, arthralgias, and nephritis. Mixed cryoglobulins and rheumatoid-factor activity are typically detectable in serum. Most patients have an associated infection with hepatitis C virus, which is thought to be etiologic. A very distinctive and diagnostically useful complement abnormality is the presence of very low levels of early components (especially C4) with normal or slightly low C3 levels. As with Henoch–Schönlein purpura, the main cause of morbidity is progressive glomerulonephritis, which most often has a type I membranoproliferative phenotype.
• Mild disease, such as slight purpura and arthralgias, usually is adequately treated with nonsteroidal anti-inflammatory drugs alone. Serious visceral involvement, such as in glomerulonephritis, usually requires treatment with corticosteroids combined with a cytotoxic drug (e.g., cyclophosphamide), which improves the outcome of glomerulonephritis and also ameliorates purpura, arthralgias, and other vasculitic symptoms. Plasmapheresis has been used, but its value is unproven. Recently, interferon alfa has been touted as a beneficial adjuvant in patients with cryoglobulinemic vasculitis associated with hepatitis C virus infection, but larger controlled trials are required before the value of this approach can be conclusively determined.

Anca-Associated Small-Vessel Vasculitis

• ANCA-associated small-vessel vasculitis is the most common primary systemic small-vessel vasculitis in adults and includes three major categories: Wegener’s granulomatosis, microscopic polyangiitis, and Churg–Strauss syndrome. These histologically identical small-vessel vasculitides preferentially involve venules, capillaries, and arterioles, and may also involve arteries and veins  Wegener’s granulomatosis is differentiated from the other two by the presence of necrotizing granulomatous inflammation in the absence of asthma; Churg–Strauss syndrome is differentiated by the presence of asthma, eosinophilia, and necrotizing granulomatous inflammation; and microscopic polyangiitis is differentiated by the absence of granulomatous inflammation and asthma. Rapid diagnosis of ANCA-associated small-vessel vasculitis is critically important because life-threatening injury to organs often develops quickly and is mitigated dramatically by immunosuppressive treatment.
• ANCA-associated small-vessel vasculitis affects people of all ages but is most common in older adults in their 50s and 60s, and it affects men and women equally. In the United States, the disease is more frequent among whites than blacks. Its incidence is approximately 2 in 100,000 people in the United Kingdom and approximately 1 in 100,000 in Sweden. Although Wegener’s granulomatosis, microscopic polyangiitis, and Churg–Strauss syndrome are categorized as ANCA-associated small-vessel vasculitis, it is important to realize that a minority of patients with typical clinical and pathological features of these diseases are ANCA-negative.

Wegener’s granulomatosis 

• Over 90 percent of patients with Wegener’s granulomatosis have upper or lower respiratory tract disease or both. Manifestations of upper respiratory tract disease include sinus pain, purulent sinus drainage, nasal mucosal ulceration with epistaxis, and otitis media. More serious complications include necrosis of the nasal septum with perforation or saddle-nose deformation and injury to the facial nerve by otitis media resulting in facial paralysis. Tracheal inflammation and sclerosis, often in the subglottic region, cause stridor and may lead to dangerous airway stenosis, which occurs in approximately 15 percent of adults and almost 50 percent of children with this disease. A minority of patients initially have indolent or aggressive upper respiratory tract disease alone, but most also have pulmonary disease.
• Necrotizing granulomatous pulmonary inflammation produces nodular radiographic densities, whereas alveolar capillaritis causes pulmonary hemorrhage with less fixed and more irregular infiltrates. Massive pulmonary hemorrhage caused by capillaritis is the most life-threatening manifestation of ANCA-associated small-vessel vasculitis and warrants rapid institution of aggressive immunosuppressive therapy.
• Approximately 80 percent of patients with Wegener’s granulomatosis will go on to have glomerulonephritis, although less than 20 percent have nephritis at the time of presentation. The glomerulonephritis is characterized by focal necrosis, crescent formation, and the absence or paucity of immunoglobulin deposits. An identical pauci-immune necrotizing and crescentic glomerulonephritis occurs in patients with microscopic polyangiitis and Churg–Strauss syndrome, and also occurs as a disease limited to the kidneys. Other manifestations of the disease include ocular inflammation, cutaneous purpura and nodules, peripheral neuropathy, arthritis, and diverse abdominal visceral involvement.
• The classic triad of respiratory tract granulomatous inflammation, systemic small-vessel vasculitis, and necrotizing glomerulonephritis readily suggests the diagnosis, but atypical presentations, such as isolated subglottic stenosis or orbital pseudotumor, may not. In patients with the latter presentation, a positive ANCA test is helpful for substantiating a diagnosis of Wegener’s granulomatosis.
• Treatment of aggressive Wegener’s granulomatosis, as well as of microscopic polyangiitis, has three phases: induction of remission, maintenance of remission, and treatment of relapse. After the seminal observations of Novack and Pearson, Fauci and his associates documented the value of cyclophosphamide in the treatment of Wegener’s granulomatosis. Current induction therapy often uses cyclophosphamide combined with corticosteroids. Corticosteroids alone may be adequate for ameliorating indolent limited disease but are inadequate for patients with the generalized disease.
• In patients with Wegener’s granulomatosis or microscopic polyangiitis who have aggressive diseases, such as acute nephritis or pulmonary hemorrhage, we recommend induction with intravenous methylprednisolone at a dose of 7 mg per kilogram of body weight per day for three days, followed by tapering doses of prednisone. This treatment is combined with oral cyclophosphamide at 2 mg per kilogram per day, or intravenous cyclophosphamide at 0.5 g per square meter of body-surface area per month, adjusted upward to 1 g per square meter on the basis of the patient’s leukocyte count. Combined therapy with corticosteroids and cyclophosphamide induces improvement in over 90 percent of patients with Wegener’s granulomatosis and complete remission in 75 percent. A common strategy is to discontinue corticosteroids after remission is achieved, usually within 3 to 5 months, and to continue cyclophosphamide for 6 to 12 months. An alternative strategy for maintaining remission is a conversion from cyclophosphamide to azathioprine once remission is achieved. Approximately 50 percent of patients with Wegener’s granulomatosis have at least one relapse within five years. The best treatment for reversing relapses is controversial but usually involves reinstituting treatment similar to the induction regimen.
• Both corticosteroids and cyclophosphamide predispose patients to life-threatening infections, and cyclophosphamide causes hemorrhagic cystitis, ovarian and testicular failure, and cancer. For example, Talar-Williams et al. have estimated the incidence of bladder cancer after the first exposure to cyclophosphamide to be 5 percent 10 years after treatment and 16 percent after 15 years. The risks and benefits of aggressive immunosuppression must be assessed in each patient, and the treatment tailored accordingly. There should be vigilance for and prompt treatment of complications arising from treatment.
• Less-toxic therapy may be sufficient in patients with localized or mild Wegener’s granulomatosis. For example, Sneller et al. achieved remission with low-dose methotrexate plus prednisone in 71 percent of patients with Wegener’s granulomatosis that was “not immediately life-threatening.” Methotrexate also may be useful for maintenance of remission. Treatment with methotrexate is limited in patients with renal disease because of increased toxicity.

Because relapses are associated with respiratory tract infections and with chronic nasal carriage of Staphylococcus aureus, the antimicrobial agent trimethoprim-sulfamethoxazole has been evaluated for maintenance of remission, with mixed results. Stegeman et al. concluded that it is useful for maintaining remission, but de Groot et al. did not agree.

Microscopic polyangiitis

• Microscopic polyangiitis is characterized by pauses-immune necrotizing small-vessel vasculitis without clinical or pathological evidence of necrotizing granulomatous inflammation. Over 80 percent of patients with microscopic polyangiitis have ANCA, most often perinuclear ANCA (MPO-ANCA). This helps distinguish microscopic polyangiitis from ANCA-negative small-vessel vasculitis but does not distinguish microscopic polyangiitis from other types of disease associated with ANCA. Positive ANCA and negative serologic tests for hepatitis B help differentiate microscopic polyangiitis from polyarteritis nodosa.
• Pathologically, microscopic polyangiitis may cause necrotizing arteritis that is histologically identical to that caused by polyarteritis nodosa. By the approach advocated by the Chapel Hill Consensus Conference polyarteritis nodosa and microscopic polyangiitis are distinguished pathologically by the absence of vasculitis in vessels other than arteries in polyarteritis nodosa and the presence of vasculitis in vessels smaller than arteries (i.e., arterioles, venules, and capillaries) in microscopic polyangiitis. According to this definition, the presence of dermal leukocytoclastic venulitis, glomerulonephritis, pulmonary alveolar capillaritis, or vasculitis in any vessel smaller than an artery would exclude a diagnosis of polyarteritis nodosa and indicate some form of small-vessel vasculitis. On the other hand, identification of necrotizing arteritis in a skeletal-muscle biopsy or peripheral-nerve biopsy, for example, indicates some form of necrotizing vasculitis but is not diagnostic of polyarteritis nodosa, because many other necrotizing vasculitides, such as microscopic polyangiitis, Wegener’s granulomatosis, and Churg–Strauss syndrome, can also affect arteries
• Microscopic polyangiitis has the same spectrum of manifestations of small-vessel vasculitis as Wegener’s granulomatosis but does not include granulomatous inflammation. Approximately 90 percent of patients have glomerulonephritis, which is accompanied by a variety of other organ involvements. Microscopic polyangiitis is the most common cause of the pulmonary–renal syndrome.
• Microscopic polyangiitis that is causing major organ damage is treated with a combination of corticosteroids and cytotoxic agents. Our treatment approach is the same as that for aggressive Wegener’s granulomatosis, which was described earlier in this review, and uses intravenous methylprednisolone followed by prednisone combined with intravenous or oral cyclophosphamide. Alveolar capillaritis with pulmonary hemorrhage is the most life-threatening complication and should be treated promptly with combined therapy, and possibly with plasmapheresis. The glomerulonephritis is usually rapidly progressive if not promptly and appropriately treated with a combination of high-dose corticosteroids and cyclophosphamide, which induces remission in approximately 80 percent of patients. The greatest risk factor for a poor renal outcome is a delay in treatment until renal insufficiency has developed. Relapse occurs in about a third of patients within two years. Approximately two-thirds of patients who relapse respond to an immunosuppressive regimen similar to the induction therapy.

Because the treatment of microscopic polyangiitis and Wegener’s granulomatosis is essentially the same when there is major organ injury, it is not necessary to distinguish conclusively between these closely related variants of ANCA-associated small-vessel vasculitis before starting treatment. For example, an ANCA-positive patient with pulmonary infiltrates, hemoptysis, and pauci-immune crescentic glomerulonephritis on renal biopsy may have either microscopic polyangiitis or Wegener’s granulomatosis. Resolving this differential diagnosis should not delay the start of induction therapy with combined corticosteroids and cyclophosphamide.

Churg–Strauss syndrome

• Churg–Strauss syndrome has three phases: allergic rhinitis and asthma; eosinophilic infiltrative disease, such as eosinophilic pneumonia or gastroenteritis; and systemic small-vessel vasculitis with granulomatous inflammation. The vasculitic phase usually develops within three years of the onset of asthma, although it may be delayed for several decades. Approximately 70 percent of patients with this disease have ANCA, usually perinuclear ANCA (MPO-ANCA). Virtually all patients have eosinophilia (more than 10 percent eosinophils in the blood).

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