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Ocular features associated with anticardiolipin antibodies: a descriptive study
REFERENCES
1. Otto AJ, Spekreije H. Intraorbital volume discrepancies and intraorbital pressure. Int Ophthalmol 1987;11:113–114. 2. Otto AJ, Spekreije H. Volume discrepancies in the orbit and the effect on intraorbital pressure. Orbit 1989;8:233–244. 3. Ohtsuka K. Intraocular pressure and proptosis in 95 patients with Graves ophthalmopathy. Am J Ophthalmol 1997;124: 570 –572.
Ocular Features Associated With Anticardiolipin Antibodies: A Descriptive Study EDITOR: IN THEIR REPORT “OCULAR FEATURES ASSOCIATED WITH
anticardiolipin antibodies: a descriptive study,” Miserocchi and colleagues describe a range of ocular findings among 13 patients who were seen over a period of approximately 13 years at the Massachusetts Eye and Ear Infirmary and who were noted to produce anticardiolipin antibodies (Am J Ophthalmol 131:451– 456, 2001). This report is a potential landmark study because it comes from an eminent group and it expands the spectrum of disease associated with anticardiolipin antibodies. Based on their data, the authors “do not conclude that there is a causative role of anticardiolipin antibodies in some patients with uveitis.” However, they advise that “one might want to include anticardiolipin antibody screening in all patients presenting with uveitis of unclear cause in which retinal vasculitis is involved.”1 We disagree with these statements. To evaluate the conclusions of this report, it is important to recognize specifics about the anticardiolipin antibody and general principles about laboratory testing. Numerous studies have reported an association between occlusive retinal vascular disease, often associated with some degree of intraocular inflammation, and antiphospholipid antibodies, including the anticardiolipin antibody.2 Like other autoantibodies, anticardiolipin antibodies may be expressed at low levels by healthy individuals. Anticardiolipin antibodies are more commonly detected in patients with specific inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis and autoimmune thyroiditis, certain infections including syphilis, and the primary antiphospholipid antibody syndrome. When present in clinically significant titers, the antibodies are believed to have a causative role in vascular occlusive episodes and pregnancy losses. To evaluate whether the presence of anticardiolipin antibody was clinically significant in the patients reported by Miserocchi and coworkers, one needs to know the following information: 1. Were measurements of the anticardiolipin antibody titers performed more than once for each patient? VOL. 133, NO. 2
High interlaboratory variation in titer levels and a general lack of test result consensus between laboratories are substantial concerns in the interpretation of anticardiolipin antibody assays.3 Measurement of increased levels of anticardiolipin antibody on two or more occasions, at least 6 weeks apart, is considered to be clinically significant.3 2. What were considered normal and increased anticardiolipin antibody titers in the authors’ laboratory? The degree of increase is usually critical in evaluating the clinical implication of this antibody. Current guidelines suggest that medium or high titers of anticardiolipin IgM and IgG have clinical significance, whereas low titers of IgM and IgG, or an IgA of any titer do not.3 3. How often was the anticardiolipin antibody titer negative in a control population? Because as many as 9.1% of otherwise healthy individuals may have a positive test for the antibody,4 did the frequency of positive tests exceed expectation? The Bayes theorem provides a mathematical framework to evaluate the value of a laboratory test based on the test’s sensitivity and specificity, as well as the pretest likelihood that the patient has the suspected condition. We have previously utilized the Bayes theorem to demonstrate that routine screening tests such as antinuclear antibody and purified protein derivative testing should not be indiscriminately ordered for all patients with uveitis.5 We agree with the conclusions of another prominent group6 that laboratory testing should be selectively ordered for patients with primary retinal vasculitis. The ultimate value of a laboratory test is its therapeutic implication. Patients with clinically significant anticardiolipin antibody titers are generally treated with highintensity oral anticoagulation, a therapy that has potential risk. Rather than screening all patients with retinal vasculitis of uncertain cause for the presence of anticardiolipin antibodies, we recommend this test for patients younger than age 45 who have suffered retinal vascular thrombosis and for patients with retinal vasculitis occurring in association with a collagen-vascular disease or a history of vascular thrombosis or pregnancy loss. JAMES T. ROSENBAUM, MD JUSTINE R. SMITH, MBBS, PHD
Portland, Oregon
REFERENCES
1. Giorgi D, David V, Afeltra A, Gabrieli CB. Transient visual symptoms in systemic lupus erythematosus and antiphospholipid syndrome. Ocul Immunol Inflamm 2001;9:49 –57. 2. Favaloro EJ, Silvestrini R, Mohammed A. Clinical utility of anticardiolipin antibody assays: high inter-laboratory variation and limited consensus by participants of external quality
CORRESPONDENCE
293
3.
4. 5.
6.
assurance programs signals a cautious approach. Pathology 1999;31:142–147. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309 –1311. Tsapanos V, Kanellopoulos N, Cardamakis E, et al. Anticardiolipin antibodies levels in healthy pregnant and nonpregnant woman. Arch Gynecol Obstet 2000;263:111–115. Rosenbaum JT, Wernick R. The utility of routine screening of patients with uveitis for systemic lupus erythematosus or tuberculosis. A Bayesian analysis. Arch Ophthalmol 1990; 108:1291–1293. George RK, Walton RC, Whitcup SM, Nussenblatt RB. Primary retinal vasculitis. Systemic associations and diagnostic evaluation. Ophthalmology 1996;103:384 –389.
body testing should probably be considered negligent. Similarly, Rosenbaum and Smith appear to have “fixity” based on the theory, whose testing instrument is the Bayes theorem that testing for anticardiolipin antibodies should be performed only in patients with “primary retinal vasculitis,” that is, patients with retinal vasculitis associated with a known systemic autoimmune disease such as systemic lupus erythematosus. I vigorously disagree and predict that this diagnostic testing nihilism will result in some patients irretrievably losing vision. I would point out that we tested patients in whom reasonable physicians would conclude that autoimmune-mediated vasculopathy could logically be considered on the differential diagnostic list of possibilities for that patient. For example, only patients with fluorescein angiographic evidence of retinal vasculitis, vascular thrombosis, or history of fetal loss were tested. Seven patients had potential neurologic involvement from the suspected vascular disease, one had a central retinal artery occlusion, one had recent thrombosis extraocularly, one had hematuria, and two had livedo reticularis, another extraocular manifestation of the possibility of one of the classic autoimmune collagen vascular disorders. Although Rosenbaum and Smith are to be commended for their “scientific purity” in guarding against excessive, expensive, and potentially misleading diagnostic testing in the evaluation of patients with ocular inflammatory disease, I believe that they would do well to recognize that, although parsimony in these matters is laudable, one may risk, in the process of proselytizing on this point, misleading the ophthalmic population at large into diagnostic pessimism and undertesting in patients with potentially serious (even potentially lethal) systemic autoimmune disease manifesting itself first as ocular inflammation, including retinal vasculitis. The point of our article was to alert readers to the fact that anticardiolipin antibodies may be associated with conditions other than classic autoimmune disease, such as systemic lupus erythematosus or the antiphospholipid antibody syndrome, and we reject the idea that the tests should be dogmatically restricted only to those patients with problems traditionally associated with a positive test. Responsible use of laboratory testing may well improve the care of individual patients and may expand our understanding of disease pathogenesis for a large group of individuals previously believed to have “idiopathic” uveitis.
AUTHOR REPLY THANKS FOR GIVING US THE OPPORTUNITY TO RESPOND
to the “Letter to the Editor” by Rosenbaum and Smith relating to our publication on “Ocular Features Associated With Anticardiolipin Antibodies: A Descriptive Study.” Rosenbaum and Smith disagree with “these statements:” 1. The authors (Miserocchi and Foster) “do not conclude that there is a causative role of anticardiolipin antibodies in some patients with uveitis.” 2. They (the authors) advise that “one might want to include anticardiolipin antibody screening in all patients presenting with uveitis of unclear cause in which retinal vasculitis is involved.” Rosenbaum and Smith have probably misspoken in that they probably do not mean that they “disagree with these statements.” Specifically, they probably do not disagree with the first statement, which they included in quotation marks; surely they must not imagine, given the tenor of their argument, that, in fact there is a causative role of anticardiolipin antibodies in some patients with uveitis. Therefore, if my guess is correct, they do, in fact, agree with the first statement enumerated above. It is, rather, the second statement with which they disagree. Dr. Rosenbaum has been a champion of decrying the indiscriminant use of any particular laboratory test in the investigations of patients with uveitis. In particular, he has emphasized the wastefulness of routine screening of uveitis patients with antinuclear antibody testing. Regrettably, some physicians take this to mean (and it is almost certain that Dr. Rosenbaum does not mean this) that ANA testing is inappropriate and wasteful in the diagnostic evaluation of a patient with uveitis. Nothing could be further from the truth. If an antinuclear antibody-associated disease, such as systemic lupus erythematosus, is appropriately on the physician’s mind as part of the differential diagnosis in a patient with uveitis, by virtue of pertinent positives on the history, review of systems, extraocular examination, and ocular examination, then not to request antinuclear anti294
AMERICAN JOURNAL
C. STEPHEN FOSTER, MD
Boston, Massachusetts
Prognosis for Placebo-treated Eyes in VIP Report 2 EDITOR: THE VERTEPORFIN IN PHOTODYNAMIC THERAPY (VIP) RE-
port 2 (Am J Ophthalmol;131:541–560, 2001) came to the OF
OPHTHALMOLOGY
FEBRUARY 2002
1. Otto AJ, Spekreije H. Intraorbital volume discrepancies and intraorbital pressure. Int Ophthalmol 1987;11:113–114. 2. Otto AJ, Spekreije H. Volume discrepancies in the orbit and the effect on intraorbital pressure. Orbit 1989;8:233–244. 3. Ohtsuka K. Intraocular pressure and proptosis in 95 patients with Graves ophthalmopathy. Am J Ophthalmol 1997;124: 570 –572.
Ocular Features Associated With Anticardiolipin Antibodies: A Descriptive Study EDITOR: IN THEIR REPORT “OCULAR FEATURES ASSOCIATED WITH
anticardiolipin antibodies: a descriptive study,” Miserocchi and colleagues describe a range of ocular findings among 13 patients who were seen over a period of approximately 13 years at the Massachusetts Eye and Ear Infirmary and who were noted to produce anticardiolipin antibodies (Am J Ophthalmol 131:451– 456, 2001). This report is a potential landmark study because it comes from an eminent group and it expands the spectrum of disease associated with anticardiolipin antibodies. Based on their data, the authors “do not conclude that there is a causative role of anticardiolipin antibodies in some patients with uveitis.” However, they advise that “one might want to include anticardiolipin antibody screening in all patients presenting with uveitis of unclear cause in which retinal vasculitis is involved.”1 We disagree with these statements. To evaluate the conclusions of this report, it is important to recognize specifics about the anticardiolipin antibody and general principles about laboratory testing. Numerous studies have reported an association between occlusive retinal vascular disease, often associated with some degree of intraocular inflammation, and antiphospholipid antibodies, including the anticardiolipin antibody.2 Like other autoantibodies, anticardiolipin antibodies may be expressed at low levels by healthy individuals. Anticardiolipin antibodies are more commonly detected in patients with specific inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis and autoimmune thyroiditis, certain infections including syphilis, and the primary antiphospholipid antibody syndrome. When present in clinically significant titers, the antibodies are believed to have a causative role in vascular occlusive episodes and pregnancy losses. To evaluate whether the presence of anticardiolipin antibody was clinically significant in the patients reported by Miserocchi and coworkers, one needs to know the following information: 1. Were measurements of the anticardiolipin antibody titers performed more than once for each patient? VOL. 133, NO. 2
High interlaboratory variation in titer levels and a general lack of test result consensus between laboratories are substantial concerns in the interpretation of anticardiolipin antibody assays.3 Measurement of increased levels of anticardiolipin antibody on two or more occasions, at least 6 weeks apart, is considered to be clinically significant.3 2. What were considered normal and increased anticardiolipin antibody titers in the authors’ laboratory? The degree of increase is usually critical in evaluating the clinical implication of this antibody. Current guidelines suggest that medium or high titers of anticardiolipin IgM and IgG have clinical significance, whereas low titers of IgM and IgG, or an IgA of any titer do not.3 3. How often was the anticardiolipin antibody titer negative in a control population? Because as many as 9.1% of otherwise healthy individuals may have a positive test for the antibody,4 did the frequency of positive tests exceed expectation? The Bayes theorem provides a mathematical framework to evaluate the value of a laboratory test based on the test’s sensitivity and specificity, as well as the pretest likelihood that the patient has the suspected condition. We have previously utilized the Bayes theorem to demonstrate that routine screening tests such as antinuclear antibody and purified protein derivative testing should not be indiscriminately ordered for all patients with uveitis.5 We agree with the conclusions of another prominent group6 that laboratory testing should be selectively ordered for patients with primary retinal vasculitis. The ultimate value of a laboratory test is its therapeutic implication. Patients with clinically significant anticardiolipin antibody titers are generally treated with highintensity oral anticoagulation, a therapy that has potential risk. Rather than screening all patients with retinal vasculitis of uncertain cause for the presence of anticardiolipin antibodies, we recommend this test for patients younger than age 45 who have suffered retinal vascular thrombosis and for patients with retinal vasculitis occurring in association with a collagen-vascular disease or a history of vascular thrombosis or pregnancy loss. JAMES T. ROSENBAUM, MD JUSTINE R. SMITH, MBBS, PHD
Portland, Oregon
REFERENCES
1. Giorgi D, David V, Afeltra A, Gabrieli CB. Transient visual symptoms in systemic lupus erythematosus and antiphospholipid syndrome. Ocul Immunol Inflamm 2001;9:49 –57. 2. Favaloro EJ, Silvestrini R, Mohammed A. Clinical utility of anticardiolipin antibody assays: high inter-laboratory variation and limited consensus by participants of external quality
CORRESPONDENCE
293
3.
4. 5.
6.
assurance programs signals a cautious approach. Pathology 1999;31:142–147. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309 –1311. Tsapanos V, Kanellopoulos N, Cardamakis E, et al. Anticardiolipin antibodies levels in healthy pregnant and nonpregnant woman. Arch Gynecol Obstet 2000;263:111–115. Rosenbaum JT, Wernick R. The utility of routine screening of patients with uveitis for systemic lupus erythematosus or tuberculosis. A Bayesian analysis. Arch Ophthalmol 1990; 108:1291–1293. George RK, Walton RC, Whitcup SM, Nussenblatt RB. Primary retinal vasculitis. Systemic associations and diagnostic evaluation. Ophthalmology 1996;103:384 –389.
body testing should probably be considered negligent. Similarly, Rosenbaum and Smith appear to have “fixity” based on the theory, whose testing instrument is the Bayes theorem that testing for anticardiolipin antibodies should be performed only in patients with “primary retinal vasculitis,” that is, patients with retinal vasculitis associated with a known systemic autoimmune disease such as systemic lupus erythematosus. I vigorously disagree and predict that this diagnostic testing nihilism will result in some patients irretrievably losing vision. I would point out that we tested patients in whom reasonable physicians would conclude that autoimmune-mediated vasculopathy could logically be considered on the differential diagnostic list of possibilities for that patient. For example, only patients with fluorescein angiographic evidence of retinal vasculitis, vascular thrombosis, or history of fetal loss were tested. Seven patients had potential neurologic involvement from the suspected vascular disease, one had a central retinal artery occlusion, one had recent thrombosis extraocularly, one had hematuria, and two had livedo reticularis, another extraocular manifestation of the possibility of one of the classic autoimmune collagen vascular disorders. Although Rosenbaum and Smith are to be commended for their “scientific purity” in guarding against excessive, expensive, and potentially misleading diagnostic testing in the evaluation of patients with ocular inflammatory disease, I believe that they would do well to recognize that, although parsimony in these matters is laudable, one may risk, in the process of proselytizing on this point, misleading the ophthalmic population at large into diagnostic pessimism and undertesting in patients with potentially serious (even potentially lethal) systemic autoimmune disease manifesting itself first as ocular inflammation, including retinal vasculitis. The point of our article was to alert readers to the fact that anticardiolipin antibodies may be associated with conditions other than classic autoimmune disease, such as systemic lupus erythematosus or the antiphospholipid antibody syndrome, and we reject the idea that the tests should be dogmatically restricted only to those patients with problems traditionally associated with a positive test. Responsible use of laboratory testing may well improve the care of individual patients and may expand our understanding of disease pathogenesis for a large group of individuals previously believed to have “idiopathic” uveitis.
AUTHOR REPLY THANKS FOR GIVING US THE OPPORTUNITY TO RESPOND
to the “Letter to the Editor” by Rosenbaum and Smith relating to our publication on “Ocular Features Associated With Anticardiolipin Antibodies: A Descriptive Study.” Rosenbaum and Smith disagree with “these statements:” 1. The authors (Miserocchi and Foster) “do not conclude that there is a causative role of anticardiolipin antibodies in some patients with uveitis.” 2. They (the authors) advise that “one might want to include anticardiolipin antibody screening in all patients presenting with uveitis of unclear cause in which retinal vasculitis is involved.” Rosenbaum and Smith have probably misspoken in that they probably do not mean that they “disagree with these statements.” Specifically, they probably do not disagree with the first statement, which they included in quotation marks; surely they must not imagine, given the tenor of their argument, that, in fact there is a causative role of anticardiolipin antibodies in some patients with uveitis. Therefore, if my guess is correct, they do, in fact, agree with the first statement enumerated above. It is, rather, the second statement with which they disagree. Dr. Rosenbaum has been a champion of decrying the indiscriminant use of any particular laboratory test in the investigations of patients with uveitis. In particular, he has emphasized the wastefulness of routine screening of uveitis patients with antinuclear antibody testing. Regrettably, some physicians take this to mean (and it is almost certain that Dr. Rosenbaum does not mean this) that ANA testing is inappropriate and wasteful in the diagnostic evaluation of a patient with uveitis. Nothing could be further from the truth. If an antinuclear antibody-associated disease, such as systemic lupus erythematosus, is appropriately on the physician’s mind as part of the differential diagnosis in a patient with uveitis, by virtue of pertinent positives on the history, review of systems, extraocular examination, and ocular examination, then not to request antinuclear anti294
AMERICAN JOURNAL
C. STEPHEN FOSTER, MD
Boston, Massachusetts
Prognosis for Placebo-treated Eyes in VIP Report 2 EDITOR: THE VERTEPORFIN IN PHOTODYNAMIC THERAPY (VIP) RE-
port 2 (Am J Ophthalmol;131:541–560, 2001) came to the OF
OPHTHALMOLOGY
FEBRUARY 2002