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* From the Autoimmune Lung Center (Drs. Swigris, Cosgrove, Frankel, and Brown); the Department of Rheumatology (Drs. Fischer and Meehan); and the Department of Radiology (Dr. Lynch), National Jewish Medical and Research Centers, Denver, CO. Division of Pulmonary Sciences (Dr. Olsen), University of Colorado Health Sciences, Denver, CO.
Correspondence to: Jeffrey J. Swigris, DO, MS, Interstitial Lung Disease Program, National Jewish Medical and Research Center, 1400 Jackson St, Molly Blank J229, Denver, CO 80206; e-mail: swigrisj{at}njc.org
Abstract
Background: Interstitial lung disease (ILD) frequently complicates connective tissue diseases (CTDs). Glucocorticoids and immunomodulatory agents are regarded as mainstays of therapy for CTD-related ILD; however, apart from those studies that have evaluated certain medications for patients with scleroderma, few studies have been performed. In this study, our objectives were to examine the safety and tolerability of mycophenolate mofetil (MMF) and to determine its impact on lung function in patients with CTD-ILD.
Methods: In this retrospective observational study, we analyzed patients at our center who ever received MMF for CTD-ILD. We examined the frequency and severity of side effects associated with MMF and used longitudinal data analytic methods to determine the ability of MMF to maintain lung function over time.
Results: Twenty-eight patients were treated with MMF over 35.9 patient-years. The most common underlying CTD diagnosis was scleroderma (n = 9). The most common reason for initiating MMF was an adverse effect of a prior immunomodulatory agent. Six patients had clinically significant side effects related to MMF; all resolved with dose reduction. Compared to before MMF, the mean daily prednisone dose while patients were receiving MMF was lower (10 mg/d vs 15 mg/d, p = 0.09). In addition, since starting MMF, the average percentage of predicted forced vital capacity (FVC), average percentage of predicted total lung capacity, and average percentage of predicted diffusing capacity of the lung for carbon monoxide for the cohort increased by 2.3%, 4.0%, and 2.6%, respectively
Conclusion: MMF appears to be safe and well tolerated in patients with CTD-ILD. Larger-scale studies are needed to further evaluate the efficacy of MMF in this patient population.
Key Words: connective tissue disease • interstitial lung disease • mycophenolate mofetil
The connective tissue diseases (CTDs) are a heterogeneous group of disorders characterized by inflammatory and fibrotic tissue injury. The lung is commonly affected by CTD. Because of the abundant connective tissue in the lung (and perhaps because of its large blood supply), any of its compartments (airways, parenchyma, vasculature, or pleura)—and not uncommonly multiple compartments simultaneously—are affected in cases of CTD.
The interstitial lung diseases (ILDs) or diffuse parenchymal lung diseases are a group of heterogeneous disorders with both unknown and known causes.1 Known causes include inhalational exposures and drugs; in addition, ILD occasionally occurs as a manifestation of an underlying systemic illness. The association between CTD and ILD has been known for many years,23 and it is estimated that among patients who present with ILD, approximately 15% have or will acquire a defined CTD.4 However, therapy for CTD-related ILD (CTD-ILD) has been based largely on biological rationale, uncontrolled series, case reports, and anecdotal experience. Although it is recommended that therapy be considered on a case-by-case basis, a common approach to treating a patient with any CTD-ILD extends from the increasingly accepted scheme for treating patients with ILD related to the scleroderma spectrum of disease. In that framework, patients with evidence of a more inflammatory pulmonary phenotype (eg, ground-glass opacities on chest high-resolution CT [HRCT] scans, BAL cellular differential showing neutrophils or eosinophils, or cellular interstitial infiltrates in surgical lung biopsy specimens) are treated more aggressively—and respond more favorably—than patients with a fibrotic pulmonary phenotype.5 A large, retrospective study5 showed that cyclophosphamide (CYC) improves lung function and survival in patients with scleroderma-related alveolitis. Further, the results from a recently completed, multicentered, placebo-controlled trial (The Scleroderma Lung Study), which were presented at the 2005 international meeting of the American Thoracic Society, revealed that CYC preserved lung function and improved quality of life.
In an effort to limit a patient’s exposure to the adverse effects of glucocorticoids, certain immunomodulatory agents (eg, CYC or azathioprine [AZA]) have been incorporated into CTD-ILD treatment regimens as steroid-sparing agents. However, like glucocorticoids, these agents carry their own potential toxicities and side effects. Recently, mycophenolate mofetil (MMF), an inhibitor of proliferating lymphocytes via its effects on the purine synthesis pathway,6 has been used to treat patients with several connective tissue and other diseases, including lupus nephritis,7 Wegener granulomatosis,8 polymyositis,9 and dermatomyositis.10 However, experience with using MMF for CTD-ILD is extremely limited.1112 We conducted this study to analyze the experience of our center with treating CTD-ILD patients with MMF. Our primary objective was to evaluate the safety and tolerability of using MMF in a heterogeneous sample of patients with various CTD-ILDs. A secondary objective of this study was to examine the impact of MMF on pulmonary physiology in these patients.
Materials and Methods
After a waiver of informed consent was granted by the National Jewish Medical and Research Center Institutional Review Board, we identified all patients who were ever treated with MMF for CTD-ILD at our institution. During the time frame of the study, the authors (J.S., A.F., G.C., S.F., R.M., and K.B.) were the only physicians at our institution who prescribed MMF or followed up patients receiving MMF for this indication; therefore, we were able to identify all potential subjects. All patients who received MMF primarily for their CTD-ILD and returned to our institution for at least one follow-up visit were included in this study. Each subject satisfied American College of Rheumatology criteria for a specific CTD diagnosis as applied by board-certified rheumatologists (R.M. or A.F.). Subjects with undifferentiated CTD (UCTD) had symptoms and diagnostic studies consistent with a systemic autoimmune disorder but lacked full diagnostic criteria for a more classifiable condition. Each diagnosis of ILD was made using one of two methods: (1) a diagnostic surgical lung biopsy, as interpreted by an expert pulmonary pathologist; or (2) abnormalities on chest HRCT interpreted by an expert thoracic radiologist as consistent with diffuse parenchymal lung disease.
We reviewed the complete medical records of included subjects and abstracted data pertaining to the following: demographics, the diagnosis of and therapies for both the CTD and ILD components of their disorder, treatments and treatment-related side effects, and pulmonary physiology before and after the initiation of MMF. Vital status was ascertained via query of the Social Security Death Index on November 1, 2005. Four subjects from this study were included in a previously published abstract.12
Statistical Analysis
Data are presented as counts or either as medians with full or interquartile ranges or as means with SDs. The effect of MMF on lung function was examined by using longitudinal data analytic methods. Longitudinal models were utilized to examine each of three continuous pulmonary physiology variables (FVC, total lung capacity [TLC], and diffusing capacity of the lung for carbon monoxide [DLCO]). Each model modeled the mean of the given physiology variable at each of three time points: (1) before MMF initiation; median, 166 days; (2) at the time of MMF initiation ±33 days; and (3) after MMF initiation; median, 371 days. Thus, a model yielded least-squared means estimates for its physiology variable at each of the three time points, and the null hypothesis of equality among the three mean values for a given variable was tested. Compound symmetry was confirmed as the appropriate method for handling the within-subject correlation of the repeated measures in these models by examining fit statistics (eg, –2 residual log likelihood and the Akaike information criterion) in the output from SAS PROC MIXED (SAS Institute; Cary, NC). By using PROC MIXED, we were able to take advantage of using all available data points (ie, patients who had missing data were not excluded from the longitudinal analyses). All p values from the longitudinal analysis were adjusted for multiple comparisons using the Tukey-Kramer method. Prednisone doses before and after initiation of MMF were compared by using the Wilcoxon signed-rank test. Mean differences in pulmonary physiology variables that occurred over the two study time intervals—the first interval was from before MMF initiation to the time of MMF initiation, and the second interval was from the time of MMF initiation to the time of the most recent study—were compared using paired t tests. All statistical analyses were performed using statistical software (version 9.1; SAS Institute; Cary, NC). We considered p values < 0.05 to be statistically significant.
Results
A total of 67 patients were being treated with MMF. Twenty-eight patients received MMF primarily for CTD-ILD. The other 39 patients were excluded for the following reasons: (1) 29 patients had CTD but no ILD; (2) 6 patients with CTD-ILD had not yet returned for a follow-up visit; and (3) 4 patients had an idiopathic interstitial pneumonia (nonspecific interstitial pneumonia). Sixty-four percent (n = 18) of the patients in our cohort were women, and most were white (Table 1 ). Nine patients had scleroderma, five had poly-/dermatomyositis, and five had UCTD. Among the patients with UCTD, all had esophageal disease in addition to physical examination or otherwise unexplained serologic abnormalities suggestive of an underlying CTD. A diagnosis of ILD was made by surgical lung biopsy in 13 patients. The primary pathologic pattern seen in the biopsy specimens was fibrosing nonspecific interstitial pneumonia. On average, mild-to-moderate restrictive lung physiology and a severely reduced DLCO were observed at the time of MMF initiation (median FVC, 2.4 L, 65% of predicted; median Dlco, 11.2 mL/min/mm Hg, 38% of predicted).
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While being treated with MMF, five patients had worsening respiratory symptoms, pulmonary physiology, or HRCT scans a median of 700 days (range, 211 to 1,105 days) after MMF initiation, which prompted either an increase in daily MMF or in prednisone dose. The average increase in daily prednisone dose over baseline in these cases was 14.5 mg; the average maximal prednisone dose during these episodes was 21 mg/d. The average duration that patients were receiving higher-than-baseline doses of prednisone for these episodes prior to returning to their usual dose was 12 weeks.
During a total of 36 patient-years of follow-up, five patients had identified side effects from MMF, which occurred a median 470 days (range, 31 to 792 days) after MMF initiation. No patient discontinued MMF because of side effects, and only two patients in the cohort discontinued MMF for any reason. No patient had more than one side effect; in each case, the side effect resolved with MMF dose reduction. One patient, with a history of peptic ulcer disease and GI bleeding had MMF discontinued as a precaution when she was found to be anemic, most likely due to a GI source. Another patient had MMF discontinued because it did not control arthralgias.
The most common side effect of MMF was diarrhea (n = 2). One patient had MMF-related leucopenia. This patient was started on MMF as an alternative to CYC after completing 15 months of CYC. With MMF at 1,500 mg bid, his total WBC count fell to < 4,000/µL. The MMF dose was reduced to 1,000 mg bid, and his total WBC rose and has remained > 8,000/µL.
Pulmonary physiology data from at least two time points—one prior to and one after starting MMF—were available for the majority of patients. Pulmonary physiology remained stable from time points prior to MMF initiation to most recent evaluations while receiving MMF therapy (Fig 1
). Since MMF initiation, the average cohort percentage of predicted FVC (FVC%), percentage of predicted TLC (TLC%), and percentage of predicted DLCO (Dlco%) had increased by 2.3%, 4.0%, and 2.6%, respectively. Similar changes and a trend toward statistical significance was observed in DLCO% (Table 3
). From the time of MMF initiation to the most recent pulmonary physiology study (ie, over the course of interval two), FVC% in four patients, TLC% in three other patients, and DLCO% in two other patients increased by 
10%. Over the same time interval, the FVC% in one patient, the TLC% in another patient, and the DLCO% in another patient decreased by 10%.
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In this study, 28 subjects with CTD-ILD received MMF for nearly 36 patient-years. MMF was very well tolerated; only two patients discontinued MMF for any reason. In contrast, prior to being started on MMF, 15 patients discontinued other immunomodulatory agents, most because of adverse effects. In addition, MMF maintained pulmonary physiology without increasing the median daily dose of glucocorticoids. Values for FVC, TLC, and DLCO did not decrease while patients were receiving MMF. In fact, clinically significant increases in these values were seen in nine patients as a result of MMF therapy.
To our knowledge, this is the first study examining the use of MMF specifically for the ILD component of CTD. Stratton and colleagues13 treated 13 patients with recently diagnosed diffuse scleroderma with a regimen of MMF and antithymocyte globulin. They found that FVC% and DLCO% remained stable over 12 months. However, the number of patients with ILD at study entry or completion was not reported. In that study—despite using similar doses of MMF (1,800 mg/d) to our cohort (2,000 mg/d)—43% of patients had adverse effects from MMF, and 16% of patients discontinued MMF because of adverse effects. We observed MMF to be extremely safe and well tolerated in our cohort.
Treiber11 described a patient with recurrent ILD associated with ulcerative colitis. The patient had ILD that was refractory to therapy with AZA and CYC; however, MMF led to improvements in chest CT findings, pulmonary physiology, and measures of gas exchange, along with a dramatic reduction in daily oral glucocorticoid dose. Based on that case report and other data suggesting that MMF suppresses primary human lung fibroblast proliferation in vitro, Altschuler14 speculated that MMF would be a reasonable therapy for IPF, a devastating fibrosing lung disease of unknown etiology and with pathologic features sometimes found in patients with CTD-ILD.
There are few studies that offer guidance in the treatment of CTD-ILD, and perhaps the most valid ones come from those examining treatment strategies for patients within the scleroderma spectrum of disease.5 In that paradigm, patients with "alveolitis," as demonstrated by ground-glass opacities on HRCT or either neutrophilia or eosinophilia on BAL, are treated with CYC because of the high likelihood that the lung parenchymal disease will progress. Unpublished results from the Scleroderma Lung Study, presented at the 2005 international conference of the American Thoracic Society, suggest that CYC improves lung function (and skin scores) in patients with scleroderma-related alveolitis (ie, ILD). Full results from that study are eagerly awaited. Such definitive studies have not been conducted for other CTD-ILD.
Recognized limitations in this study include the variability in therapeutic regimens and the lack of systematic data collection. Although MMF appeared to be well tolerated, in the absence of prospective evaluations, the rates of adverse effects of MMF observed in this study may be underestimated. Most patients in our study received prednisone along with MMF; therefore, it is difficult to determine the beneficial effects of either medication individually. However, by tabulating total and daily prednisone intake for each patient, we found that daily prednisone doses on average were not increased while disease control was maintained with MMF. In fact, five patients were able to discontinue their long-term, daily prednisone altogether after reaching their goal MMF doses. Our small sample size prohibited us from performing a more rigorous statistical analysis and from formulating more inferences regarding the apparent beneficial effects of MMF for CTD-ILD.
Conclusion
MMF appears to be safe and well tolerated in subjects with CTD-ILD. Given this and the evidence of disease control, we suggest that further longitudinal studies of MMF for CTD-ILD are warranted.
Acknowledgements
We thank Becki Bucher Bartelson for her assistance with statistical analysis.
Footnotes
Abbreviations: AZA = azathioprine; CTD = connective tissue disease; CYC = cyclophosphamide; DLCO = diffusion capacity of the lung for carbon monoxide; Dlco% = percentage of predicted diffusion capacity of the lung for carbon monoxide; FVC% = percentage of predicted FVC; HRCT = high-resolution CT; ILD = interstitial lung disease; MMF = mycophenolate mofetil; TLC = total lung capacity; TLC% = percentage of predicted total lung capacity; UCTD = undifferentiated connective tissue disease
The authors have no financial disclosures to make on this topic.
Received for publication December 12, 2005. Accepted for publication January 12, 2006.
References
This article has been cited by other articles:
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  A. J. Gerbino, C. H. Goss, and J. A. Molitor Effect of Mycophenolate Mofetil on Pulmonary Function in Scleroderma-Associated Interstitial Lung Disease Chest, February 1, 2008; 133(2): 455 - 460. [Abstract] [Full Text] [PDF]
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J. J. Swigris, A. Fischer, J. Gilles, R. T. Meehan, and K. K. Brown Pulmonary and Thrombotic Manifestations of Systemic Lupus Erythematosus Chest, January 1, 2008; 133(1): 271 - 280. [Abstract] [Full Text] [PDF]
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