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Vasculitis Masquerading as Vasculitis
Editorial Vasculitis Masquerading as Vasculitis In this issue of the Mayo Clinic Proceedings (pages 115 to 121), Nishino and colleagues describe five patients who initially were diagnosed as having giant cell arteritis (GCA) but in whom the full clinical expression of Wegener's granulomatosis (WG) subsequently developed. The article raises several interesting points about the apparent expression of two clinical syndromes in one patient. Types of Relationships.-Several potential relationships may explain the coexpression of the two clinical syndromes of CGA and WG. First, the development of two uncommon diseases in one patient may result from the independent expression of the respective conditions. Depending on the incidence of the two diseases, the development of two uncommon disorders in one person would be a rare but identifiable event. This first possibility might be considered the "bad luck" or "lightning striking twice" scenario. Second, a causal relationship between two disease processes is also possible. In this relationship, one disease directly or indirectly contributes to the clinical expression of the second process. An example of such a causal relationship would be the development of polyarteritis nodosa in a patient with chronic hepatitis B virus infection. Third, a common predisposing factor or factors may result in the development of two clinical processes. The development of thromboangiitis obliterans (Buerger's disease) and pulmonary emphysematous changes in a person who smokes cigarettes is an example of a common risk factor that can lead to the expression of two clinical syndromes. Finally, one clinical syndrome may manifest in an unusual or atypical pattern that mimics another disease process and results in an initial misdiagnosis. With the full clinical expression of the disease process, the true diagnosis is established. This apparent relationship is characterized as the "masquerading" scenario. The initial manifestation of amyloid-related vasculopathy as jaw claudication that is misdiagnosed as GCA would be an example of such a "masquerading" relationship. Of these four potential alternatives, the last relationship is the most likely explanation for the current cases reported by Address reprint requests to Dr. T. R. Cupps, Division of Rheumatology, Immunology and Allergy, LL Gorman Building, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007-2197. Mayo Clin Proc 1993; 68:194-196
Nishino and colleagues. On the basis of the clinical information provided in this article, the initial, atypical manifestation of WG mimicked GCA clinically. With time, the full clinical expression of WG became apparent, and the correct diagnosis was established. Diagnostic Difficulties.-The potential for one vasculitis masquerading as another vasculitis is not surprising when two observations are considered. First, the clinical response to inflammation of blood vessels is limited and includes (1) the clinical consequences of decreased blood flow (that is, ischemic dysfunction or infarction), (2) hemorrhage, and (3) pain over the involved vessel. The pattern of clinical involvement varies with both the size and the site of the involved vessels. For a given blood vessel size in a specific vascular bed, the clinical expression tends to be stereotypic regardless of the underlying pathologic process. Second, several recognized vasculitic syndromes may involve blood vessels of a specific size. The medium-sized muscular arteries, for example, may represent a watershed distribution for many vasculitides. Vasculitis of mediumsized muscular arteries occurs in various frequencies in the following syndromes:' polyarteritis nodosa, Churg-Strauss syndrome (allergic granulomatosis and angiitis), WG, Kawasaki syndrome, Takayasu's arteritis, and GCA. Thus, vasculitis manifesting as predominantly clinical involvement of medium-sized muscular arteries may be difficult to categorize. These two observations demonstate the potential for one vasculitis to masquerade as another vasculitis. In addition, these observations underscore the complexity of establishing an appropriate definition or suitable criteria for both classification and diagnosis of a particular vasculitic syndrome. Classification Criteria/or WG.-The five cases reported by Nishino and colleagues highlight the complexities of both classifying the vasculitides and establishing the diagnosis of a specific vasculitic syndrome in an individual patient. In the assessment of this series, the authors use both the American College of Rheumatology 1990 criteria for classification (traditional format) of WG 1 and a modification of the "ELK system'? (in which the site of involvement is denoted as E = upper airway or ear, nose, and throat; L = lungs; and K = kidneys). When the actual nature of classification criteria is considered, the fact that only four of the five patients fulfilled the American College of Rheumatology 1990 criteria for the classification of WG is not surprising. As emphasized by Dr. Gene G. Hunder and other members of the American College of Rheumatology Subcommittee on Clas194
© 1993 Mayo Foundation for Medical Education and Research
Mayo Clin Proc, February 1993, Vol 68
sification of Vasculitis,' classification criteria consist of clinical variables that both identify the disease and separate it from other clinical entities. Classification criteria tend to favor specificity over sensitivity and are useful for defining a well-characterized group of patients for clinical, therapeutic, and epidemiologic studies. Inasmuch as the American College of Rheumatology 1990 criteria for the classification of WG (traditional format) has a sensitivity of 88.2%, any series of patients defined by these criteria would exclude substantial numbers of those with a legitimate diagnosis of WG. On the basis of the clinical information provided, the authors' decision to include one patient (case 3) who failed to fulfill the American College of Rheumatology 1990 criteria for classification of WG seems appropriate. Classification Criteriafor GCA.- The current cases described by Nishino and coworkers also satisfied the American College of Rheumatology 1990 criteria for classification of GCA (traditional format).' Several observations should be made about these criteria relative to the diagnosis of WG. The presence of three of five criteria yields a sensitivity of 93.5% and a specificity of 91.2% for the diagnosis of GCA. Three of these criteria are noteworthy relative to the diagnosis of WG. The first criterion is that the onset of symptoms occurs at the age of 50 years or older. Because the mean age of patients at onset of WG is 45 ± 1.8 years,' a considerable number of patients with WG would fulfill the first criterion of GCA. The second criterion-a new headache or new type of localized pain in the head-may be a common finding in WG, which is characterized by the high frequency of ocular, nasal, otic, sinus, and oral involvement, particularly at the initial manifestation of the disease. A third criterion, an increased erythrocyte sedimentation rate (50 mm or more in 1 hour by the Westergren method), would also be present in many patients with WG. The mean Westergren erythrocyte sedimentation rate before therapeutic intervention in a large series of patients with WG was 71 mm in 1 hour.' With use of just these three criteria, the potential for a patient with WG to fulfill the classification criteria for GCA would be substantial. Indeed, of the 52 patients who satisfied the criteria for GCA but had some other vasculitic syndrome, 21 were diagnosed as having WG. 4 Certainly the potential for diagnostic confusion between GCA and WG exists. The observations by Nishino and colleagues confirm this potential, especially during the early clinical course of these two vasculitides. The Clinical Setting.-The challenge of establishing the diagnosis of a specific vasculitic syndrome in a rapidly evolving clinical setting is complex. As one leaves the investigator's arena of black or white binary responses (yes or no) to classification criteria and enters the clinician's realm of subtle shades of gray that characterize diagnostic criteria, the rules change. Diagnostic criteria focus on com-
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binations of clinical, laboratory, and pathologic findings that must be present to establish the existence of a particular disease process.' Findings that are not unique to, but commonly present in, a certain disease are frequently included among the diagnostic criteria. In one sense, establishing the diagnosis of a particular vasculitis in a specific patient becomes a process of recognizing clinicopathologic patterns. Uniformly accepted diagnostic criteria for the vasculitides are currently unavailable. Establishing a definitive diagnosis of a particular vasculitic syndrome in a clinical setting is challenging for several reasons. The vasculitides, particularly the systemic syndromes, are truly diseases of "protean manifestations." The early clinical symptoms of many of the vasculitides tend to be nonspecific and common to many disease processes. The more suggestive or characteristic findings may not be expressed until later during the course of the disease. Many useful diagnostic tests, such as biopsy and angiography, are invasive and frequently performed to confirm a clinical impression. As such, establishing the diagnosis of vasculitis tends to be an active rather than a passive process. Accelerated disease activity accompanied by progressive dysfunction of organ systems may, in some cases, dictate aggressive therapeutic intervention before a definitive diagnosis is established. Such therapeutic interventions, however, may further confound diagnostic considerations. Establishing the diagnosis of vasculitis is a dynamic process that evolves during days, weeks, or even longer periods as additional clinical, laboratory, and histopathologic information becomes available. The American College of Rheumatology 1990 criteria for vasculitis, which are based on the full clinical expression of the disease and designed to discriminate among the vasculitides but not between vasculitis and other disease categories, are unsuitable for diagnosing a specific vasculitic syndrome in an individual patient. These criteria for the classification of vasculitis are a critical investigative tool that may provide more effective diagnostic standards for the vasculitides. Current Study.-The observations by Nishino and colleagues highlight several salient clinical points. First, the presence of vasculitis in a biopsy specimen of a temporal artery does not establish the definitive diagnosis of GCA. Both polyarteritis nodosa and WG may involve the temporal artery and should be included in the differential diagnosis. Second, the histopathologic pattern of vasculitis in the temporal artery may provide important diagnostic information. Of the temporal artery biopsy specimens in this series, only one revealed the histologic pattern of giant cells. Usually, giant cells are absent from temporal artery lesions in patients with polyarteritis nodosa." In the absence of prior glucocorticoid therapy, the finding of temporal arteritis without granulomas or giant cells should suggest the possibility of a
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vasculitic syndrome other than GCA. Further clinical evaluation for subtle manifestations of either polyarteritis nodosa or WG may be appropriate. Finally, the observations by Nishino and colleagues also emphasize the potential clinical consequences of treating systemic vasculitides other than GCA with only glucocorticoids. In three of the patients, significant morbidity developed after glucocorticoid therapy was initiated. In one patient, bowel infarction attributable to active vasculitis developed, and two patients had deterioration to chronic renal failure. In patients with WG, bowel infarction is uncommon.' This complication occurs more frequently in patients with polyarteritis nodosa who have been treated with only glucocorticoids. These agents may mask the early signs and symptoms of bowel ischemia associated with smoldering vasculitis. An awareness of this possibility is clinically important because the surgical mortality among patients with vasculitis-induced bowel infarction in this clinical setting is high. Progressive renal damage has been noted in patients with polyarteritis nodosa and those with WG who receive glucocorticoids only. Clinical signs and symptoms ascribed to the renal involvement are characteristically absent until late in the course of the disease. The development of hypertension in patients with polyarteritis nodosa may be the first indication of smoldering renal damage, despite glucocorticoid therapy. Evidence of proteinuria or the development of erythrocyte casts in the urinary sediment is suggestive of progressive renal disease in both polyarteritis nodosa and WG. Because clinical signs and symptoms are unreliable indicators of disease activity in the gastrointestinal tract
Mayo CIiDProc, February 1993, Vol 68
and kidneys, appropriate medical follow-up to detect progressive disease in these two organ systems is warranted. An appreciation of these details becomes clinically important when one vasculitis masquerades as another vasculitis. Thomas R. Cupps, M.D. Division of Rheumatology, Immunology and Allergy Georgetown University Medical Center Washington, DC REFERENCES 1. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. ArthritisRheum 1990;33:1101-1107 2. DeRemee RA, McDonald TJ, Harrison EG Jr, Coles DT. Wegener's granulomatosis: anatomic correlates, a proposed classification. Mayo Clin Proc 1976;51:777-781 3. Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, et al. The American College of Rheumatology 1990 criteriafor the classification of vasculitis: introduction. Arthritis Rheum 1990;33:1065-1067 4. Hunder GG, Bloch DA, Michel BA, Stevens MB, Arend WP, CalabreseLH, et al. The American Collegeof Rheumatology 1990criteriafor the classification of giantcell arteritis. Arthritis Rheum 1990;33:1122-1128 5. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et at Wegenergranulomatosis: an analysisof 158 patients. Ann Intern Med 1992; 116:488-498 6. Morgan GJ Jr, Harris ED Jr. Non-giantcell temporal arteritis: three cases and a review of the literature. Arthritis Rheum 1978;21:362-366
Nishino and colleagues. On the basis of the clinical information provided in this article, the initial, atypical manifestation of WG mimicked GCA clinically. With time, the full clinical expression of WG became apparent, and the correct diagnosis was established. Diagnostic Difficulties.-The potential for one vasculitis masquerading as another vasculitis is not surprising when two observations are considered. First, the clinical response to inflammation of blood vessels is limited and includes (1) the clinical consequences of decreased blood flow (that is, ischemic dysfunction or infarction), (2) hemorrhage, and (3) pain over the involved vessel. The pattern of clinical involvement varies with both the size and the site of the involved vessels. For a given blood vessel size in a specific vascular bed, the clinical expression tends to be stereotypic regardless of the underlying pathologic process. Second, several recognized vasculitic syndromes may involve blood vessels of a specific size. The medium-sized muscular arteries, for example, may represent a watershed distribution for many vasculitides. Vasculitis of mediumsized muscular arteries occurs in various frequencies in the following syndromes:' polyarteritis nodosa, Churg-Strauss syndrome (allergic granulomatosis and angiitis), WG, Kawasaki syndrome, Takayasu's arteritis, and GCA. Thus, vasculitis manifesting as predominantly clinical involvement of medium-sized muscular arteries may be difficult to categorize. These two observations demonstate the potential for one vasculitis to masquerade as another vasculitis. In addition, these observations underscore the complexity of establishing an appropriate definition or suitable criteria for both classification and diagnosis of a particular vasculitic syndrome. Classification Criteria/or WG.-The five cases reported by Nishino and colleagues highlight the complexities of both classifying the vasculitides and establishing the diagnosis of a specific vasculitic syndrome in an individual patient. In the assessment of this series, the authors use both the American College of Rheumatology 1990 criteria for classification (traditional format) of WG 1 and a modification of the "ELK system'? (in which the site of involvement is denoted as E = upper airway or ear, nose, and throat; L = lungs; and K = kidneys). When the actual nature of classification criteria is considered, the fact that only four of the five patients fulfilled the American College of Rheumatology 1990 criteria for the classification of WG is not surprising. As emphasized by Dr. Gene G. Hunder and other members of the American College of Rheumatology Subcommittee on Clas194
© 1993 Mayo Foundation for Medical Education and Research
Mayo Clin Proc, February 1993, Vol 68
sification of Vasculitis,' classification criteria consist of clinical variables that both identify the disease and separate it from other clinical entities. Classification criteria tend to favor specificity over sensitivity and are useful for defining a well-characterized group of patients for clinical, therapeutic, and epidemiologic studies. Inasmuch as the American College of Rheumatology 1990 criteria for the classification of WG (traditional format) has a sensitivity of 88.2%, any series of patients defined by these criteria would exclude substantial numbers of those with a legitimate diagnosis of WG. On the basis of the clinical information provided, the authors' decision to include one patient (case 3) who failed to fulfill the American College of Rheumatology 1990 criteria for classification of WG seems appropriate. Classification Criteriafor GCA.- The current cases described by Nishino and coworkers also satisfied the American College of Rheumatology 1990 criteria for classification of GCA (traditional format).' Several observations should be made about these criteria relative to the diagnosis of WG. The presence of three of five criteria yields a sensitivity of 93.5% and a specificity of 91.2% for the diagnosis of GCA. Three of these criteria are noteworthy relative to the diagnosis of WG. The first criterion is that the onset of symptoms occurs at the age of 50 years or older. Because the mean age of patients at onset of WG is 45 ± 1.8 years,' a considerable number of patients with WG would fulfill the first criterion of GCA. The second criterion-a new headache or new type of localized pain in the head-may be a common finding in WG, which is characterized by the high frequency of ocular, nasal, otic, sinus, and oral involvement, particularly at the initial manifestation of the disease. A third criterion, an increased erythrocyte sedimentation rate (50 mm or more in 1 hour by the Westergren method), would also be present in many patients with WG. The mean Westergren erythrocyte sedimentation rate before therapeutic intervention in a large series of patients with WG was 71 mm in 1 hour.' With use of just these three criteria, the potential for a patient with WG to fulfill the classification criteria for GCA would be substantial. Indeed, of the 52 patients who satisfied the criteria for GCA but had some other vasculitic syndrome, 21 were diagnosed as having WG. 4 Certainly the potential for diagnostic confusion between GCA and WG exists. The observations by Nishino and colleagues confirm this potential, especially during the early clinical course of these two vasculitides. The Clinical Setting.-The challenge of establishing the diagnosis of a specific vasculitic syndrome in a rapidly evolving clinical setting is complex. As one leaves the investigator's arena of black or white binary responses (yes or no) to classification criteria and enters the clinician's realm of subtle shades of gray that characterize diagnostic criteria, the rules change. Diagnostic criteria focus on com-
EDITORIAL
195
binations of clinical, laboratory, and pathologic findings that must be present to establish the existence of a particular disease process.' Findings that are not unique to, but commonly present in, a certain disease are frequently included among the diagnostic criteria. In one sense, establishing the diagnosis of a particular vasculitis in a specific patient becomes a process of recognizing clinicopathologic patterns. Uniformly accepted diagnostic criteria for the vasculitides are currently unavailable. Establishing a definitive diagnosis of a particular vasculitic syndrome in a clinical setting is challenging for several reasons. The vasculitides, particularly the systemic syndromes, are truly diseases of "protean manifestations." The early clinical symptoms of many of the vasculitides tend to be nonspecific and common to many disease processes. The more suggestive or characteristic findings may not be expressed until later during the course of the disease. Many useful diagnostic tests, such as biopsy and angiography, are invasive and frequently performed to confirm a clinical impression. As such, establishing the diagnosis of vasculitis tends to be an active rather than a passive process. Accelerated disease activity accompanied by progressive dysfunction of organ systems may, in some cases, dictate aggressive therapeutic intervention before a definitive diagnosis is established. Such therapeutic interventions, however, may further confound diagnostic considerations. Establishing the diagnosis of vasculitis is a dynamic process that evolves during days, weeks, or even longer periods as additional clinical, laboratory, and histopathologic information becomes available. The American College of Rheumatology 1990 criteria for vasculitis, which are based on the full clinical expression of the disease and designed to discriminate among the vasculitides but not between vasculitis and other disease categories, are unsuitable for diagnosing a specific vasculitic syndrome in an individual patient. These criteria for the classification of vasculitis are a critical investigative tool that may provide more effective diagnostic standards for the vasculitides. Current Study.-The observations by Nishino and colleagues highlight several salient clinical points. First, the presence of vasculitis in a biopsy specimen of a temporal artery does not establish the definitive diagnosis of GCA. Both polyarteritis nodosa and WG may involve the temporal artery and should be included in the differential diagnosis. Second, the histopathologic pattern of vasculitis in the temporal artery may provide important diagnostic information. Of the temporal artery biopsy specimens in this series, only one revealed the histologic pattern of giant cells. Usually, giant cells are absent from temporal artery lesions in patients with polyarteritis nodosa." In the absence of prior glucocorticoid therapy, the finding of temporal arteritis without granulomas or giant cells should suggest the possibility of a
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vasculitic syndrome other than GCA. Further clinical evaluation for subtle manifestations of either polyarteritis nodosa or WG may be appropriate. Finally, the observations by Nishino and colleagues also emphasize the potential clinical consequences of treating systemic vasculitides other than GCA with only glucocorticoids. In three of the patients, significant morbidity developed after glucocorticoid therapy was initiated. In one patient, bowel infarction attributable to active vasculitis developed, and two patients had deterioration to chronic renal failure. In patients with WG, bowel infarction is uncommon.' This complication occurs more frequently in patients with polyarteritis nodosa who have been treated with only glucocorticoids. These agents may mask the early signs and symptoms of bowel ischemia associated with smoldering vasculitis. An awareness of this possibility is clinically important because the surgical mortality among patients with vasculitis-induced bowel infarction in this clinical setting is high. Progressive renal damage has been noted in patients with polyarteritis nodosa and those with WG who receive glucocorticoids only. Clinical signs and symptoms ascribed to the renal involvement are characteristically absent until late in the course of the disease. The development of hypertension in patients with polyarteritis nodosa may be the first indication of smoldering renal damage, despite glucocorticoid therapy. Evidence of proteinuria or the development of erythrocyte casts in the urinary sediment is suggestive of progressive renal disease in both polyarteritis nodosa and WG. Because clinical signs and symptoms are unreliable indicators of disease activity in the gastrointestinal tract
Mayo CIiDProc, February 1993, Vol 68
and kidneys, appropriate medical follow-up to detect progressive disease in these two organ systems is warranted. An appreciation of these details becomes clinically important when one vasculitis masquerades as another vasculitis. Thomas R. Cupps, M.D. Division of Rheumatology, Immunology and Allergy Georgetown University Medical Center Washington, DC REFERENCES 1. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. ArthritisRheum 1990;33:1101-1107 2. DeRemee RA, McDonald TJ, Harrison EG Jr, Coles DT. Wegener's granulomatosis: anatomic correlates, a proposed classification. Mayo Clin Proc 1976;51:777-781 3. Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, et al. The American College of Rheumatology 1990 criteriafor the classification of vasculitis: introduction. Arthritis Rheum 1990;33:1065-1067 4. Hunder GG, Bloch DA, Michel BA, Stevens MB, Arend WP, CalabreseLH, et al. The American Collegeof Rheumatology 1990criteriafor the classification of giantcell arteritis. Arthritis Rheum 1990;33:1122-1128 5. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et at Wegenergranulomatosis: an analysisof 158 patients. Ann Intern Med 1992; 116:488-498 6. Morgan GJ Jr, Harris ED Jr. Non-giantcell temporal arteritis: three cases and a review of the literature. Arthritis Rheum 1978;21:362-366