Takayasu’s Arteritis
Definition
Takayasu’s arteritis is an inflammatory and stenotic disease of medium- and large-sized arteries characterized by a strong predilection for the aortic arch and its branches. For this reason, it is often referred to as the aortic arch syndrome.
Incidence and Prevalence
Takayasu’s arteritis is an uncommon disease with an estimated annual incidence rate of 1.2-2.6 cases per million. It is most prevalent in adolescent girls and young women. Although it is more common in Asia, it is neither racially nor geographically restricted.
Pathology and Pathogenesis
The disease involves medium- and large-sized arteries, with a strong predilection for the aortic arch and its branches; the pulmonary artery may also be involved. The most commonly affected arteries seen by angiography are listed in Table 10-6. The involvement of the major branches of the aorta is much more marked at their origin than distally. The disease is a panarteritis with inflammatory mononuclear cell infiltrates and occasionally giant cells. There are marked intimal proliferation and fibrosis, scarring and vascularization of the media, and disruption and degeneration of the elastic lamina. Narrowing of the lumen occurs with or without thrombosis. The vasa vasorum are frequently involved. Pathologic changes in various organs reflect the compromise of blood flow through the involved vessels.
Immunopathogenic mechanisms, the precise nature of which is uncertain, are suspected in this disease. As with several of the vasculitis syndromes, circulating immune complexes have been demonstrated, but their pathogenic significance is unclear.
Clinical and Laboratory Manifestations
Takayasu’s arteritis is a systemic disease with generalized as well as vascular symptoms. The generalized symptoms include malaise, fever, night sweats, arthralgias, anorexia, and weight loss, which may occur months before vessel involvement is apparent. These symptoms may merge into those related to vascular compromise and organ ischemia. Pulses are commonly absent in the involved vessels, particularly the subclavian artery. The frequency of arterio-graphic abnormalities and the potentially associated clinical manifestations are listed in Table 10-6. Hypertension occurs in 32 to 93% of patients and contributes to renal, cardiac, and cerebral injury.
Characteristic laboratory findings include an elevated ESR, mild anemia, and elevated immunoglobulin levels.
Diagnosis
The diagnosis of Takayasu’s arteritis should be suspected strongly in a young woman who develops a decrease or absence of peripheral pulses, discrepancies in blood pressure, and arterial bruits. The diagnosis is confirmed by the characteristic pattern on arteriography, which includes irregular vessel walls, stenosis, poststenotic dilatation, aneurysm formation, occlusion, and evidence of increased collateral circulation. Complete aortic arteriography by catheter-directed dye arteriography, magnetic resonance arteriography, or computerized tomography arteriography should be obtained, in order to fully delineate the distribution and degree of arterial disease. Histopathologic demonstration of inflamed vessels adds confirmatory data; however, tissue is rarely readily available for examination.
TABLE 10-6
|
FREQUENCY OF ARTERIOGRAPHIC ABNORMALITIES AND POTENTIAL CLINICAL MANIFESTATIONS OF ARTERIAL INVOLVEMENT IN TAKAYASU’S ARTERITIS |
||
|
ARTERY |
PERCENT OF ARTERIOGRAPHIC ABNORMALITIES |
POTENTIAL CLINICAL MANIFESTATIONS |
|
Subclavian |
93 |
Arm claudication, Raynaud’s phenomenon |
|
Common carotid |
58 |
Visual changes, syncope, transient ischemic attacks, stroke |
|
Abdominal aortaa |
47 |
Abdominal pain, nausea, vomiting |
|
Renal |
38 |
Hypertension, renal failure |
|
Aortic arch or root |
35 |
Aortic insufficiency, congestive heart failure |
|
Vertebral |
35 |
Visual changes, dizziness |
|
Coeliac axisa |
18 |
Abdominal pain, nausea, vomiting |
|
Superior mesenterica |
18 |
Abdominal pain, nausea, vomiting |
|
Iliac |
17 |
Leg claudication |
|
Pulmonary |
10-40 |
Atypical chest pain, dyspnea |
|
Coronary |
<10 |
Chest pain, myocardial infarction |
aArteriographic lesions at these locations are usually asymptomatic but may potentially cause these symptoms.
Treatment:
Takayasu’s Arteritis
The long-term outcome of patients with Takayasu’s arteritis has varied widely between studies. Although two North American reports found overall survival to be >94%, the 5-year mortality rate from other studies has ranged from 0-35%. Disease-related mortality most often occurs from congestive heart failure, cerebrovascular events, myocardial infarction,aneurysm rupture,or renal failure. Even in the absence of life-threatening disease Takayasu’s arteritis can be associated with significant morbidity.The course of the disease is variable, and although spontaneous remissions may occur,Takayasu’s arteritis is most often chronic and relapsing. Although glucocorticoid therapy in doses of 40-60 mg prednisone per day alleviates symptoms, there are no convincing studies that indicate that they increase survival. The combination of glucocorticoid therapy for acute signs and symptoms and an aggressive surgical and/or angioplastic approach to stenosed vessels has markedly improved outcome and decreased morbidity by lessening the risk of stroke, correcting hypertension due to renal artery stenosis, and improving blood flow to ischemic viscera and limbs. Unless it is urgently required, surgical correction of stenosed arteries should be undertaken only when the vascular inflammatory process is well controlled with medical therapy. In individuals who are refractory to or unable to taper glucocorticoids, methotrexate in doses up to 25 mg/week has yielded encouraging results. Open-label studies have suggested that anti-TNF therapies may provide benefit, although efficacy cannot be determined in the absence of a randomized trial.
Henoch-Schönlein purpura
Definition
Henoch-Schönlein purpura, also referred to as anaphylactoid purpura, is a distinct systemic vasculitis syndrome that is characterized by palpable purpura (most commonly distributed over the buttocks and lower extremities), arthralgias, gastrointestinal signs and symptoms, and glomerulonephritis. It is a small-vessel vasculitis.
Incidence and Prevalence
Henoch-Schönlein purpura is usually seen in children; most patients range in age from 4-7 years; however, the disease may also be seen in infants and adults. It is not a rare disease; in one series it accounted for between 5 and 24 admissions per year at a pediatric hospital. The male-to-female ratio is 1.5:1.A seasonal variation with a peak incidence in spring has been noted.
Pathology and Pathogenesis
The presumptive pathogenic mechanism for Henoch-Schönlein purpura is immune-complex deposition. A number of inciting antigens have been suggested including upper respiratory tract infections, various drugs, foods, insect bites, and immunizations. IgA is the antibody class most often seen in the immune complexes and has been demonstrated in the renal biopsies of these patients.
Clinical and Laboratory Manifestations
In pediatric patients, palpable purpura is seen in virtually all patients; most patients develop polyarthralgias in the absence of frank arthritis. Gastrointestinal involvement, which is seen in almost 70% of pediatric patients, is characterized by colicky abdominal pain usually associated with nausea, vomiting, diarrhea, or constipation and is frequently accompanied by the passage of blood and mucus per rectum; bowel intussusception may occur. Renal involvement occurs in 10-50% of patients and is usually characterized by mild glomerulonephritis leading to proteinuria and microscopic hematuria, with red blood cell casts in the majority of patients; it usually resolves spontaneously without therapy. Rarely, a progressive glomerulonephritis will develop. In adults, presenting symptoms are most frequently related to the skin and joints, while initial complaints related to the gut are less common. Although certain studies have found that renal disease is more frequent and more severe in adults, this has not been a consistent finding. However, the course of renal disease in adults may be more insidious and thus requires close follow-up. Myocardial involvement can occur in adults but is rare in children.
Laboratory studies generally show a mild leukocytosis, a normal platelet count, and occasionally eosinophilia. Serum complement components are normal, and IgA levels are elevated in about one-half of patients.
Diagnosis
The diagnosis of Henoch-Schönlein purpura is based on clinical signs and symptoms. Skin biopsy specimen can be useful in confirming leukocytoclastic vasculitis with IgA and C3 deposition by immunofluorescence. Renal biopsy is rarely needed for diagnosis but may provide prognostic information in some patients.
Treatment:
Henoch-Schönlein purpura
The prognosis of Henoch-Schönlein purpura is excellent. Mortality is exceedingly rare, and 1-5% of children progress to end-stage renal disease.Most patients recover completely, and some do not require therapy.Treatment is similar for adults and children. When glucocorticoid therapy is required, prednisone, in doses of 1 mg/kg per d and tapered according to clinical response, has been shown to be useful in decreasing tissue edema, arthralgias, and abdominal discomfort; however, it has not proven beneficial in the treatment of skin or renal disease and does not appear to shorten the duration of active disease or lessen the chance of recurrence. Patients with rapidly progressive glomerulonephritis have been anecdotally reported to benefit from intensive plasma exchange combined with cytotoxic drugs. Disease recurrences have been reported in 10-40% of patients.
Idiopathic Cutaneous vasculitis
Definition
The term cutaneous vasculitis is defined broadly as inflammation of the blood vessels of the dermis. Due to its heterogeneity, cutaneous vasculitis has been described by a variety of terms including hypersensitivity vasculitis and cutaneous leukocytoclastic angiitis. However, cutaneous vasculitis is not one specific disease but a manifestation that can be seen in a variety of settings. In >70% of cases, cutaneous vasculitis occurs either as part of a primary systemic vasculitis or as a secondary vasculitis related to an inciting agent or an underlying disease (see “Secondary Vasculitis” later in the topic). In the remaining 30% of cases, cutaneous vasculitis occurs idiopathically.
Incidence and Prevalence
Cutaneous vasculitis represents the most commonly encountered vasculitis in clinical practice. The exact incidence of idiopathic cutaneous vasculitis has not been determined due to the predilection for cutaneous vasculitis to be associated with an underlying process and the variability of its clinical course.
Pathology and Pathogenesis
The typical histopathologic feature of cutaneous vasculitis is the presence of vasculitis of small vessels. Postcapillary venules are the most commonly involved vessels; capillaries and arterioles may be involved less frequently. This vasculitis is characterized by a leukocytoclasis, a term that refers to the nuclear debris remaining from the neutrophils that have infiltrated in and around the vessels during the acute stages. In the subacute or chronic stages, mononuclear cells predominate; in certain subgroups, eosinophilic infiltration is seen. Erythrocytes often extravasate from the involved vessels, leading to palpable purpura.
Clinical and Laboratory Manifestations
The hallmark of idiopathic cutaneous vasculitis is the predominance of skin involvement. Skin lesions may appear typically as palpable purpura; however, other cutaneous manifestations of the vasculitis may occur, including macules, papules, vesicles, bullae, subcutaneous nodules, ulcers, and recurrent or chronic urticaria. The skin lesions may be pruritic or even quite painful, with a burning or stinging sensation. Lesions most commonly occur in the lower extremities in ambulatory patients or in the sacral area in bedridden patients due to the effects of hydrostatic forces on the postcapillary venules. Edema may accompany certain lesions, and hyperpigmentation often occurs in areas of recurrent or chronic lesions.
There are no specific laboratory tests diagnostic of idiopathic cutaneous vasculitis. A mild leukocytosis with or without eosinophilia is characteristic, as is an elevated ESR. Laboratory studies should be aimed towards ruling out features to suggest an underlying disease or a systemic vasculitis.
Diagnosis
The diagnosis of cutaneous vasculitis is made by the demonstration of vasculitis on biopsy. An important diagnostic principle in patients with cutaneous vasculitis is to search for an etiology of the vasculitis—be it an exogenous agent, such as a drug or an infection, or an endogenous condition, such as an underlying disease (Fig. 10-1). In addition, a careful physical and laboratory examination should be performed to rule out the possibility of systemic vasculitis. This should start with the least invasive diagnostic approach and proceed to the more invasive only if clinically indicated.
Treatment:
Idiopathic Cutaneous vasculitis
When an antigenic stimulus is recognized as the precipitating factor in the cutaneous vasculitis, it should be removed; if this is a microbe, appropriate antimicrobial therapy should be instituted. If the vasculitis is associated with another underlying disease, treatment of the latter often results in resolution of the former. In situations where disease is apparently self-limited, no therapy, except possibly symptomatic therapy, is indicated. When cutaneous vasculitis persists and when there is no evidence of an inciting agent, an associated disease, or an underlying systemic vasculitis, the decision to treat should be based on weighing the balance between the degree of symptoms and the risk of treatment. Some cases of idiopathic cutaneous vasculitis resolve spontaneously, while others remit and relapse. In those patients with persistent vasculitis,a variety of therapeutic regimens have been tried with variable results. In general, the treatment of idiopathic cutaneous vasculitis has not been satisfactory. Fortunately, since the disease is generally limited to the skin, this lack of consistent response to therapy usually does not lead to a life-threatening situation. Glucocorticoids are often used in the treatment of idiopathic cutaneous vasculitis. Therapy is usually instituted as prednisone, 1 mg/kg per d, with rapid tapering where possible, either directly to discontinuation or by conversion to an alternate-day regimen followed by ultimate discontinuation. In cases that prove refractory to glucocorticoids, a trial of a cytotoxic agent may be indicated. Patients with chronic vasculitis isolated to cutaneous venules rarely respond dramatically to any therapeutic regimen, and cytotoxic agents should be used only as a last resort in these patients. Methotrexate and azathioprine have been used in such situations in anecdotal reports. Although cyclophosphamide is the most effective therapy for the systemic vasculitides, it should almost never be used for idiopathic cutaneous vasculitis because of the potential toxicity.Other agents with which there have been anecdotal reports of success include dapsone,colchicine,and nonsteroidal anti-inflammatory agents.
Essential Mixed Cryoglobulinemia
Definition
Cryoglobulins are cold-precipitable monoclonal or polyclonal immunoglobulins. Cryoglobulinemia may be associated with a systemic vasculitis characterized by palpable purpura, arthralgias, weakness, neuropathy, and glomerulonephritis. Although this can be observed in association with a variety of underlying disorders including multiple myeloma, lymphoproliferative disorders, connective tissue diseases, infection, and liver disease, in many instances it appears to be idiopathic. Because of the apparent absence of an underlying disease and the presence of cryoprecipi-tate containing oligoclonal/polyclonal immunoglobulins, this entity was referred to as essential mixed cryoglobulinemia. Since the discovery of hepatitis C, it has been established that in the vast majority of patients, essential mixed cryoglobulinemia is related to an aberrant immune response to chronic hepatitis C infection.
Incidence and Prevalence
The incidence of essential mixed cryoglobulinemia has not been established. It has been estimated, however, that 5% of patients with chronic hepatitis C will develop the syndrome of essential mixed cryoglobulinemia.
Pathology and Pathogenesis
Skin biopsies in essential mixed cryoglobulinemia reveal an inflammatory infiltrate surrounding and involving blood vessel walls, with fibrinoid necrosis, endothelial cell hyperplasia, and hemorrhage. Deposition of immunoglobulin and complement is common. Abnormalities of uninvolved skin including basement membrane alterations and deposits in vessel walls may be found. Membranoprolif-erative glomerulonephritis is responsible for 80% of all renal lesions in essential mixed cryoglobulinemia.
The association between hepatitis C and essential mixed cryoglobulinemia has been supported by the high frequency of documented hepatitis C infection, the presence of hepatitis C RNA and anti-hepatitis C antibodies in serum cryoprecipitates, evidence of hepatitis C antigens in vasculitic skin lesions, and the effectiveness of antiviral therapy (see below). Current evidence suggests that in the majority of cases, essential mixed cryoglobulinemia occurs when an aberrant immune response to hepatitis C infection leads to the formation of immune complexes consisting of hepatitis C antigens, polyclonal hepatitis C-specific IgG, and monoclonal IgM rheumatoid factor. The deposition of these immune complexes in blood vessel walls triggers an inflammatory cascade that results in the clinical syndrome of essential mixed cryoglobulinemia.
Clinical and Laboratory Manifestations
The most common clinical manifestations of essential mixed cryoglobulinemia are cutaneous vasculitis, arthritis, peripheral neuropathy, and glomerulonephritis. Renal disease develops in 10-30% of patients. Life-threatening rapidly progressive glomerulonephritis or vasculitis of the CNS, gastrointestinal tract, or heart occurs infrequently.
The presence of circulating cryoprecipitates is the fundamental finding in essential mixed cryoglobulinemia. Rheumatoid factor is almost always found and may be a useful clue to the disease when cryoglobulins are not detected. Hypocomplementemia occurs in 90% of patients. An elevated ESR and anemia occur frequently. Evidence for hepatitis C infection must be sought in all patients by testing for hepatitis C antibodies and hepatitis C RNA.
Treatment:
Essential Mixed Cryoglobulinemia
Acute mortality from essential mixed cryoglobulinemia is uncommon, but the presence of glomerulonephritis is a poor prognostic sign for overall outcome. In such patients, 15% progress to end-stage renal disease, with 40% later experiencing fatal cardiovascular disease, infection, or liver failure. As indicated above, the majority of cases are associated with hepatitis C infection. In such patients, treatment with IFN-α and ribavirin can prove beneficial. Clinical improvement with antiviral therapy is dependent on the virologic response. Patients who clear hepatitis C from the blood have objective improvement in their vasculitis along with significant reductions in levels of circulating cryoglobulins, IgM,and rheumatoid factor. However, substantial portions of patients with hepatitis C do not have a sustained virologic response to such therapy,and the vasculitis typically relapses with the return of viremia.While transient improvement can be observed with glucocorticoids, a complete response is seen in only 7% of patients. Plasmapheresis and cytotoxic agents have been used in anecdotal reports.These observations have not been confirmed, and such therapies carry significant risks.
