Churg-Strauss Syndrome
Definition
Churg-Strauss syndrome, also referred to as allergic angiitis and granulomatosis, was described in 1951 by Churg and Strauss and is characterized by asthma, peripheral and tissue eosinophilia, extravascular granuloma formation, and vasculitis of multiple organ systems.
Incidence and Prevalence
Churg-Strauss syndrome is an uncommon disease with an estimated annual incidence of 1-3 per million. The disease can occur at any age with the possible exception of infants. The mean age of onset is 48 years, with a female-to-male ratio of 1.2:1.
Pathology and Pathogenesis
The necrotizing vasculitis of Churg-Strauss syndrome involves small- and medium-sized muscular arteries, capillaries, veins, and venules. A characteristic histopathologic feature of Churg-Strauss syndrome is granulomatous reactions that may be present in the tissues or even within the walls of the vessels themselves. These are usually associated with infiltration of the tissues with eosinophils.This process can occur in any organ in the body; lung involvement is predominant, with skin, cardiovascular system, kidney, peripheral nervous system, and gastrointestinal tract also commonly involved. Although the precise pathogenesis of this disease is uncertain, its strong association with asthma and its clinicopathologic manifestations, including eosinophilia, granuloma, and vasculitis, point to aberrant immunologic phenomena.
Clinical and Laboratory Manifestations
Patients with Churg-Strauss syndrome often exhibit nonspecific manifestations such as fever, malaise, anorexia, and weight loss, which are characteristic of a multisystem disease. The pulmonary findings in Churg-Strauss syndrome clearly dominate the clinical picture with severe asthmatic attacks and the presence of pulmonary infiltrates. Mononeuritis multiplex is the second most common manifestation and occurs in up to 72% of patients.Aller-gic rhinitis and sinusitis develop in up to 61% of patients and are often observed early in the course of disease. Clinically recognizable heart disease occurs in ~14% of patients and is an important cause of mortality. Skin lesions occur in ~51% of patients and include purpura in addition to cutaneous and subcutaneous nodules. The renal disease in Churg-Strauss syndrome is less common and generally less severe than that of Wegener’s granulomatosis and microscopic polyangiitis.
The characteristic laboratory finding in virtually all patients with Churg-Strauss syndrome is a striking eosino-philia, which reaches levels >1000 cells^L in >80% of patients. Evidence of inflammation as evidenced by elevated ESR, fibrinogen, or α2-globulins can be found in 81% of patients. The other laboratory findings reflect the organ systems involved. Approximately 48% of patients with Churg-Strauss syndrome have circulating ANCA that is usually antimyeloperoxidase.
Diagnosis
Although the diagnosis of Churg-Strauss syndrome is optimally made by biopsy in a patient with the characteristic clinical manifestations (see above), histologic confirmation can be challenging as the pathognomonic features often do not occur simultaneously. In order to be diagnosed with Churg-Strauss syndrome, a patient should have evidence of asthma, peripheral blood eosinophilia, and clinical features consistent with vasculitis.
Treatment:
Churg-Strauss Syndrome
The prognosis of untreated Churg-Strauss syndrome is poor, with a reported 5-year survival of 25%.With treatment, prognosis is favorable, with one study finding a 78-month actuarial survival rate of 72%. Myocardial involvement is the most frequent cause of death and is responsible for 39% of patient mortality. Glucocorticoids alone appear to be effective in many patients. Dosage tapering is often limited by asthma, and many patients require low-dose prednisone for persistent asthma many years after clinical recovery from vasculitis. In glucocorticoid failure or in patients who present with fulminant multisystem disease, the treatment of choice is a combined regimen of daily cyclophosphamide and prednisone (see "Wegener’s Granulomatosis"for a detailed description of this therapeutic regimen).
Polyarteritis Nodisa
Definition
PAN, also referred to as classic PAN, was described in 1866 by Kussmaul and Maier. It is a multisystem, necrotizing vasculitis of small- and medium-sized muscular arteries in which involvement of the renal and visceral arteries is characteristic. PAN does not involve pulmonary arteries, although bronchial vessels may be involved; granulomas, significant eosinophilia, and an allergic diathesis are not observed.
Incidence and Prevalence
It is difficult to establish an accurate incidence of PAN because previous reports have included PAN and microscopic polyangiitis as well as other related vasculitides. PAN, as currently defined, is felt to be a very uncommon disease.
Pathology and Pathogenesis
The vascular lesion in PAN is a necrotizing inflammation of small- and medium-sized muscular arteries. The lesions are segmental and tend to involve bifurcations and branchings of arteries. They may spread circumferentially to involve adjacent veins. However, involvement of venules is not seen in PAN and, if present, suggests microscopic polyangiitis (see below). In the acute stages of disease, polymorphonuclear neutrophils infiltrate all layers of the vessel wall and perivascular areas, which results in intimal proliferation and degeneration of the vessel wall. Mononuclear cells infiltrate the area as the lesions progress to the subacute and chronic stages. Fibrinoid necrosis of the vessels ensues with compromise of the lumen, thrombosis, infarction of the tissues supplied by the involved vessel, and, in some cases, hemorrhage. As the lesions heal, there is collagen deposition, which may lead to further occlusion of the vessel lumen. Aneurysmal dilatations up to 1 cm in size along the involved arteries are characteristic of PAN. Granulomas and substantial eosinophilia with eosinophilic tissue infiltrations are not characteristically found and suggest Churg-Strauss syndrome (see above).
Multiple organ systems are involved, and the clinico-pathologic findings reflect the degree and location of vessel involvement and the resulting ischemic changes. As mentioned above, pulmonary arteries are not involved in PAN, and bronchial artery involvement is uncommon. The pathology in the kidney in classic PAN is that of arteritis without glomerulonephritis. In patients with significant hypertension, typical pathologic features of glomerulosclerosis may be seen. In addition, pathologic sequelae of hypertension may be found elsewhere in the body.
The presence of hepatitis B antigenemia in ~10-30% of patients with systemic vasculitis, particularly of the PAN type, together with the isolation of circulating immune complexes composed of hepatitis B antigen and immunoglobulin, and the demonstration by immunofluorescence of hepatitis B antigen, IgM, and complement in the blood vessel walls, strongly suggest the role of immunologic phenomena in the pathogenesis of this disease. Hairy cell leukemia can be associated with PAN; the pathogenic mechanisms of this association are unclear.
Clinical and Laboratory Manifestations
Nonspecific signs and symptoms are the hallmarks of PAN. Fever, weight loss, and malaise are present in over one-half of cases. Patients usually present with vague symptoms such as weakness, malaise, headache, abdominal pain, and myalgias that can rapidly progress to a fulminant illness. Specific complaints related to the vascular involvement within a particular organ system may also dominate the presenting clinical picture as well as the entire course of the illness (Table 10-5). In PAN, renal involvement most commonly manifests as hypertension, renal insufficiency, or hemorrhage due to microaneurysms.
There are no diagnostic serologic tests for PAN. In >75% of patients, the leukocyte count is elevated with a predominance of neutrophils. Eosinophilia is seen only rarely and, when present at high levels, suggests the diagnosis of Churg-Strauss syndrome. The anemia of chronic disease may be seen, and an elevated ESR is almost always present. Other common laboratory findings reflect the particular organ involved. Hypergammaglobulinemia may be present, and up to 30% of patients have a positive test for hepatitis B surface antigen. Antibodies against myeloperoxidase or proteinase-3 (ANCA) are rarely found in patients with PAN.
TABLE 10-5
CLINICAL MANIFESTATIONS RELATED TO ORGAN SYSTEM INVOLVEMENT IN CLASSIC POLYARTERITIS NODOSA
|
ORGAN SYSTEM |
PERCENT INCIDENCE |
CLINICAL MANIFESTATIONS |
|
Renal |
60 |
Renal failure, hypertension |
|
Musculoskeletal |
64 |
Arthritis, arthralgia, myalgia |
|
Peripheral nervous system |
51 |
Peripheral neuropathy, mononeuritis multiplex |
|
Gastrointestinal tract |
44 |
Abdominal pain, nausea and vomiting, bleeding, bowel infarction and perforation, cholecystitis, hepatic infarction, pancreatic infarction |
|
Skin |
43 |
Rash, purpura, nodules, cutaneous infarcts, livedo reticularis, Raynaud’s phenomenon |
|
Cardiac |
36 |
Congestive heart failure, myocardial infarction, pericarditis |
|
Genitourinary |
25 |
Testicular, ovarian, or epididymal pain |
|
Central nervous system |
23 |
Cerebral vascular accident, altered mental status, seizure |
Diagnosis
The diagnosis of PAN is based on the demonstration of characteristic findings of vasculitis on biopsy material of involved organs. In the absence of easily accessible tissue for biopsy, the angiographic demonstration of involved vessels, particularly in the form of aneurysms of small-and medium-sized arteries in the renal, hepatic, and visceral vasculature, is sufficient to make the diagnosis. Aneurysms of vessels are not pathognomonic of PAN; furthermore, aneurysms need not always be present, and angiographic findings may be limited to stenotic segments and obliteration of vessels. Biopsy of symptomatic organs such as nodular skin lesions, painful testes, and nerve/muscle provides the highest diagnostic yields.
Treatment:
POLYARTERITIS NODOSA
The prognosis of untreated PAN is extremely poor, with a reported 5-year survival rate between 10 and 20%. Death usually results from gastrointestinal complications, particularly bowel infarcts and perforation, and cardiovascular causes. Intractable hypertension often compounds dysfunction in other organ systems, such as the kidneys, heart, and CNS, leading to additional late morbidity and mortality in PAN. With the introduction of treatment, survival rate has increased substantially. Favorable therapeutic results have been reported in
PAN with the combination of prednisone and cyclophosphamide (see "Wegener’s Granulomatosis"for a detailed description of this therapeutic regimen). In less severe cases of PAN,glucocorticoids alone have resulted in disease remission. Favorable results have also been reported in the treatment of PAN related to hepatitis B virus with antiviral therapy in combination with glucocorticoids and plasma exchange.Careful attention to the treatment of hypertension can lessen the acute and late morbidity and mortality associated with renal, cardiac, and CNS complications of PAN. Following successful treatment, relapse of PAN has been estimated to occur in only 10% of patients.
Microscopic Polyangiitis
Definition
The term microscopic polyarteritis was introduced into the literature by Davson in 1948 in recognition of the presence of glomerulonephritis in patients with PAN. In 1992, the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis adopted the term microscopic polyangiitis to connote a necrotizing vasculitis with few or no immune complexes affecting small vessels (capillaries, venules, or arterioles). Glomerulonephritis is very common in microscopic polyangiitis, and pulmonary capillaritis often occurs. The absence of granulomatous inflammation in microscopic polyangiitis is said to differentiate it from Wegener’s granulomatosis.
Incidence and Prevalence
The incidence ofmicroscopic polyangiitis has not yet been reliably established due to its previous inclusion as part of PAN.The mean age of onset is ~57 years of age, and males are slightly more frequently affected than females.
Pathology and Pathogenesis
The vascular lesion in microscopic polyangiitis is histologically similar to that in PAN. Unlike PAN, the vasculitis seen in microscopic polyangiitis has a predilection to involve capillaries and venules in addition to small- and medium-sized arteries. Immunohistochemical staining reveals a paucity of immunoglobulin deposition in the vascular lesion of microscopic polyangiitis, suggesting that immune complex formation does not play a role in the pathogenesis of this syndrome. The renal lesion seen in microscopic polyangiitis is identical to that of Wegener’s granulomatosis. Like Wegener’s granulomatosis, microscopic polyangiitis is highly associated with the presence of ANCA, which may play a role in pathogenesis of this syndrome (see above).
Clinical and Laboratory Manifestations
Because of its predilection to involve the small vessels, microscopic polyangiitis and Wegener’s granulomatosis share similar clinical features. Disease onset may be gradual with initial symptoms of fever, weight loss, and musculoskeletal pain; however, it is often acute. Glomerulonephritis occurs in at least 79% of patients and can be rapidly progressive, leading to renal failure. Hemoptysis may be the first symptom of alveolar hemorrhage, which occurs in 12% of patients. Other manifestations include mononeuritis multiplex and gastrointestinal tract and cutaneous vasculitis. Upper airways disease and pulmonary nodules are not typically found in microscopic polyangiitis and,if present, suggest Wegener’s granulomatosis.
Features of inflammation may be seen, including an elevated ESR, anemia, leukocytosis, and thrombocytosis. ANCA are present in 75% of patients with microscopic polyangiitis, with antimyeloperoxidase antibodies being the predominant ANCA associated with this disease.
Diagnosis
The diagnosis is based on histologic evidence of vasculitis or pauci-immune glomerulonephritis in a patient with compatible clinical features of multisystem disease. Although microscopic polyangiitis is strongly ANCA-associated, no studies have as yet established the sensitivity and specificity of ANCA in this disease.
Treatment:
Microscopic Polyangiitis
The 5-year survival rate for patients with treated microscopic polyangiitis is 74%, with disease-related mortality occurring from alveolar hemorrhage or gastrointestinal, cardiac, or renal disease.To date there has been limited disease-specific information on the treatment of microscopic polyangiitis.Available data together with a predilection for this disease to affect the small vessels support a therapeutic approach similar to that used in Wegener’s granulomatosis. Patients with immediately life-threatening disease should be treated with the combination of prednisone and cyclophosphamide (see "Wegener’s Granulomatosis"for a detailed description of this therapeutic regimen). Disease relapse has been observed in at least 34% of patients.Treatment for such relapses would be similar to that used at the time of initial presentation and based upon site and severity of disease.
Giant Cell Arteritis and Polymyalgia Rheumatica
Definition
Giant cell arteritis, also referred to as cranial arteritis or temporal arteritis, is an inflammation of medium- and largesized arteries. It characteristically involves one or more branches of the carotid artery, particularly the temporal artery. However, it is a systemic disease that can involve arteries in multiple locations, particularly the aorta and its main branches.
Giant cell arteritis is closely associated with polymyalgia rheumatica, which is characterized by stiffness, aching, and pain in the muscles of the neck, shoulders, lower back, hips, and thighs. Most commonly, polymyalgia rheumatica occurs in isolation, but it may be seen in 40-50% ofpatients with giant cell arteritis. In addition,~10-20% of patients who initially present with features of isolated polymyalgia rheumatica later go on to develop giant cell arteritis. This strong clinical association together with data from pathophysiologic studies has increasingly supported that giant cell arteritis and polymyalgia rheumatica represent differing clinical spectrums of a single disease process.
Incidence and Prevalence
Giant cell arteritis occurs almost exclusively in individuals >50 years. It is more common in women than in men and is rare in blacks. The incidence of giant cell arteritis varies widely in different studies and in different geographic regions. A high incidence has been found in Scandinavia and in regions of the United States with large Scandinavian populations, compared to a lower incidence in southern Europe. The annual incidence rates in individuals ^50 years range from 6.9-32.8 per 100,000 population. Familial aggregation has been reported, as has an association with HLA-DR4. In addition, genetic linkage studies have demonstrated an association of giant cell arteritis with alleles at the HLA-DRB1 locus, particularly HLA-DRB1*04 variants. In Olmsted County, Minnesota, the annual incidence of polymyalgia rheumatica in individuals ^50 years is 58.7 per 100,000 population.
Pathology and Pathogenesis
Although the temporal artery is most frequently involved in giant cell arteritis, patients often have a systemic vasculitis of multiple medium- and large-sized arteries, which may go undetected. Histopathologically, the disease is a panarteritis with inflammatory mononuclear cell infiltrates within the vessel wall with frequent giant cell formation. There is proliferation of the intima and fragmentation of the internal elastic lamina. Pathophysiologic findings in organs result from the ischemia related to the involved vessels.
Experimental data support that giant cell arteritis is an antigen-driven disease in which activated T lymphocytes, macrophages, and dendritic cells play a critical role in the disease pathogenesis. Sequence analysis of the T cell receptor of tissue-infiltrating T cells in lesions of giant cell arteritis indicates restricted clonal expansion, suggesting the presence of an antigen residing in the arterial wall. Giant cell arteritis is believed to be initiated in the adventitia where CD4+ T cells become activated and orchestrate macrophage differentiation. T cells recruited to vasculitic lesions in patients with giant cell arteritis produce predominantly IL-2 and IFN-γ, and the latter has been suggested to be involved in the progression to overt arteritis.
Clinical and Laboratory Manifestations
Giant cell arteritis is characterized clinically by the complex of fever, anemia, high ESR, and headaches in a patient over the age of 50 years. Other manifestations include malaise, fatigue, anorexia, weight loss, sweats, arthralgias, and associated polymyalgia rheumatica.
In patients with involvement of the temporal artery, headache is the predominant symptom and may be associated with a tender, thickened, or nodular artery, which may pulsate early in the disease but may become occluded later. Scalp pain and claudication of the jaw and tongue may occur. A well-recognized and dreaded complication of giant cell arteritis, particularly in untreated patients, is ischemic optic neuropathy, which may lead to serious visual symptoms, even sudden blindness in some patients. However, most patients have complaints relating to the head or eyes before visual loss. Attention to such symptoms with institution of appropriate therapy (see below) will usually avoid this complication. Claudication of the extremities, strokes, myocardial infarctions, and infarctions of visceral organs have been reported. Of note, giant cell arteritis is associated with an increased risk of aortic aneurysm, which is usually a late complication and may lead to dissection and death.
Characteristic laboratory findings in addition to the elevated ESR include a normochromic or slightly hypochromic anemia. Liver function abnormalities are common, particularly increased alkaline phosphatase levels. Increased levels of IgG and complement have been reported. Levels of enzymes indicative of muscle damage such as serum creatine kinase are not elevated.
Diagnosis
The diagnosis of giant cell arteritis and its associated clini-copathologic syndrome can often be suggested clinically by the demonstration of the complex of fever, anemia, and high ESR with or without symptoms of polymyalgia rheumatica in a patient >50 years. The diagnosis is confirmed by biopsy of the temporal artery. Since involvement of the vessel may be segmental, positive yield is increased by obtaining a biopsy segment of 3-5 cm together with serial sectioning of biopsy specimens. Ultrasonography of the temporal artery has been reported to be helpful in diagnosis. A temporal artery biopsy should be obtained as quickly as possible in the setting of ocular signs and symptoms, and under these circumstances therapy should not be delayed pending a biopsy. In this regard, it has been reported that temporal artery biopsies may show vasculitis even after ~14 days of glucocorticoid therapy. A dramatic clinical response to a trial of glucocorticoid therapy can further support the diagnosis.
Isolated polymyalgia rheumatica is a clinical diagnosis made by the presence of typical symptoms of stiffness, aching, and pain in the muscles of the hip and shoulder girdle, an increased ESR, the absence of clinical features suggestive of giant cell arteritis, and a prompt therapeutic response to low dose prednisone.
Treatment:
Giant Cell Arteritis and Polymyalgia Rheumatica
Disease-related mortality from giant cell arteritis is very uncommon with fatalities occurring from cerebrovascular events, myocardial infarction, or aortic aneurysm rupture.
The goals of treatment in giant cell arteritis are to reduce symptoms and, most importantly, to prevent visual loss. Giant cell arteritis and its associated symptoms are exquisitely sensitive to glucocorticoid therapy. Treatment should begin with prednisone, 40-60 mg/d for ~1 month, followed by a gradual tapering. When ocular signs and symptoms occur, it is important that therapy be initiated or adjusted to control them. Although the optimal duration of glucocorticoid therapy has not been established, most series have found that patients require treatment for >2 years. Symptom recurrence during prednisone tapering develops in 60-85% of patients with giant cell arteritis, requiring a dosage increase.The ESR can serve as a useful indicator of inflammatory disease activity in monitoring and tapering therapy and can be used to judge the pace of the tapering schedule. However, minor increases in the ESR can occur as glucocorticoids are being tapered and do not necessarily reflect an exacerbation of arteritis, particularly if the patient remains symptom-free. Under these circumstances,the tapering should continue with caution. Glucocorticoid toxicity occurs in 35-65% of patients and represents an important cause of patient morbidity. Aspirin has been found to reduce the occurrence of cranial ischemic complications in giant cell arteritis and should be given in addition to glucocorticoids in patients who do not have contraindications. The use of weekly methotrexate as a glucocorticoid-sparing agent has been examined in two randomized placebo-controlled trials that reached conflicting conclusions. In two randomized trials, infliximab was found to provide no benefit and had a higher rate of infection in patients with giant cell arteritis and in polymyalgia rheumatica.
Patients with isolated polymyalgia rheumatica respond promptly to prednisone,which can be started at a lower dose of 10-20 mg/d. Similar to giant cell arteritis,the ESR can serve as a useful indicator in monitoring and prednisone reduction. Recurrent polymyalgia symptoms develop in the majority of patients during prednisone tapering. One study of weekly methotrexate found that the use of this drug reduced the prednisone dose on average by only 1 mg and did not decrease prednisone-related side effects.
