Risk Factors for Methotrexate-Induced Lung Injury in Patients with Rheumatoid Arthritis: A Multicenter, Case-Control Study

  1. Graciela S. Alarcon, MD, MPH;
  2. Joel M. Kremer, MD;
  3. Maurizio Macaluso, MD, DrPH;
  4. Michael E. Weinblatt, MD;
  5. Grant W. Cannon, MD;
  6. William R. Palmer, MD;
  7. E. William St. Clair, MD;
  8. John S. Sundy, MD;
  9. Ronald W. Alexander, MS;
  10. G.J. Walker Smith, MD; and
  11. Constantine A. Axiotis, MD
  1. For the Methotrexate-Lung Study Group From University of Alabama at Birmingham School of Medicine and University of Alabama at Birmingham School of Public Health, Birmingham, Alabama; Albany Medical College, Albany, New York; Harvard Medical School, Boston, Massachusetts; the Veterans Affairs Medical Center and University of Utah School of Medicine, Salt Lake City, Utah; Internal Medicine Associates, Omaha, Nebraska; Duke University Medical Center, Durham, North Carolina; Columbus Hospital, Great Falls, Montana; and Kings County Hospital, Brooklyn, New York. Acknowledgment: The authors thank Ella Henderson for expert secretarial assistance. Grant Support: In part by a grant from Lederle Laboratories, Pearl River, New Jersey, to Albany Medical College. Requests for Reprints: Graciela S. Alarcon, MD, MPH, University of Alabama at Birmingham Station-MEB 615, 1813 6th Avenue South, Birmingham, AL 35294. Current Author Addresses: Dr. Alarcon and Mr. Alexander: University of Alabama at Birmingham Station-MEB 615, 1813 6th Avenue South, Birmingham, AL 35294.
     
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    Abstract

    Background: Toxicity limits the use of methotrexate.

    Objective: To identify risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis.

    Design: Case-control study.

    Setting: One private and five academic rheumatology practices.

    Participants: Methotrexate recipients with rheumatoid arthritis with and without lung injury.

    Measurements: Potential risk factors examined were sociodemographic and lifestyle characteristics, medical history, clinical and ancillary features and treatment of rheumatoid arthritis before methotrexate therapy, and characteristics of methotrexate therapy. Cases of lung injury were defined according to the modified criteria of Searles and McKendry.

    Results: Ninety-four percent of the study participants were white, and 67% were women. Case-patients (n = 29) were older than controls (n = 82) (61.5 compared with 54.5 years of age). The strongest predictors of lung injury, after adjustment for other variables, were older age (odds ratio [OR], 5.1 [95% CI, 1.2 to 21.1]), diabetes (OR, 35.6 [CI, 1.3 to ∞]), rheumatoid pleuropulmonary involvement (OR, 7.1 [CI, 1.1 to 45.4]), previous use of disease-modifying antirheumatic drugs (OR, 5.6 [CI, 1.2 to 27.0]), and hypoalbuminemia (OR, 19.5 [CI, 3.5 to 109.7]). Previous use of disease-modifying antirheumatic drugs and hypoalbuminemia had very large attributable risks.

    Conclusion: Knowledge of the risk factors that predispose patients with rheumatoid arthritis to the toxic effects of methotrexate on the lung may provide a rationale for monitoring high-risk patients and may facilitate their management.

    Methotrexate is often used as the initial disease-modifying antirheumatic drug in patients with early aggressive rheumatoid arthritis who are at high risk for the development of joint destruction [1-4]. The clinical usefulness of methotrexate must be balanced against its potential side effects [5-10]. Some of these effects can be prevented or alleviated by the concomitant use of folic acid or folinic acid [11-16]; others, such as liver disease, may be avoided by monitoring liver aminotransferase and serum albumin levels and by knowing which risk factors predispose patients to their occurrence [17, 18].

    Little is known about the risk factors for methotrexate-induced lung injury and appropriate surveillance to minimize its occurrence. Carroll and colleagues [19] and Golden and coworkers [20] have suggested that previous lung disease may predispose patients to methotrexate-induced lung injury. In addition, in a small case–control study, Carroll and colleagues [19] found that methotrexate-induced lung injury tended to occur early in the course of methotrexate therapy. The incidence of this complication and the spectrum of its clinical manifestations are largely unknown because published series have been unable to identify and describe the entire population at risk [5, 19-30]. Moreover, methotrexate-induced lung injury, rheumatoid lung, and pulmonary infection may be difficult to distinguish on clinical grounds alone [31-45]. We thus did a multicenter case–control study to identify factors associated with methotrexate-induced lung injury.

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    Methods

    Study Centers

    University-based and private practice-based centers known to have large numbers of methotrexate-treated patients with rheumatoid arthritis were invited to participate in this study. Each center had to identify at least four cases of methotrexate-induced lung injury and had to have an identifiable cohort of patients from which controls could be selected. Participating institutions were the University of Alabama at Birmingham School of Medicine (Birmingham, Alabama), Albany Medical College (Albany, New York), Brigham and Women's Hospital (Boston, Massachusetts), the Veterans Affairs Medical Center and University of Utah School of Medicine (Salt Lake City, Utah), Duke University Medical Center (Durham, North Carolina), and Internal Medicine Associates of Omaha (Omaha, Nebraska). The study was approved by the institutional review boards of the first five centers listed and by all practicing rheumatologists at Internal Medicine Associates of Omaha.

    Patient Selection

    Case-patients and controls were eligible for the study if they were members of the methotrexate-treated cohort with rheumatoid arthritis at any study center between 1 July 1981 and 30 June 1993. Case-patients must have had methotrexate-induced lung injury during this period. Controls were selected from the cohort of methotrexate-treated patients with rheumatoid arthritis at each center; for a control to be eligible, he or she had to have been given methotrexate during the same year in which it was administered to the index case-patient. Controls were selected if they had received methotrexate therapy and had no evidence of methotrexate-related pulmonary disease up to the time that the adverse event occurred in the index case-patient. Controls were not otherwise matched to the case-patients. Medical records were reviewed until three controls had been identified for each case-patient or until no more eligible persons were available.

    Cases were defined as definite or probable according to the modified criteria of Searles and McKendry [25] (Table 1). A definite case had to meet major criterion 1 (pathologic evidence) or criteria 2 (radiologic evidence or an abnormal chest radiograph) and 3 (negative cultures) plus three of the five minor criteria (shortness of breath, nonproductive cough, O2 saturation ≤ 90%, DLCO [diffusing capacity of the lung for carbon monoxide] ≤ 70%, and leukocyte count ≤ 15 000 cells/mm3). Patients were said to have met major criterion 3 if they were afebrile and did not produce sputum, even if no blood or sputum cultures were done. In some patients, bronchoalveolar lavage fluid was cultured to rule out infectious causes of disease. Probable case-patients had to meet major criteria 2 and 3 plus two of the five minor criteria. No other case-patients were considered to have methotrexate-induced lung injury.

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    Table 1. Adverse Pulmonary Events Resulting from Methotrexate Therapy: Revised Diagnostic Criteria*

    Histopathologic material was available for 20 case-patients. Slides were blindly and independently reviewed by two experienced pathologists and were classified as showing definite, probable, possible, or no methotrexate-induced lung injury. This classification was based on the presence of stable abnormalities (fibrosis, honeycombed architecture, and lymphoid hyperplasia for rheumatoid lung; type II alveolar cells and fibroblastic proliferation for methotrexate-induced lung injury). Even if pneumocyte proliferation was present, probable toxicity was diagnosed if desquamative interstitial pneumonia or eosinophilia or both were also present. After the pathologists had each classified the slides, they resolved any differences in their classifications by conferring between themselves.

    Thirty-six suspected cases of methotrexate-induced lung injury were identified, abstracted, reviewed, and independently classified by three authors as definite, probable, or neither [25]. Seven of the cases did not meet the criteria for either definite or probable methotrexate-induced lung injury and were excluded from further analyses; four of the seven were excluded on the basis of the histopathologic data. Of the 29 remaining cases, 27 were classified as definite and 2 were classified as probable. Each index case had three predefined critical times: onset of rheumatoid arthritis, initiation of methotrexate therapy, and occurrence of the adverse pulmonary event. Three controls were identified for 25 of the 29 case-patients, 2 controls were identified for 3 of the 29 case-patients, and 1 control was identified for 1 of the 29 case-patients, for a total of 82 controls.

    Risk Factors

    Potential risk factors were grouped into five domains: sociodemographic and lifestyle factors (age, sex, race, level of education, occupation, smoking, drinking, and location of residence), medical history (comorbid conditions), features and treatment of rheumatoid arthritis before methotrexate administration (disease duration, extraarticular manifestations, and use of disease-modifying antirheumatic drugs), ancillary features before the initiation of methotrexate treatment (hematologic and biochemical variables, chest radiograph), and characteristics of methotrexate therapy (treatment duration, weekly and cumulative doses, and side effects).

    Statistical Analysis

    The odds ratio was the measure of association. For each risk factor, a reference category was selected (for example, the reference category for smoking was nonsmoking) and the case–control odds in other categories were divided by the case–control odds in the reference category. For continuous variables, category boundaries were defined by using tertiles or quartiles of the distribution of values in the control group. Logistic regression models were used to compute unadjusted odds ratios and their 95% CIs.

    Logistic regression models were also used to control for confounding and to assess interaction between variables. The logistic models' goodness of fit was evaluated by using Hosmer and Lemeshow's c-statistic [46] and by examining the sensitivity of regression coefficients to the effect of influential or poorly fit observations [47]. A separate regression model was evaluated for each of the five domains described above.

    The risk factor with the largest adjusted odds ratios or the risk factors that were statistically significant predictors of methotrexate-induced lung injury within a domain-specific analysis were included in the final logistic regression analysis, which combined risk factors from all domains. A variable for center was also included in this regression. In addition, the potential clinical importance and the biological plausibility of an association were considered in specifying the final model. Age and sex were forced into all models because they were considered potential confounders a priori. Finally, the population-attributable risk (etiologic fraction [48]) was computed as a measure of the effect of a specific risk factor on the incidence of methotrexate-induced lung injury; the attributable risk estimates the proportion of disease incidence that is associated with exposure to a risk factor. It is a function of the odds ratio and of the frequency of exposure of the case-patients to the risk factors. Analyses were done by using the Statistical Analyses System for Personal Computers, version 6.11 (SAS Institute, Inc., Cary, North Carolina).

    Role of Sponsor

    The study was supported in part by an unrestricted grant from Lederle Laboratories (Pearl River, New Jersey) to Albany Medical College, which disbursed the funds to the participating centers according to their involvement in the study. Lederle Laboratories had input into and approved the study design but was not involved in the conduct of the study, the analysis or interpretation of the data, or the preparation of this report.

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    Results

    Sociodemographic and Lifestyle Factors

    Table 2 shows the distribution of case-patients and controls according to sociodemographic and lifestyle factors. Case-patients were older than controls (61.5 compared with 54.8 years); approximately 52% of the case-patients and 72% of the controls were women. Compared with study participants younger than 50 years of age, participants 50 to 59 years of age had a twofold increase in risk for lung injury (odds ratio [OR], 2.3 [95% CI, 0.4 to 12.3]) and participants 60 years of age or older had a sixfold increase (OR, 5.8 [CI, 1.3 to 26.4]). Approximately 94% of all participants were white, and no appreciable difference in race was seen between case-patients and controls. History of employment in nonsedentary occupations was associated with methotrexate-induced lung injury in women but not in men; this association was weak and was not statistically significant after we controlled for other factors. Cigarette smoking seemed to be a stronger risk factor for men than for women. This interaction, however, was more significant and the overall association was of borderline statistical significance after we controlled for other factors (OR, 2.9 [CI, 1.0 to 8.5]). Alcohol consumption was reported frequently among case-patients and controls, but the case-patients seemed to be heavier drinkers than the controls (3.1 compared with 0.7 drinks per week). Participants who reported drinking an average of more than one alcoholic beverage per week had a threefold increase in methotrexate-induced lung toxicity compared with participants who reported drinking less. This association was not statistically significant after we controlled for other factors (OR, 3.4 [CI, 0.8 to 14.3]).

    View this table:
    Table 2. Selected Sociodemographic and Lifestyle Features at Baseline*

    One case-patient and two controls reported exposure to asbestos, and slightly more than 10% reported occupational or environmental exposure to other nonspecified toxic chemicals. The association of methotrexate-induced lung injury with such exposures was weak and nonsignificant. A modest increase in risk (OR, 1.9 [CI, 0.6 to 5.6]) was seen in participants living in urban areas compared with participants living in rural areas; this association was not statistically significant. Age was the only significant factor identified after we controlled for all other factors in this domain.

    Medical History

    As shown in Table 3, a history of cardiovascular disease (such as coronary artery disease or hypertension) (OR, 1.9 [CI, 0.7 to 5.7]) and a history of pulmonary disease (such as chronic bronchitis or emphysema) were modestly associated with methotrexate-induced lung injury. A history of pulmonary disease before the initiation of methotrexate therapy, determined primarily by an abnormal chest radiograph, seemed to predict methotrexate-induced lung injury, but reports of previous radiographs were available for only 26 of the 111 study participants. The combined effect of pulmonary pathologic findings present before methotrexate therapy and of an abnormal chest radiograph on methotrexate-induced lung injury was modest (OR, 1.2 [CI, 0.2 to 5.9]); this association lost statistical significance after we controlled for other factors. Diabetes mellitus was a strong predictor of methotrexate-induced lung injury. It was reported in 7 of the 29 case-patients but in only 2 of the 82 controls; 4 case-patients and 1 control were receiving insulin, and the remaining participants were receiving an oral hypoglycemic agent or had their disease controlled with diet.

    View this table:
    Table 3. Selected Previous and Current Conditions*

    Other medical conditions showed a moderately protective effect. Peptic ulcer disease was the most common condition in this category; it occurred in two case-patients and eight controls. This condition, however, did not have a clear protective effect. The apparent protection was associated with unrelated conditions that may have been selectively under-reported for case-patients. Thus, other conditions were not examined further. The association of methotrexate-induced lung injury with diabetes mellitus was enhanced after we adjusted for other risk factors (OR, 14.8 [CI, 2.0 to 112.0]). However, the CI of the odds ratio is wide, and the measure is therefore imprecise.

    Features and Treatment of Rheumatoid Arthritis before Methotrexate Therapy

    As shown in Table 4, case-patients had a slightly shorter history of rheumatoid arthritis than controls, but this difference was not statistically significant. Extraarticular manifestations of rheumatoid arthritis, such as subcutaneous nodules, sicca, anemia, pleuropulmonary involvement, pericarditis, and vasculitis, were associated with an increased risk for methotrexate-induced lung injury. Sicca or subcutaneous nodules conferred a nonsignificant increase in risk (OR, 1.9 [CI, 0.7 to 5.5]), whereas pleuropulmonary involvement showed a significant sixfold increase (OR, 5.4 [CI, 1.3 to 21.8]). The odds ratio for methotrexate-induced lung injury increased with the number of extraarticular features of rheumatoid arthritis and ranged from 1 (for no extraarticular features) to 4.1 [CI, 1.0 to 16.4]) for two or more. The association with pleuropulmonary involvement with the number of extraarticular features persisted in multiple regression analyses but was statistically significant only for pleuropulmonary involvement.

    View this table:
    Table 4. Features of Rheumatoid Arthritis

    Most participants had been treated with one or more disease-modifying antirheumatic drugs before initiation of methotrexate therapy (data not shown). Treatment with sulfasalazine, oral gold, D-penicillamine, and parenteral gold was associated with methotrexate-induced lung injury but either lost significance or could not be tested for significance because of multiple collinearity when we controlled for other factors. The aggregated effect of these treatments was evaluated in the final model (vide infra, combined analyses).

    Before the initiation of methotrexate therapy, most of the laboratory variables were not significantly associated with methotrexate-induced lung injury (data not shown). The associations were weak and inconsistent, although baseline albumin levels less than 3.9 g/dL (39 g/L) seemed to be associated with an increased risk for methotrexate-induced lung injury. A chest radiograph was more likely to have been obtained in case-patients than in controls (48% compared with 24%), reflecting the increased concern about pulmonary pathologic findings with regard to the case-patients. Thus, this feature was not examined further. None of these associations remained significant after we controlled for multiple risk factors.

    Methotrexate Therapy

    As Table 5 shows, cases of methotrexate-induced lung injury tended to be diagnosed early in the course of methotrexate therapy. The rate of methotrexate-induced lung injury was greater during the first 32 weeks of treatment than afterward. Cumulative dose, which is also related to treatment duration, was inversely associated with methotrexate-induced lung injury. However, the association was weak. No association was seen between the weekly methotrexate dose administered immediately before the event and the risk for methotrexate-induced lung injury. Patients with methotrexate-induced lung injury had a higher frequency of hypoalbuminemia and central nervous system manifestations than did the controls. Logistic regression analyses confirmed these findings, but central nervous system symptoms could not be evaluated in a model with other variables because of numerical problems (separation) in fitting the regression equation. Omission of this variable is not likely to confound the observations made with other variables because central nervous system manifestations were reported in only three case-patients and one control.

    View this table:
    Table 5. Methotrexate Therapy*

    Combined Analyses

    The results of these analyses (Table 6) confirm the role of older age, diabetes mellitus, rheumatoid pleuropulmonary involvement, previous use of selected disease-modifying antirheumatic drugs (sulfasalazine, gold, or D-penicillamine), and hypoalbuminemia in predicting methotrexate-induced lung injury. The wide CIs indicate imprecision due to the small study size, but it is very unlikely that the associations observed are caused by chance. In particular, the lower 95% CI of the odds ratio for hypoalbuminemia is 3.5, which suggests that at least a moderate increase in the risk for methotrexate-induced lung injury is associated with low albumin level. The effect of sex and previous lung disease is weak and statistically nonsignificant. The odds ratios for smoking, urban residence, and alcohol consumption do not seem to be confounded by other risk factors; however, they have wide CIs and are not statistically significant in this analysis. Additional analyses were conducted to evaluate the sensitivity of the final logistic regression model to the effect of highly influential or poorly fit observations or to the effect of restricting the number of predictor variables in this model. The results of these analyses are similar to those shown in Table 6. The observed associations are real, but the imprecision of the estimates does not allow us to clearly assess their relative importance. Population-attributable risks were 85% for hypoalbuminemia, 75% for previous use of disease-modifying antirheumatic drugs, and 23% for diabetes mellitus; these figures reflecting the relative impact of the risk factors identified.

    View this table:
    Table 6. Logistic Regression Analysis of Risk Factors from Methotrexate-Induced Lung Injury
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    Discussion

    Possible risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis have been suggested [19, 20, 22-2527-3049, 50]; these factors include previous or concomitant lung disease, relatively short duration of methotrexate treatment, hypoalbuminemia, and increased serum creatinine concentration [19, 20, 28]. We did a multicenter, case–control study to better define predictors of methotrexate-induced lung injury, and our data show a number of potential risk factors. Age, nonsedentary occupations (for women only), and smoking (for men only) were identified from the sociodemographic and lifestyle domain; diabetes mellitus was identified from the medical history domain; the number of extraarticular features of rheumatoid arthritis, rheumatoid pleuropulmonary involvement, and previous treatment with a disease-modifying antirheumatic drug (particularly sulfasalazine, oral gold, and D-penicillamine) were identified from the rheumatoid arthritis clinical features domain; and hypoalbuminemia and central nervous system manifestations during methotrexate therapy were identified from the methotrexate therapy domain. Finally, the initial period of methotrexate therapy was associated with the highest rate of methotrexate-induced lung injury.

    Some of the factors identified could be anticipated; others (such as duration of therapy) may be viewed as part of the event rather than as true predictors of it. Age, for example, has been shown to play a role in the expression of rheumatoid arthritis [51, 52], response to therapies [53, 54], and pattern of toxicities. Nonsteroidal anti-inflammatory drug-induced gastropathy and methotrexate-related liver injury, for example, occur more frequently in elderly patients [17, 55, 56]. Smoking and nonsedentary occupations may be associated with greater exposure of the respiratory tract to potentially hazardous material and may contribute to the pathogenesis of methotrexate-induced lung injury. Pleuropulmonary involvement of any cause has been described by Carroll and colleagues [19] and Golden and coworkers [20] as a factor predisposing patients to methotrexate-induced lung injury. This association was also found in our study, but it was not significant and weak when compared to some of the other associations found.

    Other risk factors, such as diabetes mellitus, previous use of disease-modifying antirheumatic drugs, hypoalbuminemia, and central nervous system manifestations during methotrexate therapy were not suspected of being associated with methotrexate-induced lung injury. Previous disease-modifying antirheumatic drug therapy may be a proxy for disease activity or severity [58-60] or for predisposition to disease-modifying antirheumatic drug toxicity requiring use of multiple agents [61-69]. Others have noted that most patients with rheumatoid arthritis who develop methotrexate-induced lung injury had previously received gold salt therapy [24, 27, 30, 70, 71]; this suggests an effect derived from cumulative toxic insults. We further examined our data to determine whether the greater exposure to previous disease-modifying antirheumatic drugs in the case-patients relative to the controls was due to lack of efficacy or to toxicity, but we were unable to distinguish between the two.

    Although a low serum albumin level before the initiation of methotrexate therapy probably represents disease activity, persistent hypoalbuminemia during methotrexate therapy in the face of a favorable clinical response to methotrexate probably represents liver toxicity. However, we were unable to determine whether the low serum albumin levels found in our patients represented liver toxicity or disease activity. No significant differences between case-patients and controls were seen in other laboratory indicators of liver involvement.

    The strongest association with methotrexate-induced lung injury was shown by diabetes mellitus, the onset of which usually preceded the onset of rheumatoid arthritis. None of the controls and only two of the case-patients had evidence of diabetes mellitus-related organ system involvement. Diabetes is a known risk factor for methotrexate-induced liver injury in patients with psoriasis, but it has not previously been reported to predispose patients to lung injury [72]. In a previous case–control study, diabetes mellitus was not identified as a risk factor for methotrexate-induced liver disease in patients with rheumatoid arthritis [17, 18]. Recent evaluation of the guidelines for monitoring liver toxicity concluded, however, that diabetes mellitus should be added to the list of contributing factors to increase the overall predictive value of that list [73]. The manner in which diabetes mellitus may contribute to the occurrence of lung or liver injury as a result of methotrexate administration needs to be examined further.

    The lack of information for some potential predictors is a weakness of our study and is a relatively common weakness in case–control studies based on chart review. For example, more case-patients than controls had a baseline chest radiograph (suggesting previous rheumatoid or nonrheumatoid pulmonary involvement), and physicians may have been more concerned about and may have been more likely to obtain repeated radiographs for these patients if they developed pulmonary manifestations. The possibility that a few of the case-patients had exacerbations of rheumatoid pleuropulmonary involvement (more extraarticular features of rheumatoid arthritis were seen in the case-patients than in the controls) cannot be excluded. However, we consider this alternative unlikely because no evidence of exacerbation of other extraarticular features of rheumatoid arthritis occurred along with the adverse pulmonary event. Moreover, more than half of the cases had histopathologic confirmation.

    In summary, we used rigorous epidemiologic research methods to identify several risk factors for methotrexate-induced lung injury. These factors include age; rheumatoid pleuropulmonary involvement; previous use of disease-modifying antirheumatic drugs; low serum albumin level; and, to a lesser extent, occupation, smoking, and number of extraarticular manifestations of rheumatoid arthritis. Although diabetes mellitus seems to be the strongest risk factor, it cannot explain a large proportion of the incidence of methotrexate-induced lung injury because it is relatively uncommon. Hypoalbuminemia and previous use of disease-modifying antirheumatic drugs were much more common among the case-patients than among the controls and may explain a larger proportion of the incidence of injury. Among nondiabetic patients with rheumatoid arthritis, these risk factors are paramount; diabetic patients should be considered at high risk for methotrexate-induced parenchymal toxicity, including both pulmonary and hepatic injury. Patients with multiple risk factors should be informed of the increased risk for lung injury and should be instructed to promptly report even subtle changes in respiratory status or cough to their physicians. Clinicians should weigh the potential risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis and should have a very low threshold for discontinuation of drug therapy, especially during the first several months of methotrexate therapy.

    Dr. Kremer: Division of Rheumatology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208.

    Dr. Macaluso: 106 MIH School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294.

    Dr. Weinblatt: Rheumatology and Immunology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

    Dr. Cannon: Division of Rheumatology, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132.

    Dr. Palmer: 650 Doctors Building, 4242 Farnam, Omaha, NE 68131.

    Dr. St. Clair: Department of Medicine, Duke University Medical Center, Box 3824, Durham, NC 27710.

    Dr. Sundy: Rheumatology and Immunology, Box 3258, Duke University Medical College, Box 2918 DUMC, Durham, NC 27710.

    Dr. Smith: Department of Pathology, Columbus Hospital, 500 15th Avenue South, Great Falls, MT 59405.

    Dr. Axiotis: Department of Anatomic Pathology, Kings County Hospital, 451 Clarkson Avenue, Brooklyn, NY 11203.

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