The Editors welcome submissions for possible publication in the Letters section. Authors of letters should: • Include no more than 400 words of text, three authors, and five references • Type with double-spacing • Send three copies of the letter and a transfer-of-copyright form (see Table of Contents for location) signed by all authors • Provide a self-addressed envelope if they want to be notified that the letter was received Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
Pharmaceutical Ads in Journals
To the Editors: It is unfortunate that the Editors of the Annals did not seek the views of the pharmaceutical industry for publication in the same issue as the study by Wilkes and colleagues on prescription drug advertisements (1). Although they are important, the views of Food and Drug Administration (FDA) Commissioner David Kessler and those of Drs. Robert and Suzanne Fletcher comprise only two thirds of the other side of this issue. Advertising and promotion are important aspects of free market economies. After spending an average of $230 million and 10 years to introduce a new product, a company has an average of 7 years to earn back its investment and is entitled to use FDA-regulated advertising. From the industry's perspective, there are several problems with the Wilkes' study. First, why were medical reviewers of journal articles rather than those with regulatory experience chosen to judge the compliance of advertisements with FDA regulations? Wilkes stated that his "experts identified areas suggesting potential lack of compliance with FDA regulations in 92% of the advertisements, with a mean of four areas not in compliance with these regulations" (1). In fiscal year 1990, the FDA reviewed 1800 prescription drug ads and sent a total of 139 (8%) notice of violation letters and four regulatory letters to companies. (Feather K. Personal communication.) Obviously, Wilkes' reviewers were not using the FDA's criteria. The FDA's numbers contradict Wilkes' thesis that regulatory deficiencies are the rule rather than the exception. Second, according to the Annals'9 own press release on the study: "The major deficiency was inadequate scientific documentation." However, the FDA requires all prescription drug claims to be backed by controlled clinical studies before it approves a product for marketing. If Wilkes and associates could not find the documentation for these claims elsewhere, why did they not seek such information at the FDA? The study authors say: "The major problem areas in advertisements identified by our reviewers included inaccurate statements and inadequate information on side effects and contraindications, the effect of the drugs in particular populations, efficacy, and safety." This statement is also difficult to under616
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stand. Again, by law, a summary of the FDA-approved package labeling—including warnings, contraindications, and adverse reactions—is printed next to the ad copy in every pharmaceutical advertisement, except for "reminder" ads that carry no message except the product's name. This is essentially the same information physicians get from The Physicians' Desk Reference, which contains verbatim FDA labeling. How many of the advertisements were "reminder" ads? Another major deficiency we see in this study was its underlying assumption that advertisements should be judged by the same criteria as peer-reviewed journal articles. Advertisements are not journal articles; they are commercial communications that—unlike journal articles—are regulated by the government. By their nature, advertisements are designed to attract attention to and raise awareness about a particular product. They can never be—and should never be—anyone's sole source of information. Every consumer understands this. Physicians certainly do and have no trouble distinguishing a scientific article from a journal advertisement. The situation was well summarized by Dr. Arnold Relman, former editor of The New England Journal of Medicine, who said of the Wilkes study: "Everyone knows that advertisements are meant to promote sales of drugs and they're not supposed to be scientific communications. They cannot possibly have the accuracy and the balance and the strength of evidence that one would expect for a scientific article. . . . And to demand that it be comparable to a research paper is rather silly" (2). John F. Beary, III, MD Senior Vice President, Science and Technology Pharmaceutical Manufacturers Association Washington, DC 20005 References 1. Wilkes MS, Doblin B, Shapiro M. Pharmaceutical advertisements in leading medical journals: experts' assessments. Ann Intern Med. 1992;116:912-9. 2. Relman A. Pharmaceutical advertisements. Interview on "Morning Edition." WAMU FM radio (National Public Radio). 2 June 1992.
To the Editors: The Coalition of Healthcare Communicators, representing nine organizations involved in all aspects of pharmaceutical marketing, finds the article by Wilkes and colleagues (1) filled with paradox, flaws, and irony. Annals is an outstanding peer-reviewed journal devoted to fair balance and scientific rigor. The paradox relates to why an industry representative was not allowed to examine the data and present another view, as Dr. Kessler of the FDA was? To further compound the matter, a press release was issued to spread the " n e w s " via the lay press, always hungry to report on any perceived offensive actions in the healthcare arena, without providing any perspective on the environment in which advertising in medical journals appears. For instance, all ads must contain a disclosure of FDA-approved information about the drug, often numbering several columns and including adverse information like side effects, contraindications, and warnings. The unfair reporting by the lay press and inappropriate conclusions by the study authors conveyed the impression of widespread wrongdoing. The study's flaws were many. The Advertising Research Foundation will be conducting a technical analysis of the research methods. However, there are glaring questions about the study design that occur even to those who are not "expert" at pharmaceutical advertising: For example, as the Drs.
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Fletcher wisely noted in their editorial (2), a reasonable person would not judge an advertisement by the same standards as a peer-reviewed article. Second, would it not have made more sense for practicing physicians to whom the ad is directed to evaluate the educational worth of the ads rather than an academic drug expert? Finally, the study indicated that the reviewers had not received formal training on current FDA regulations, yet one of the two objectives of the study was to assess compliance with FDA regulations. Is this fair? And now the irony. Pharmaceutical promotion is meticulously scrutinized by the FDA, and we doubt it would have allowed the authors to make the claims they did based on this research. Although your attempt to offer some balance to the article through the editorial (2) was a noble one, Fm afraid it paled in comparison to the negative public impact the article and your press release have had on a very serious and dedicated industry. Those of us involved in the business of healthcare communications wonder when some of this intellectual energy will be directed toward solving some of the real healthcare delivery problems facing this country rather than using it to demean one of our few remaining internationally successful and essential industries. Jack F. Angel Executive Director Coalition of Healthcare Communications Greenwich, CT 06830 References 1. Wilkes MS, Doblin B, Shapiro M. Pharmaceutical advertisements in leading medical journals: experts' assessments. Ann Intern Med. 1992;116:912-9. 2. Fletcher RH, Fletcher SW. Pharmaceutical advertisements in medical journals [Editorial]. 1992;116:951-2. To the Editors: The study by Wilkes and colleagues (1) lacks scientific credibility because the reviewers were unfamiliar with the subject. I challenge the premise that reviewers of scientific studies submitted for publication in their respective fields can apply the same criteria to the content of prescription drug advertisements. That a brief summary of prescribing information including warnings, contraindications, and so forth is part of every published advertisement was not considered. Agreement between the FDA and drug company executives on whether a promotional message meets the restrictions of approved drug labeling is a negotiated one and not within the reviewers' expertise. I write as president of the Association of Medical Publications, an organization of 24 major medical associations and independent commercial firms that publish 60 journals for physicians, including some of the best-known medical publications in the United States, although the opinions expressed are my own. The FDA must approve all promotional materials for new products before release. Thereafter, the agency sees all drug advertising that appears in journals and can send warning letters to drug companies when it finds ad messages to be unacceptable. It has done so with increasing frequency, requiring remedial promotional programs. The FDA also exercises its power to label a prescription drug "misbranded" for improper promotional activity and to sue in court to remove it from the market. The matter of accuracy and balance in drug promotion does not go unattended. The Wilkes study's simplistic approach casts great doubt on the validity of its results. Milton Liebman President, The Association of Medical Publications, Inc. New York, NY 10173 Reference 1. Wilkes MS, Doblin B, Shapiro M. Pharmaceutical advertisements in leading medical journals: experts' assessments. Ann Intern Med. 1992;116:912-9.
To the Editors: Prescreening journal advertisements before they appear in print is a good idea in principle (1), but the Canadian Pharmaceutical Advertising Advisory Board's (PAAB) implementation should not serve as a model for the United States. Its Code of Advertising Acceptance is both weak and poorly enforced. The only provision that applies to the pictorial, or non-textual, content of advertisement refers to the non-imitation of other firms' ads. The PAAB does not see the final version of the pictorial part of an ad. In the past, this lack of control allowed the appearance of advertisements such as one with a picture of a kneeling, naked woman under the caption "for a great performance." The code requires that the brand or trade name and the generic name must appear together at least once in both the advertising and prescribing information. Nothing is said about the relative print sizes of the brand and generic names so there may be a fourfold or greater difference in favor of the trade name. The code states that "data presentations that are misleading or ambiguous . . . will be considered in violation of the PAAB Code." Yet the PAAB approved an ad emphasizing a reduction in nonfatal cardiac events after using a certain drug; the ad failed to mention the lack of difference in overall mortality. Seven clauses in the code cover claims, quotations, and references, but ads are approved with statements that do not always accurately reflect the data in the reference. Perhaps the most serious gap in the code is its lack of effective sanctions. If a complaint is upheld, the code merely requires that the advertisement be amended or withdrawn. By the time a complaint is registered, the appeals procedure is exhausted, and a decision against an ad is confirmed, the ad may have finished its run. Finally, the PAAB does not publicly release data about the number, type, and disposition of complaints. In the early 1970s, the U.S. National Council of Churches of Christ held a series of public hearings on the issue of drug advertising. With respect to voluntary codes, it concluded: "The self-regulatory mechanisms of the pharmaceutical industry . . . are minimal and ineffective. Where advertising codes exist, compliance is voluntary and unenforced; the responsible parties resist establishing sanctions for code violations. The existence of advertising codes without enforcement procedures gives the consumer a false assurance that drug advertisements are true" (2). That judgment is still valid today. Joel Lexchin, MD 121 Walmer Road Toronto, Ontario M5R 2X8 References 1. Fletcher RH, Fletcher SW. Pharmaceutical advertisements in medical journals [Editorial]. Ann Intern Med. 1992;116:951-2. 2. National Council of Churches of Christ. Findings and conclusions of the NCCC project on drug advertising. J Drug Issues. 1974;4:310-2. To the Editors: At the conclusion of their editorial (1), Drs. Robert and Suzanne Fletcher stated that, "The pharmaceutical industry can be expected to police itself (11), but they should not be alone in the process." They cited a study by Herxheimer and Collier that examined the effectiveness of a code of practice instituted in 1958 by the Association of British Pharmaceutical Industry (ABPI) attempting to regulate the promotion of prescription medicines (2). The authors analyzed 6 years (1983 to 1989) of complaints considered by a code of practice committee, the committee's annual reports, and additional breaches detailed by the ABPI secretariat. The complaints came mainly from doctors (48%) and competing companies (33%). Herxheimer and Collier stated that, " . . .the evidence suggests that the code has failed to deter promotional excesses. The ABPI's wish to secure compliance with the code seems weaker than its wish to pre-empt outside criticism and action; its self regulation seems to be a service to itself rather than to the public." Thus the study actually showed that the pharmaceutical industry cannot be expected to police itself. Codes and guidelines that carry no penalties, no enforcement mechanisms, nor any disclosure requirements are unlikely to be effective.
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Robert C. Noble, MD University of Kentucky College of Medicine Lexington, KY 40536 References 1. Fletcher RH, Fletcher SW. Pharmaceutical advertisements in medical journals [Editorial]. Ann Intern Med. 1992;116:951-2. 2. Herxheimer A, Collier J. Promotion in the British pharmaceutical industry, 1983-8: a critical analysis of self-regulation. BMJ. 1990;300: 307-11.
To the Editors: I like the ads! Many are creative, interesting, and even slightly educational. Of course, I would no more rely on them for definitive information than I would accept a drug rep's sales pitch as gospel. But the ads can serve as clever reminders of what drugs are new, of dosage schedules, and of which indications have FDA approval. As pointed out by Dr. Voth, a uninterested physician can simply tear them off. Surely the subscription cost of the reputable medical journals would increase without the ads—the drug companies are really subsidizing our education. Too bad MKSAP IX had no drug ads—I paid $417.50 for it. Two other physicians in our primary care office did not purchase this program because of the cost. Anita Y. Agzarian, MD 10,000 Venice Boulevard Culver City, CA 90232 To the Editors: Wilkes and colleagues (1) and the accompanying editorialists (2, 3) have correctly defined a serious problem and options for improvement of pharmaceutical advertising. That manufacturers would devise keen methods of promoting products to physicians was known one hundred years ago. It was recognized then that "for a manufacturer to attempt to create a fictitious demand for his products by assuming the role of medical instructor, is an insult to each individual practitioner. . ." and "how criminal it is to permit the statements of such interested parties to have the slightest weight in deciding questions of treatment. . . . " These words still apply (4). One answer to the dilemma of obtaining accurate, objective, and reliable drug information is your pharmacist, who has received extensive training in all aspects of drug therapy and who has the responsibility to maintain current databases for all medications. A great deal of our time is spent "counter detailing" physicians, providing unbiased information that often does not coincide with claims made by sales representatives. Ask questions of your pharmacists, and include them in decision making; we have so much more to offer to society than "count, pour, lick, and stick." Daniel L. Krinsky, MS, RPh Clinical Information Specialist Kaiser Permanente, Ohio Region Brooklyn Heights, OH 44313
References 1. Wilkes MS, Doblin B, Shapiro M. Pharmaceutical advertisements in leading medical journals: experts' assessments. Ann Intern Med. 1992;116:912-9. 2. Kessler DA. Addressing the problem of misleading advertising [Editorial]. Ann Intern Med. 1992;116:950-1. 3. Fletcher RH, Fletcher SW. Pharmaceutical advertisements in medical journals [Editorial]. Ann Intern Med. 1992;116:951-2. 4. Drug manufacturers as medical teachers. JAMA. 1892;18:563. [Reprinted in JAMA. 1992;267:2172.]
In response: Dr. Beary and Mr. Angel and Mr. Liebman take exception to our study for relying on reviewers who were experts in the clinical use of the drugs advertised and who had acted as reviewers for medical journals. Dr. Beary proposes that "reviewers with regulatory experience" be used. We believe our selection of reviewers represents the best nonbiased sample we could find. For example, by choosing a leading expert in the field of hypertension to review a hypertensive advertisement, we gained far more information about the advertisement than if we had used someone who, although thor618
oughly familiar with the FDA regulations, possessed far less expertise about the drug product. The questions that our reviewers answered were directly derived from FDA guidelines and were explicit and self-explanatory. They did not require a thorough understanding of FDA regulations. We asked, "Does this study use statistics derived from inconclusive, dissimilar, or poorly designed studies?"; "Does this advertisement use a headline, subheadline, or image in a manner which misleads the reader about the side effects or contraindications?"; "If the advertisement contains a suggestion that the drug is safe, is it in agreement with current scientific knowledge regarding the drug?" We believe that these are reasonable questions for individuals who know a great deal about a content area, whether or not they are experts in regulation. Dr. Beary's comment that the FDA only judged a small portion of the advertisements to be out of compliance with FDA regulations is beside the point. The FDA has not subjected all advertisements to rigorous review because it does not have the staff or resources to do this. They certainly do not review all drug advertising copy that appears in journals, as Mr. Liebman suggests. In the past, the FDA has often reviewed an advertisement only after the advertisement has been brought to its attention, either by a clinician or a competing pharmaceutical company. We have been informed by the office of the Inspector General that when the FDA reviewed the advertisements in our study, it concluded that a large proportion were, indeed, out of compliance. In taking exception to our statement that, despite aggressive attempts to secure all of the literature cited in advertisements, we often were unable to do so, Dr. Beary suggests that we should have contacted the FDA. However, most of these citations involved studies not used as the basis for initial approval of the product and therefore not contained in the FDA files. It is our strong belief that manufacturers should be able to provide supporting literature for any claim made in their advertisements. Not infrequently, we received letters back from pharmaceutical manufacturers stating that they were unable to send us a scientific article unobtainable in a library or would not release to us an unpublished reference which they regarded as confidential. Dr. Beary, Mr. Angel, and Mr. Liebman emphasize that the FDA regulates the claims made on behalf of the product in the package insert information at the end of the advertisement. The FDA does state that no advertisement may go beyond FDA approved claims, but this applies only to the information in very small print at the end of the advertisement-the socalled package insert material. This does not pertain to claims made in the text of an advertisement. Yet, it is the headlines, images, and large-type copy of an advertisement that are read most often. Claims appear there that are quite different in tone and substance from those in the small print. Finally, Dr. Beary suggests that everyone knows that advertisements are promotional and therefore should not be someone's sole source of information. Advertisements and promotion are indeed important aspects of a free market economy. However, this does not mean, as implied, that such information does not need to be completely accurate, honest, and truthful. We thank Daniel Krinsky for pointing out that many of the arguments being made today concerning misleading advertising were made over 100 years ago in an attempt to regulate the pharmaceutical industry. It is interesting how, despite aggressive legislation, the pharmaceutical industry continues to disseminate half-truths and mis-truths about their drug products. Further, we wholeheartedly agree that pharmacists need to play a much greater role in both educating physicians and consumers about pharmaceutical products and in helping us make clearer, safer, more cost-effective choices for our patients. In conclusion, there is compelling evidence, most of it well known to the pharmaceutical companies, that advertisements profoundly influence the way prescription drugs are used in our society. If pharmaceutical advertisements were not effective in changing physicians' prescribing practices, why would the industry spend over $300 million annually to promote drugs to physicians through them? Given our results, we strongly
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agree that advertisements should never be anyone's sole source of information. Yet, too often, they are the decisive source of information about new pharmaceutical products. This is a difficult and embarrassing point for the medical community to accept: Nobody likes feeling as though he or she has been duped into behaving in a certain manner. The medical community needs to acknowledge and take action on the fact that the pharmaceutical manufacturers, through their promotions and sponsored events, have a great deal of influence on the way physicians prescribe drugs. Until then, we can expect to see the industry continue to use strategies to maximize their sales, even if that means misrepresenting their products. Michael S. Wilkes, MD Bruce H. Doblin, MD, MPH Martin F. Shapiro, MD UCLA School of Medicine Los Angeles, CA 90024-1685 Surrogate Markers in AIDS To the Editors: The editorial by Lagakos and Hoth (1) addresses an interesting aspect of clinical trials involving the acquired immunodeficiency syndrome (AIDS). Some of their statements are, however, too broad. For example, surrogate markers are not necessary when dealing with conditions with well-defined therapeutic parameters and goals (for example, normal thyroid function tests in thyroxine replacement or gastric pH above 4 in antacid prophylaxis of stress ulcer). The use of a CD4 count of 200 as a threshold in the quantitative Centers for Disease Control (CDC) definition of AIDS no longer qualifies it a surrogate marker. Zidovudine (AZT) remains the primary antiretroviral agent; dideoxyinosine (ddl) and dideoxycytidine (ddC) have been proposed for use only in patients who do not benefit from AZT. Because many HIVpositive patients are first started on AZT on the basis of their CD4 count, this criterion remains the most appropriate measure of the need for additional or alternative medications. The arguments that Lagakos and Hoth put forward are better directed against the use of a CD4 count of less than 200 to define AIDS.
Reference 1. Lagakos SW, Hoth DF. Surrogate markers in AIDS: Where are we? Where are we going? Ann Intern Med. 1992;116:599-601.
Wegener Granulomatosis To the Editors: I read the review on Wegener granulomatosis by Hoffman and colleagues (1) with great interest. Treatment with trimethoprim sulfamethoxazole (TMP-SMX) may be a useful alternative in selected patients (2, 3), as the following case suggests. A 34-year-old man presented with left nasal obstruction due to a large inverted papilloma. He had extensive nasal surgery. Three months later, he developed migratory arthralgia and arthritis, an 8-kg weight loss, infiltrates on chest radiograph, and rapidly rising blood urea nitrogen (BUN) and creatinine levels. Evidence of granulomatous vasculitis consistent with Wegener granulomatosis was found on the original pathology specimens. In addition, antineutrophil cytoplasmic antibodies (ANCA) (Mayo Medical Laboratories, Rochester, Minnesota) were positive at a titer of 1:128. The patient was started on a high-dose prednisone and daily cyclophosphamide protocol (4). Despite daily cyclophosphamide doses of up to 275 mg, he developed respiratory failure requiring ventilator assistance, and his BUN and creatinine levels increased to 21.2 mmol/L and 380 /xmol/L, respectively, before he slowly improved. The patient's subsequent treatment with cyclophosphamide was complicated by infection, anemia requiring transfusion, and leukopenia. At 10 months, repeat nasal endoscopy by the otolaryngologist showed granulomatous changes on the posterior maxillary sinus wall. At that time, ANCA remained positive in a titer of 1:64, indicative of active disease. Rather than increase the dose of cyclophosphamide or resume corticosteroids, we added TMP-SMX, and tapered the patient's dose of cyclophosphamide over the next 2 months. Repeat nasal endoscopic examination after 1 month of treatment with TMPSMX showed less evidence of recurrent granulomas. At 16 months, the patient no longer requires transfusions. He has had no further infectious complications, and his renal function has remained stable. Larry Greenbaum, MD Medical Specialists, Inc. Zanesville, OH 43701
Kofi Nuako, MD Good Samaritan Hospital Baltimore, MD 21239 Reference 1. Lagakos SW, Hoth DF. Surrogate markers in AIDS: Where are we? Where are we going? Ann Intern Med. 1992;116:599-601.
In response: We agree with Dr. Nuako that our comments (1), which focus on surrogate markers in AIDS, do not necessarily apply to other diseases. We disagree, however, that the expansion of the surveillance definition of AIDS by the CDC to include a CD4 cell count below 200/mm3 means that CD4 can no longer be considered as a surrogate marker. The main purpose of our editorial was to consider when and whether a treatment's effect on CD4 cell count or other marker implies that it will also produce meaningful clinical improvement or, conversely, the development of an AIDS-defining opportunistic infection or death. Thus, the inclusion by the CDC of decreased CD4 count as an AIDSdefining event does not alter its importance for this purpose. Finally, Dr. Nuako claims that the CD4 count "remains the most appropriate measure of the need for additional or alternative medications. . . . " Although we do not necessarily disagree, the essence of our editorial was to attempt to assess the rationale for such reliance. Stephen Lagakos, PhD Harvard University Boston, MA 02115 Daniel F. Hoth, MD National Institutes of Health Bethesda, MD 20892
References 1. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-98. 2. Valeriano-Marcet J, Spiera H. Treatment of Wegener's granulomatosis with sulfamethoxazole-trimethoprim. Arch Intern Med. 1991;151: 1649-52. 3. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983;98:76-85. 4. Roberts DE, Curd JG. Sulfonamides as antiinflammatory agents in the treatment of Wegener's granulomatosis. Arthritis Rheum. 1990; 33:1590-3.
To the Editors: The range of clinical presentations within the current concept of Wegener granulomatosis are well expressed by the ELK classification as promulgated by the Mayo group in 1976 and are validated by ANCA (1). Many patients have disease confined to the upper or lower respiratory tract (classes E, L, and EL) without evidence of disseminated vasculitis or nephritis. The Mayo group has found TMP-SMX to be extremely effective and safe in a selected group of patients (2). Of 84 patients, 71 have shown objective improvement. In 27 patients, TMP-SMX was the sole agent used without previous other treatment. For patients with evidence of vasculitis, nephritis, or both (classes EK, LK, and ELK), we continue to use traditional treatment with glucocorticoids and cyclophosphamide. For those having an indolent course in the absence of vasculitis or nephritis, however, we have initiated treatment with TMP-SMX alone, adding alternate-day prednisone if no response is elicited in 6 to 8 weeks. In a recent study, 12 of 12 patients with disease confined to
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the upper respiratory tract (E) and 2 of 2 patients treated with disease in the upper respiratory tract and lung (EL) responded completely to TMP-SMX alone. A similar result has been reported by Georgi and colleagues (3), who treated 10 patients in what they called "initial phase" (classes E and EL). All 10 patients responded and remained in remission for at least 1 year. Although only one patient treated by Hoffman and colleagues (4) with TMP-SMX showed prolonged improvement, even this result is encouraging because Wegener granulomatosis does not undergo spontaneous remission. More information concerning the ELK class of the failures might explain the outcome. Because almost one half of the deaths we observed in Wegener granulomatosis appeared to be attributable to immunosuppressant regimens (2), a safe treatment such as TMP-SMX, as opposed to toxic regimens using glucocorticoids and cyclophosphamide, should be given a reasonable trial in patients without vasculitis or nephritis. Richard A. DeRemee, MD Mayo Medical School Rochester, Minnesota 55905 References 1. DeRemee RA, McDonald TJ, Harrison EG Jr., Coles DT. Wegener's granulomatosis, anatomic correlates: a proposed classification. Mayo Clin Proc. 1976;51:777-81. 2. DeRemee RA. The treatment of Wegener's granulomatosis with trimethoprim/sulfamethoxazole: illusion or vision? Arthritis Rheum. 1988;31:1068-72. 3. Georgi J, Ulmer M, Gross WL. Co-trimoxazol bei Wegenerscher granulomatose—eine prospektive studie. Immun Infekt. 1991; 19: 97-8. 4. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-98.
To the Editors: Hoffman and colleagues' superb analysis of 158 patients with Wegener granulomatosis is an outstanding contribution (1). Can they complete their presentation of the 10 patients who had pericarditis? Literature searches for three books on pericarditis and one recent article on pericarditis in systemic diseases (2) did not reveal Wegener granulomatosis as an etiology. Did the authors' patients have Wegener lesions (that is, vasculitis) of the pericardium? What were the chemical and histologic results of pericardiocentesis and pericardiectomy in the single patient reported? Could the pericarditis have been due to uremia? David H. Spodick, MD, DSc St. Vincent Hospital Worcester, MA 01604 References 1. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-98. 2. Spodick DH. Pericarditis in systemic diseases. Cardiol Clin. 1990;8: 709-16.
To the Editors: Hoffman and colleagues (1) raised doubts about the value of perinuclear ANCA (P-ANCA) in the diagnosis of Wegener granulomatosis. Although we agree that "perinuclear (P-ANCA) immunofluorescent staining . . . is not a useful diagnostic tool for Wegener's granulomatosis," we (2) and others (3, 4) have found that autoantibodies to myeloperoxidase, one of several antigens resulting in the P-ANCA immunofluorescence pattern, are extremely useful in diagnosing the group of diseases that includes Wegener granulomatosis. Antibodies to myeloperoxidase or proteinase 3 (the antigen responsible for the cytoplasmic ANCA (C-ANCA) pattern as detected by enzyme-linked immunosorbent assay (ELISA) or recombinant immunoassay (RIA) using purified antigens, have been shown to be highly specific markers for the spectrum of diseases associated with the renal lesion of necrotizing and crescentic glomerulonephritis with scant or no immune deposits. This group includes Wegener granulomatosis, so called microscopic polyarteritis nodosa, the Churg-Strauss syndrome, idiopathic necrotizing and crescentic glomerulonephritis, and 620
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related or overlapping forms of these conditions. All require treatment with immunosuppression. Antiproteinase 3 antibodies are more often found in patients at the Wegener granulomatosis end of this spectrum, and antimyeloperoxidase antibodies are more broadly distributed throughout the spectrum. Patients at any end of the spectrum may, however, have either type of antibody, but not both (2-4). Immunofluorescence tests for P-ANCA should not be substituted for antigen-specific immunoassays for the detection of antimyeloperoxidase autoantibodies. John L. Niles, MD Robert T. McCluskey, MD M. Amin Arnaout, MD Massachusetts General Hospital Boston, MA 02114 References 1. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-98. 2. Niles JL, Pan G, Collins AB, et al. Value of antigen-specific radioimmunoassays for measuring anti-neutrophil cytoplasmic antibodies (ANCA) in the differential diagnosis of rapidly progressive glomerulonephritis. J Am Soc Nephrol. 1991;2:27-36. 3. Cohen Tervaert JW, Goldschmeding R, Elema JD, et al. Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum. 1990;33:1264-72. 4. Jennette JC, Falk RJ. Antineutrophil cytoplasmic autoantibodies and associated diseases: a review. Am J Kidney Dis. 1990;15:517-29.
In response: Dr. Greenbaum's letter describes a patient with severe life-threatening Wegener granulomatosis who, after initial deterioration, responded to conventional therapy with glucocorticoids and daily cyclophosphamide. Glucocorticoids were gradually discontinued. Ten months after treatment had begun, on the basis of the gross appearance of the maxillary sinus mucosa and a persistently positive ANCA study, it was assumed that active disease was present and TMP-SMX treatment was started. Improvement followed and was gradually discontinued. There are at least two interpretations of these observations: 1) TMP-SMX was effective treatment for Wegener granulomatosis in this patient or; 2) Active Wegener granulomatosis was not present and TMP-SMX effectively treated bacterial sinusitis. The basis upon which active disease was presumed may have been faulty. Granulomatous mucosal inflammation cannot be assumed from only gross inspection. Proof of inflammation with granulomas (that is, collections of "epithelioid cells," giant cells, lymphocytes and less numerous and variable numbers of neutrophils, plasma cells and fibroblasts) can only be determined microscopically. In addition, although a positive C-ANCA serology result would support the clinical diagnosis of Wegener granulomatosis it is neither a sufficiently sensitive or specific marker to allow the presumption of active Wegener granulomatosis. In our experience, although C-ANCA positivity was a sensitive and specific indicator of the diagnosis of Wegener granulomatosis serial C-ANCA titer changes were temporally concordant with disease status in only 55% of patients (1). In Dr. Greenbaum's patient, when Wegener granulomatosis had presumably relapsed, the C-ANCA titer in fact decreased by one tube dilution, which may or may not have been significant. Thus, this experience does not help to resolve the question of whether TMP-SMX is effective for the treatment or bacterial otolaryngic complications of Wegener granulomatosis. Dr. DeRemee suggests that our disappointing experience with TMP-SMX therapy for Wegener granulomatosis may not present a balanced view that takes into account previously reported success with this agent (2). Our study was initiated with the hope of confirming those observations. However, we were concerned that some previously reported patients with limited disease did not have diagnostic biopsies, may have had bacterial infections which so commonly affect the airway in patients with Wegener granulomatosis (3), or may have had concurrent increase in immunosuppressive medications that in fact caused improvement that was attributed to TMP-SMX therapy. Our study of TMP-SMX required biopsy proof of active WG at the time of study entry, no evidence of infection
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and no recent or concurrent increase in immunosuppressive medications. This degree of rigor resulted in only being able to identify, over 2 years, 9 eligible patients. Eight of nine patients treated with TMP-SMX did not demonstrate significant or enduring improvement. Dr. DeRemee's recent experience with 14 additional patients who have responded to TMP-SMX alone is encouraging, especially if all patients had unequivocal biopsyproven disease and did not have bacterial infections at the time of treatment. If such was the case, it is difficult to reconcile our different experiences. Dr. DeRemee is correct about the seriousness of the morbidity of Wegener granulomatosis and its treatment (3). Our TMP-SMX protocol is part of a multifaceted program to identify alternative, less toxic, effective therapies for the chronic systemic vasculitides. Dr. DeRemee is concerned that our doubts of TMP-SMX efficacy are untempered. We, however, are concerned that unbridled enthusiasm for unproven therapy may be detrimental to the care of patients. Whether TMP-SMX therapy is efficacious in patients with Wegener granulomatosis is a very important issue that should be addressed in a prospective controlled study. However, because this is a rare disease, such a study can only be accomplished through multicenter collaboration. Dr. Niles and colleagues agree that a P-ANCA positive serology study is neither a sensitive nor specific diagnostic finding in Wegener granulomatosis. However, they indicate that a positive indirect immunofluorescent study, confirmed by ELISA or RIA to be directed to myeloperoxidase, is highly specific for certain diseases related to Wegener granulomatosis, especially those processes associated with ''pauciimmune" necrotizing and crescentic glomerulonephritis. The diagnostic and pathophysiologic importance of antibodies to myeloperoxidase in diseases other than Wegener granulomatosis was not addressed in our study and is, in our judgment, still unclear. As to Dr. Spodick's inquiry, pericardial disease in patients with Wegener granulomatosis, although uncommon, has been previously reported (4, 5). Two febrile patients who did not have pericardial symptoms of effusions were identified by echocardiography in the course of evaluations to rule out endocarditis. In eight cases, medical therapy with prednisone and daily cyclophosphamide led to resolution of all abnormalities. In one patient, two episodes of pericarditis occurred concurrent with otolaryngic disease that was not initially recognized to be a feature of Wegener granulomatosis. One episode resolved after treatment with indomethacin and the other after a 10-day course of prednisone. One patient died from pulmonary hemorrhage within 3 days after presenting with a severe exacerbation that included pericarditis, but no autopsy was done. Acute renal failure occurred in 2 of the 10 patients with pericarditis. Pericarditis preceded uremia in one case and occurred concurrent with uremia in the other. In no instance was pericardial fluid available for analysis. In one patient, with normal renal function, chronic pericarditis led to pericardial constriction and need for pericardiectomy. Histopathologic examination revealed a thickened pericardium and non-specific inflammation. In short, no cause for pericarditis other than Wegener granulomatosis was identified in any patient. Gary S. Hoffman, MD Anthony S. Fauci, MD National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892 References 1. Kerr GS, Fauci AS, Leavitt RY, Fleisher TA, Hallahan CW, Hoffman GS. Limited prognostic value of antineutrophil cytoplasmic antibody in patients with Wegener's granulomatosis. Arthritis Rheum. 1992; 35(S)R5. 2. DeRemee RA, McDonald TJ, Weiland LH. Wegener's granulomatosis: observations on treatment with antimicrobial agents. Mayo Clin Proc. 1985;60:27-32. 3. Hofifman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-98. 4. Fauci AS, Wolff SM. Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine 1973;42:535-61. 5. Forstot JZ, Overlie PA, Neurfeld GK, Harmon CE, Forstot SL. Car-
diac complications of Wegener's granulomatosis. Semin Arthritis Rheum. 1980;10:148-54.
To the Editors: In their population-based study of invasive Haemophilus influenzae infections in adults, Farley and colleagues reported only one case of H influenzae bacteremia due to serotype f-a pneumonia (1). Although uncommon, it causes invasive disease that is virtually indistinguishable from serotype b (2). We recently cared for a patient with recurrent H influenzae serotype f, biotype 1 bacteremia due to an infected abdominal aortic aneurysm. A 58-year-old black farmer presented with a 5-day history of intermittent abdominal pain, anorexia, fever, chills, and constipation. He had a history of diabetes mellitus, hypertension, peripheral vascular disease, and IgG-kappa multiple myeloma diagnosed 4 months previously. One month before, he had been hospitalized for a right upper lobe pneumonia with bacteremia due to H influenzae and received a 14-day course of intravenous ceftriaxone with complete clinical and radiologic improvement. At presentation, he was febrile to 102.7 °C, had left upper quadrant fullness, multiple abdominal bruits, and heme positive stool. The peripheral leukocyte count was 16 100/mm3 with 95% neutrophils, and the hemoglobin was 105 g/L. Chest and abdominal radiographs were unremarkable, and he was given ceftriaxone and gentamicin. Ten of 11 blood cultures grew H influenzae serotype f, biotype 1. No isolate produced beta-lactamase. A computed tomographic scan of the abdomen showed a large retroperitoneal fluid collection that communicated with an abdominal aortic aneurysm. He was treated surgically, and an inflammatory abdominal aortic aneurysm was resected. He completed a 6-week course of ceftriaxone and has been without infectious complications for 6 months. This case illustrates the invasive potential of H influenzae serotype f in an adult with impaired humoral immunity. The persistence of bacteremia on appropriate bactericidal therapy should suggest the possibility of endovascular infection. Robert Orenstein, DO Medical College of Virginia Hospitals Richmond, VA 23298-0049 References 1. Farley MM, Stephen DS, Brachman PS Jr, Harvey C, Smith JD, Wenger JD, et al. Invasive Haemophilus influenzae in adults. Ann Intern Med. 1992;116:806-12. 2. Slater LN, Guarnaccia J, Makintubee S, Istre GR. Bacteremic disease due to Haemophilus influenzae capsular type f in adults: report of five cases and review. Rev Infect Dis. 1990;12:628-35. 3. Currier J, Zaleznik DF. Recurrent Haemophilus influenzae bacteremia in a 79-year-old woman. Rev Infect Dis. 1989;11:477-84.
In response: We appreciated Dr. Orenstein's letter discussing the role of Haemophilus influenzae capsular serotype f in invasive disease in adults. Slater and colleagues (1) reported that 8% of 48 isolates from nonpediatric patients with invasive H influenzae disease were serotype f, and Wallace and associates (2) reported that 4.6% of invasive adult infections were due to serotype f (2). Overall, during more than 3 years of prospective, population-based surveillance in the Atlanta metropolitan area, serotype f accounted for 7.7% of all invasive H. influenzae disease in adults. The spectrum of disease due to H influenzae serotype f appears to be quite similar to that of serotype b. Reasons why serotype f is an infrequent, but persistent, cause of H influenzae disease in adults may include reduced virulence of serotype f strains, host susceptibility factors, and exposure to the organism. Many patients with serotype f infections appear to have a profound defect in humoral immunity. Finally, in nasopharyngeal carriage studies (done mostly in children), non-b encapsulated strains were rarely isolated (3). Whether the reported reduction in Hib carriage related to the introduction of conjugate-Hib vaccines (4) will lead to increased carriage rates of other encapsulated strains and thus
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greater exposure of individuals at risk for disease due to these strains remains to be seen. Monica M. Farley, MD David S. Stephens, MD Emory University School of Medicine VA Medical Center Decatur, GA 30033 Jay D. Wenger, MD Centers for Disease Control Atlanta, GA 30333 References 1. Slater LN, Guarnaccia J, Makintubee S, Istre GR. Bacteremic disease due to Haemophilus influenzae capsular type f in adults: report of five cases and review. Rev Infect Dis. 1990;12:628-35. 2. Wallace RJ Jr, Musher DM, Septimus EJ, McGowan JE Jr, Quinones FJ, Wiss K, et al. Haemophilus influenzae infections in adults: characterization of strains by serotypes, biotypes, and /3-lactamase production. J Infect Dis. 1981;144:101-6. 3. Turk DC. Clinical importance of Haemophilus influenzae—1981. In: Sell SH, Wright PF; eds. Haemophilus influenzae, Epidemiology, Immunology and Prevention of Disease. New York: Elsevier; 1982: 3-9. 4. Takala AK, Eskola J, Leinonen M, Kayhty H, Nissinen A, Pekkanen E, et al. Reduction of oropharyngeal carriage of Haemophilus influenzae type b (Hib) in children immunized with an Hib conjugate vaccine. J Infect Dis. 1991;164:982-6.
Osier and the Method of Zadig To the Editors: Belkin and Neelon write that the word Zadig comes from Arabic (1). In fact, it comes from the Hebrew word, tzadiq, and is found numerous times in the Bible. Also used in modern Hebrew, it is best translated as "righteous."
Reference 1. Belkin BM, Neelon, FA. The art of observation: William Osier and the method of Zadig. Ann Intern Med. 1992;116:863-5.
In response: Without doubt, the Hebrew "tzadiq" is related to the Arabic "saadiq," although the latter may well have a
1 October 1992 • Annals
Beth M. Belkin, PhD, MD Scarsdale, NY 10583 Francis Neelon, MD Duke University Medical Center Durham, NC 27710 References 1. Block HM. Introduction. In: Candide and Other Writings. New York: The Modern Library; 1956. 2. Price WR. The Symbolism of Voltaire's Novels. New York: Columbia University Press; 1911. 3. Voltaire F. Zadig or destiny: an oriental tale. In: Candide and Other Writings. New York: The Modern Library; 1956.
Correction: Gold Therapy for Rheumatoid Arthritis
Jacob Amir, MD Little Rock Diagnostic Clinic Little Rock, AR 72205
broader range of meanings. We omitted any discussion of Voltaire's derivation of Zadig because we were asked to abbreviate our discussion. We are surprised, though, at Dr. Amir's contention that Voltaire derived the hero's name from the Hebrew because authorities generally favor an Arabic origin. Block says baldly that Zadig comes "from the Arabic Saadiq, meaning the truthful one" (1). Price suggests that Voltaire was influenced by the story of Joseph and Potiphar's wife as recounted in the Koran (with which Voltaire was quite familiar), by the definitions of "Sadik" and "Siddik" in Herbelote's Bibliotheque Orientale, and by his affection for the Persian Poet, Sadi (2). Even Voltaire, in his introduction to Zadig, says: "It was originally written in ancient Chaldean [and] was translated into Arabic for the entertainment of the famous Sultan Oulougbeg, about the time when the Arabs and Persians were beginning to compose The Thousand and One Nights, The Thousand and One Days, and so forth. Ouloug preferred to read Zadig', but the ladies of his harem liked the others better" (3).
In a recent letter (1) reporting the case of a woman receiving gold therapy for rheumatoid arthritis, the Myochrysine dosage of 100 mg per week was omitted. (The standard weekly dose after initial loading is 50 mg.) Reference 1. McMahon JM. Gold therapy for rheumatoid arthritis [Letter]. Ann Intern Med. 1992;117:169-70.
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