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Correspondence
No Significant Sex Differences in Temporal Arteritis To the Editor: In recent issues of The Journal, Narváez, et al1 and Nir-Paz, et al2 reported their experience on sex-specific differences in giant cell arteritis (GCA). Narvaez, et al found that among 163 patients with GCA, including 73 with temporal arteritis (TA), the presence of constitutional symptoms was significantly more frequent in women than in men. Women also had a more protracted inflammatory response on laboratory measures. Nir-Paz, et al evaluated 88 patients with either isolated polymyalgia rheumatica (PMR) or TA and found that men and women with GCA differ on their history, presentation, and laboratory findings. Notably, the finding that men are more prone than women to develop irreversible visual ischemia led these investigators to recommend a more aggressive treatment approach to male patients. These important results compelled us to reexamine the relationship between sex and clinical presentation and prognosis in a large series of patients with TA, Our results, briefly presented below, do not support the view of major sex-related differences in the presenting features of TA, and do not indicate that TA is a more severe disease in men. Since 1976, we diagnosed and followed 234 patients with TA (190 biopsy-proven, 65 with associated PMR). Diagnosis was according to current criteria3. Data were collected prospectively using a comprehensive 174-item questionnaire. Eighty-one patients were men, with a sex ratio of 0.52. All patients were treated according to an established protocol4 and 215 patients were followed regularly (mean 11 outpatient visits and hospital admissions per patient) for a mean period of 44.6 ± 37.9 months. In addition, 30 patients initially received disulone as part of the therapeutic protocol5. Men received disulone more often than women (19.2% vs 11.3%), but the difference was not relevant statistically. The results of a comparative study of clinical, laboratory, and pathologic features in men and women with TA are shown in Table 1. Men were slightly younger than women. The only sex-related differences in the frequency of disease manifestations were a lower prevalence of rheumatic symptoms and occipitalgia, and a trend toward a higher prevalence of scalp tenderness in men. Permanent visual loss occurred less often in men (8.6%) than in women (14.4%; nonsignificant). The only significant difference in laboratory values was a lower hemoglobin level in women, a self-evident finding. Finally, similar percentages of a positive temporal artery biopsy result were observed in men and women.
A comparative study of comorbid conditions, treatment, outcome, and prognosis in men and women with TA is given in Table 2. Male and female patients did not differ by medical history, the starting prednisone dose, the mean decrement in prednisone dose at 3, 6 and 12 months, mean number of disease relapses, or mean number and type of serious treatment-related side effects. An equal proportion of men and women recovered from TA or died during treatment, and the mean duration of treatment in 110 patients who recovered from TA was not influenced by sex (27.7 ± 14.5 mo in men vs 26.5 ± 12.7 mo in women; NS). Additionally, 10 out of 27 patients whose treatment was continuing at the time of study and had lasted more than 30 months were men.
In this large homogeneous series of patients with TA, we found only subtle sex-related differences in the clinical presentation at diagnosis, in accord with the results of Narváez, et al. However, we could not confirm on clinical or laboratory grounds the finding by these investigators of a stronger inflammatory response. The reason men have less specific rheumatic manifestations than women is not known to us, but this observation compares with a male to female ratio of 2 to 3 seen in large series of cases of PMR6,7. More important, the prognosis for visual manifestations did not appear to be worse in male patients. On the contrary, men more often recalled transient visual ischemic symptoms but less frequently developed permanent visual sequelae, compared with women. We have shown previously that the mean platelet count was the only independent predictor for permanent loss of vision in patients with TA, irrespective of the temporal artery biopsy result4. We also noted that patients aged 80 years and older had the worst visual prognosis, particularly bilateral irreversible blindness8, but that sex had no influence on visual sequelae. Accordingly, 6 studies totaling more than a thousand patients with TA found no differences in sex distribution in patients with and without permanent visual loss9-14. Finally, beyond the useful considerations on variants of disease presentation, our study, validated by a large sample size and the fact that patients were treated homogeneously and followed closely, emphasizes that men and women with TA possibly share the same prognosis. ERIC LIOZON, MD; ANNE-LAURE FAUCHAIS, MD; VÉRONIQUE LOUSTAUD, MD; ELISABETH VIDAL, MD, Service de Médecine Interne A, CHRU Dupuytren, 2 rue Martin Luther-King, 87042 Limoges, France. E-mail : eric.liozon@unilim.fr REFERENCES 1. Narvaez J, Nolla-Solé JM, Valverde-Garcia J, Roig-Escofet D. Sex differences in temporal arteritis and polymyalgia rheumatica. J Rheumatol 2002;29:321-5. 2. Nir-Paz R, Gross A, Chajek-Shaul T. Sex differences in giant cell arteritis. J Rheumatol 2002;29:1219-23. 3. Hunder GG, Bloch BA, Michel DA, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990;33:1122-8. 4. Liozon E, Herrmann FR, Ly K, et al. Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients. Am J Med 2001;111:211-7. 5. Liozon F, Vidal E, Barrier JH. Dapsone in giant cell arteritis treatment. Eur J Intern Med 1993;4:207-14. 6. Sen D, Scott DGI, Harvey I, Shlepstone L. The epidemiology of polymyalgia rheumatica and giant cell arteritis: a community based study in the UK [abstract]. Arthritis Rheum 1999;42 Suppl:S300. 7. Doran MF, Crowson CS, O'Fallon WM, Hunder GG, Gabriel SE. Trends in the incidence of polymyalgia rheumatica over a 30 year period in Olmsted County, Minnesota, USA. J Rheumatol 2002;29:1694-7. 8. Liozon E, Loustaud-Ratti, Ly K, et al. Visual prognosis in extremely old patients with temporal (giant cell) arteritis. J Am Geriatr Soc 2003;51:722-3. 9. de Keyser J, De Klippel N, Ebinger G. Thrombocytosis and ischaemic complications in giant cell arteritis. BMJ 1991;303:825. 10. Liu GT, Glaser JS, Schatz NJ, Smith JL. Visual morbidity in giant cell arteritis. Clinical characteristics and prognosis for vision. Ophthalmology 1994;101:1779-85. 11. Font C, Cid MC, Coll-Vinent B, Lopez-Soto A, Grau JM. Clinical features in patients with permanent visual loss due to biopsy-proven giant cell arteritis. Br J Rheumatol 1997;36:251-4. 12. Cid MC, Font C, Oristrell J, et al. Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis. Arthritis Rheum 1998;41:26-32. 13. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol 1998;125:509-20. 14. Gonzalez-Gay MA, Blanco R, Rodriguez-Valverde V, et al. Permanent visual loss and cerebrovascular accidents in giant cell arteritis. Arthritis Rheum 1998;41:1497-504.
Drs. Nir-Paz and Chajek-Shaul reply To the Editor: Liozon, et al raise once more the intriguing question of sex differences in giant cell arteritis (GCA). This question has been discussed by us and others1-8. In their careful cohort study they show that response to treatment is similar in both men and women, a finding not universally reproduced in other studies7. However, are men and women really alike in their expression of GCA, in both the clinical presentation and response to treatment? As reported in several studies, the ratio of women to men with GCA is 2. Other differences are noted as well. Women in the Liozon series tend to have more rheumatic symptoms and occipitalgia, while men have scalp tenderness more commonly. Women are also more severely anemic, a feature reported in other studies3,5. At presentation, we found that men are more prone than women to have visual impairment5, a finding not reproduced by Liozon, et al. Moreover, they report a trend for a milder form of blindness in men. In our logistic regression model for predicting blindness we found that the combination of being a male and having a positive GCA pathology was protective against blindness (p < 0.008). As we reported5, some of the main differences between the sexes of our patients were noted in the medical history. Men more often had diabetes mellitus, as well as more frequent cerebrovascular accidents and chronic renal failure. But the overall prevalence of background diseases was the same for both sexes. As described by Duhaut, et al2, French patients have a lower incidence of "vasculopathic" comorbidities such as non-insulin-dependent diabetes mellitus. Smoking and previous vascular disease were thought to be associated with GCA in women in this study. This observation gains support from a recent report from Sweden7, in which a higher mortality due to vascular diseases was observed, especially in women with GCA. Different populations may have different patterns of sex differences in GCA, while some variables are measured differently in different studies, suggesting differences that may not exist in fact. As we suggested in our study, in order to observe sex differences a comparison to the general population should be performed as well. Although Liozon, et al did not find major differences between the sexes, they found some evidence to support our previous study. Further population-based studies on an international basis may shed more light on the intriguing question of sex differences in GCA. RAN NIR-PAZ, MD; TOVA CHAJEK-SHAUL, MD, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel. REFERENCES 1. Nordborg C, Nordborg E, Petursdottir V, Fyhr IM. Calcification of the internal elastic membrane in temporal arteries: its relation to age and gender. Clin Exp Rheumatol 2001;19:565-8. 2. Duhaut P, Pinede L, Demolombe-Rague S, et al. Giant cell arteritis and cardiovascular risk factors: a multicenter, prospective case-control study. Arthritis Rheum 1998;41:1960-5. 3. Gonzalez-Gay MA, Garcia-Porrua C, Amor-Dorado JC, Llorca J. Influence of age, sex, and place of residence on clinical expression of giant cell arteritis in northwest Spain. J Rheumatol 2003;30:1548-51. 4. Nuenninghoff DM, Hunder GG, Matteson EL. Sex differences in giant cell arteritis [letter]. J Rheumatol 2003;30:1119-20. 5. Nir-Paz R, Gross A, Chajek-Shaul T. Sex differences in giant cell arteritis. J Rheumatol 2002;29:1219-23. 6. Nordborg C, Johansson H, Petursdottir V, Nordborg E. The epidemiology of biopsy-positive giant cell arteritis: special reference to changes in the age of the population. Rheumatology Oxford 2003;42:549-52. 7. Uddhammar A, Eriksson AL, Nystrom L, Stenling R, Rantapaa-Dahlqvist S. Increased mortality due to cardiovascular disease in patients with giant cell arteritis in northern Sweden. J Rheumatol 2002;29:737-42. 8. Narvaez J, Nolla-Solé JM, Valverde-Garcia J, Roig-Escofet D. Sex differences in temporal arteritis and polymyalgia rheumatica. J Rheumatol 2002;29:321-5.
Dr. Narváez replies To the Editor: I read with interest the letter by Liozon, et al presenting their experience on sex-specific differences in temporal arteritis (TA). They compare their results with the 2 main studies that analyzed this question, including our work1,2. The main purpose of our report was to draw attention to the possible importance of sex hormones in TA and polymyalgia rheumatica (PMR). Sex differences are known to exist for many autoimmune diseases. The marked female predominance observed in TA and PMR suggests that sex hormones may play a role in etiology and/or disease expression, although the precise significance of this is still not understood because until recently sex-specific differences in both conditions were not extensively explored. We found modest differences in disease expression between women and men. In the 2 conditions, the inflammatory response seemed to be more severe in women, with greater abnormalities in clinical (constitutional syndrome and fever) and laboratory markers of inflammation. No significant differences in the classical features of TA were observed. Although this has not been clearly elucidated before, 2 other reports on TA from Spanish groups also described a strong inflammatory response in women, supporting our results3,4. Whether this strong inflammatory response observed in women implies a lower risk of developing visual loss and other cranial ischemic complications in TA is still controversial, since studies addressing the association between the inflammatory response and the risk of developing irreversible cranial ischemic complications have produced conflicting results5-7. In this regard, we found no differences in the incidence of visual complications by sex. We hypothesized that the more severe inflammatory response observed in women could explain the longer duration of treatment reported in this subgroup of patients in both PMR and TA, regardless of the treatment regimen8-12. Together, these observations indicate that female patients with these conditions can be at particularly high risk for steroid toxicity, a hypothesis that has been demonstrated in PMR13. An additional article addressing sex-specific differences in TA and PMR was published later2. In this hospital based study of patients from Israel with either isolated PMR or TA, Dr. Nir-Paz and colleagues found that men and women with both conditions differed in their history, presentation, and laboratory findings. One conclusion of these authors is that ophthalmic involvement, specifically blindness, is more common in men. However, these findings have generated controversy, and recently some investigators have questioned the value of this study for making assumptions about sex-dependent disease characteristics of TA due to its methodological limitations14. Thus the report from Dr. Liozon and colleagues is welcome in order to clarify this issue. Their findings only partially confirm our results, and also reveal subtle sex-related differences in the clinical presentation at diagnosis, without significant differences in the incidence of visual complications by sex. Regarding the laboratory markers of inflammation, they observed lower hemoglobin values in women than in men, without significant sex differences in other measures. Moreover, and contrary to other reports, they did not observe sex differences in the mean duration of treatment or in the incidence of treatment-related side effects. I cannot explain why their results are substantially different in many aspects from previous studies. It seems improbable that these differences can be explained by ethnic differences among different populations, because in another study on TA and PMR from France, Delecoeuillerie and colleagues15 found (in contrast to the findings reported by Liozon, et al) that men were more likely to experience visual and other ischemic complications than women, suggesting that "a worse prognosis seems attached to the male sex in TA." For this reason, the most acceptable hypothesis is that these differences could be related to methodologic differences, including different study designs (prospective versus retrospective studies), selection bias, or the use of specially designed versus standard patient files (the evaluation of clinical findings, when they are mild and do not emerge from a specifically designed study, may have remarkable interobserver variation). In view of these contradictory observations, prospective, multicenter, population based studies will be required to establish universally accepted, clinically relevant conclusions. While awaiting new data, on the basis of the available studies I feel that sex hormones play a role in the etiology and disease expression of both TA and PMR. This hormonal influence results in a marked female predominance, with a more severe inflammatory response and longer duration of treatment in women. It seems there are not significant sex differences for the risk of visual loss and other cranial ischemic complications; in this clinical aspect, women and men seem to have a similar prognosis. JAVIER NARVÁEZ, MD, Rheumatology Unit, Department of Internal Medicine, Clínica Delfos, Barcelona, Spain. E-mail: 31577edd@comb.es REFERENCES 1. Narvaez J, Nolla-Solé JM, Valverde-García J, Roig-Escofet D. Sex differences in temporal arteritis and polymyalgia rheumatica. J Rheumatol 2002;29:321-5. 2. Nir-Paz R, Gross A, Chajek-Shaul T. Sex differences in giant cell arteritis. J Rheumatol 2002;29:1219-23. 3. Calvo Romero JM, Magro Ledesma D, Ramos Salado JL, et al. Giant cell arteritis: a descriptive study in south-western Spain. An Med Interna Madrid 2000;17:67-70. 4. Armona J, Rodríguez-Valverde V, González-Gay MA, et al. Giant cell arteritis. Study of 191 patients. Med Clin Barc 1995;105:734-7. 5. Cid MC, Font C, Oristrell J, et al. Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell (temporal) arteritis. Arthritis Rheum 1998;41:26-32. 6. Nesher G, Sonnenblick M. No association between the inflammatory response and the risk of developing irreversible cranial ischemic complications: comment on the article by Cid et al [letter]. Arthritis Rheum 1998;41:2088. 7. Liozon E, Jauberteau MO, Loustaud V, Vidal E. Association between the inflammatory response and the risk of developing irreversible cranial ischemic complications: comment on the article by Cid, et al and the letter by Nesher and Sonnenblick [letter]. Arthritis Rheum 1999;42:2256-8. 8. Narvaez J, Nolla-Solé JM, Clavaguera MT, Valverde-Garcia J, Roig-Escofet D. Longterm therapy in polymyalgia rheumatica: Effect of coexistent temporal arteritis. J Rheumatol 1999;26:1945-52. 9. Chuang TY, Hunder GG, Ilstrup DM, Kurland LT. Polymyalgia rheumatica. A 10 year epidemiologic and clinical study. Ann Intern Med 1982;97:672-80. 10. Ayoub WT, Franklin CM, Torreti D. Polymyalgia rheumatica: Duration of therapy and long-term outcome. Am J Med 1985;79:309-15. 11. Ashraf F, Belilos E, Terenci T, Carsons SE. Gender specific differences in treatment outcomes in polymyalgia rheumatica [abstract]. Arthritis Rheum 2000;43 Suppl:1778. 12. Nordborg E, Nordborg C, Malmvall BE, Andersson R, Bengtsson BA. Giant cell arteritis. Rheum Dis Clin North Am 1995;21:1013-26. 13. Gabriel SE, Sunku J, Salvarini C, O'Fallon WM, Hunder GG. Adverse outcomes of antiinflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum 1997;40:1873-8. 14. Nuenninghoff DM, Hunder GG, Matteson EL. Sex differences in giant cell arteritis: comment on the article by Nir-Paz, et al [letter]. J Rheumatol 2003;30:1119-20. 15. Delecoeuillerie G, Joly P, Cohen de Lara A, Paolaggi JB. Polymyalgia rheumatica and temporal arteritis: a retrospective analysis of prognostic features and different corticosteroid regimens (11 year survey of 210 patients). Ann Rheum Dis 1988;47:733-9.
Disease Modifying Antirheumatic Drugs and Pregnancy To the Editor: The article by Dr. Chakravarty, et al1 points out the need for better data on the use of disease modifying antirheumatic drugs (DMARD) by pregnant women. The article also provides a reminder to rheumatologists about their responsibility to counsel women of childbearing potential regarding potential fetal risks from gestational drug exposures and the need for continued vigilance to prevent pregnancy while taking these drugs. Such counseling may also provide the opportunity to discuss the woman's interest in future pregnancy and provide preconception counseling regarding the potential complications of her disease for pregnancy including the risk of adverse pregnancy outcome and the potential for worsening of disease with pregnancy. Little is known about the teratogenic potential of most drugs. Misinformation about drug risk in pregnancy is prevalent due to inadequate data collection methodologies. While the authors should be commended for their attempt to provide much needed information, the retrospective collection of human pregnancy outcomes via a survey of physicians represents one such inappropriate methodology. Such data cannot be used to provide an estimate of risk as was done for methotrexate in this article. To provide an estimate of risk, prospective data collection that provides a numerator and denominator as well as an appropriate comparator group is needed. The authors do discuss some limitations of their study; however, other limitations include barriers to physicians to reply to the survey and lack of information on how pregnancy exposures were ascertained. The low response rate (29%) may reflect a real or perceived medical, legal, or ethical conflict of interest and physicians may be reluctant to disclose information on pregnancy outcome without maternal consent. Another bias surrounds the ascertainment of outcome, including who did the ascertainment and when it was done. The obstetrician or the rheumatologist may be far removed from an accurate ascertainment of infant health and mothers may not be the best source to acquire adequate information regarding congenital anomalies. Information on live infant outcomes should be obtained from the infant's health care provider. Limiting ascertainment of infant outcome at birth versus at later time in infancy, e.g., at 3 months, will limit the number and type of major malformations reported2. Misclassification of outcomes may lead to erroneous conclusions. To proactively encourage the conduct of well designed, scientifically valid studies in pregnancy, the US Food and Drug Administration (FDA) recently published a guidance document on establishing pregnancy exposure registries (http://www.fda.gov/cder/guidance/3626fnl.pdf). In these studies, physicians prospectively enroll their patients after exposure to a drug during pregnancy but before the outcome of pregnancy is known. Patients can also self-enroll. These prospective registries offer the opportunity to apply real-world clinical practice data on risk, or lack of risk, to ultimately benefit patient care. Unfortunately, the authors missed an excellent opportunity to encourage rheumatologists to utilize ongoing epidemiologic studies that collect information on antirheumatic drug exposure during pregnancy. The manufacturer of Arava® (leflunomide) is currently enrolling pregnant women exposed to their drug in such a registry; the labeling, or package insert, for the product includes a toll-free telephone number for physicians to register exposed pregnant patients3. In addition, the Organization of Teratology Information Services (OTIS) is conducting the Rheumatoid Arthritis and Pregnancy Study, a prospective study to evaluate risks to the embryo or fetus with the use of rheumatoid arthritis medications in pregnancy. A list of pregnancy exposure registries in progress for other drugs is available at www.fda.gov/womens/registries/default.htm Current FDA regulations, promulgated in 1979, require prescription medication labeling to contain a Pregnancy Subsection that includes a pregnancy letter category (A, B, C, D, or X) that addresses fetal risk of developmental abnormalities. The FDA recognizes these categories, usually based only on animal data, can be misleading and that for most products the pregnancy subsection of product labeling provides inadequate information either for prescribing drugs to pregnant women or for counseling about fetal risks. However, multiple other resources are available to assist physicians in assessing reproductive toxicities from drug exposures. For example, the on-line REPRORISK system available from Micromedex, Inc. contains electronic versions of 4 teratogen information databases: REPROTEXT, REPROTOX (www.reprotox.org), Shepard's Catalog4, and TERIS5. These periodically updated, scientifically reviewed resources critically evaluate the literature regarding human and animal pregnancy drug exposures. Other sources of information are the more than 20 comprehensive multidisciplinary Teratogen Information Services (TIS) located in the US and Canada, which provide patient counseling and risk assessments regarding exposures during pregnancy (www.otispregnancy.org). With an eye to the future, the FDA Pregnancy Labeling Task Force is working to improve the quantity and quality of data available in product labeling on the use of drugs during pregnancy and is in the process of revising the regulations that govern pregnancy labeling to delete the pregnancy category scheme and promote the inclusion of more useful clinical information in a narrative format6. KATHLEEN UHL, MD; DIANNE L. KENNEDY, RPh, MPH, Pregnancy Labeling Task Force, Center for Drug Evaluation and Research, US Food and Drug Administration, 1451 Rockville Pike, HFD-020, Rockville, Maryland 20852, E-mail: uhlk@cder.fda.gov; WILLIAM R. GILLILAND, MD, Department of Rheumatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. REFERENCES 1. Chakravarty EF, Sanchez-Yamamoto D, Bush TM. The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes. J Rheumatol 2003;30:241-6. 2. Honein MA, Paulozzi LJ, Cragan JD, et al. Evaluation of selected characteristics of pregnancy drug registries. Teratology 1999;60:356-64. 3. ARAVA™ Tablets (Aventis) (leflunomide). Physicians' desk reference. 57th ed. Montvale, NJ: Medical Economics Company, Inc.; 2003. 4. Shepard TH. Catalog of teratogenic agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press; 2001. 5. Friedman JM, Polifka JE. Teratogenic effects of drugs. 2nd ed. Baltimore, MD: The Johns Hopkins University Press; 2000. 6. Kweder SL, Kennedy DL, Rodriguez E. Turning the wheels of change: FDA and pregnancy labeling. The International Society for Pharmacoepidemiology, Scribe Newsletter, 2000;3:2-4,10.
Dr. Chakravarty, et al, reply To the Editor: We read with interest the letter by Dr. Uhl and colleagues in response to our article about DMARD exposure of pregnant women with rheumatoid arthritis (RA). We appreciate the interest and discussion raised by our study. We agree with the points raised by the authors and acknowledge the limitations inherent in our study. The low response rate is likely, at least in part, to stem from hesitancy on the part of the physician to disclose information about patient outcomes, particularly when they include possible risks associated with prescribed medications. It is for this reason that we did not include questions about specific details surrounding pregnancy outcomes or require detailed review of maternal and infant medical records. Unfortunately, there is currently a paucity of published information about pregnancy outcomes with in utero exposure to these DMARD. Despite over 2 decades of use of methotrexate in the treatment of RA, there have been less than 25 reported cases of pregnancy outcomes with gestational exposure to this agent. The aim of our study was to provide clinicians with additional information about pregnancy outcomes with exposure to certain DMARD while we await results from prospective studies. Our intent was to be descriptive rather than to determine accurate estimates of risks for adverse pregnancy outcomes. We are concerned about and caution against misinterpretations of the data to suggest relative risk or safety of any of these DMARD with respect to gestational exposure. It is clear that prospectively collected data of pregnancy outcomes of gestational drug exposure are essential to accurately describe and estimate risks of adverse events. As described by Dr. Uhl, agencies such as the FDA and OTIS, as well as industry sponsors, have established such scientifically valid studies. We encourage all providers and patients to enroll in these registries once pregnancy with exposure to these medications is discovered. Unfortunately, the same hesitancy on the part of providers to report pregnancies to survey questionnaires may still exist when enrolling patients in pregnancy exposure registries. These include real or perceived legal, ethical, and confidentiality issues surrounding potential adverse outcomes to prescribed medications. There is a need for increased awareness of such registries in order to enroll the maximum number of exposed pregnancies. We hope that our study and resulting discussions will encourage increased reporting to validated pregnancy registries. We applaud the FDA Pregnancy Labeling Task Force's work to improve product labeling and to provide accurate information to providers using such medications when treating women of childbearing potential. ELIZA F. CHAKRAVARTY, MD; DEANNA SANCHEZ-YAMAMOTO, RNP; THOMAS M. BUSH, MD, Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Suite 203, 1000 Welch Road, Palo Alto, California 94304, USA.
"Soft" Neurological Signs in Systemic Lupus Erythematosus To the Editor: I recently read the article by Denberg, et al on the relationship of subjective neuropsychiatric complaints to cognitive systemic lupus erythematosus (SLE). The authors conclude rightly that "minor" neuropsychiatric symptoms "may be sufficient to raise suspicion of subclinical nervous system involvement" even when standard objective tests are negative or equivocal. This view certainly agrees with what I see clinically in my practice. However, the position put forth by the authors should not be limited only to SLE but also to any illness. I am referring in particular to fibromyalgia, where patients often complain of problems with memory, concentration, etc. While it is not practical to obtain brain SPECT scans and other sophisticated objective tests in most fibromyalgia patients, the credibility of such patients should not be challenged since their symptoms, while seeming to be "soft" to us, may be incredibly disturbing to the patient.
THOMAS J. ROMANO, MD, PhD, FACP, 205 North Fifth Street, Martins Ferry, Ohio 43935, USA. REFERENCE 1. Denburg SD, Stewart KE, Hart LE, Denburg JA. How "soft" are soft neurological signs? The relationship of subjective neuropsychiatric complaints to cognitive function in systemic lupus erythematosus. J Rheumatol 2003; 30:1006-10.
Dr. Denburg replies To the Editor: Dr. Romano writes, 'The authors conclude that minor neuropsychiatric symptoms "may be sufficient to raise suspicion of subclinical nervous system involvement" even when standard objective tests are negative or equivocal.' While Dr. Romano's support is welcome, I would note that the conclusion that he cites, drawn from the article's Abstract, reads as follows: "minor NP symptoms and, in particular, a small subset of subjective complaints may be sufficient to raise suspicion of subclinical nervous system involvement in the absence of clinically evident NP-SLE." The intent of the article was to validate the subjective symptoms against objective tests, in this case cognitive tests. Our conclusion was based on data showing that increased subjective complaints were significantly associated with reduced function on these standard objective cognitive tests. It may be the case that subjective complaints that cannot be validated objectively should be taken seriously in the clinical setting; however, the point of the article was to validate these complaints against objective tests considered to reflect nervous system integrity. SUSAN D. DENBURG, PhD, CPsych, Professor, Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.
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