Usefulness of monitoring Mycophenolic Acid Exposure in Systemic Sclerosis- Related Interstitial Lung Disease: A Retrospective Cohort Study

Usefulness of monitoring Mycophenolic Acid Exposure in Systemic Sclerosis- Related Interstitial Lung Disease: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Usefulness of monitoring Mycophenolic Acid Exposure in Systemic Sclerosis- Related Interstitial Lung Disease: A Retrospective Cohort Study Jules Milesi, Emmanuelle Sampol, Audrey Benyamine, Shani Diai, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4919161/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Oct, 2024 Read the published version in BMC Pulmonary Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Background : Systemic sclerosis-related interstitial lung disease (SSc-ILD) represents a significant cause of morbidity and mortality in Systemic Sclerosis (SSc). Mycophenolate mofetil (MMF) is currently the first line treatment for SSc-ILD. There is no recommendation on the dosage of mycophenolic acid (MPA) blood concentrations, so we aimed to study the correlation between MPA exposure and respiratory outcomes in this population. Methods: We conducted a retrospective cohort study of SSc-ILD patients treated with MMF in our center. According to our policy, a complete patient evaluation was performed approximately one year after MMF initiation, during which the mycophenolic acid (MPA) residual rate (RR) was measured. We analyzed the association between RR and changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time. Results : Forty-three SSc-ILD patients were included. Patients with higher RR levels (1.5 mg/L) had a significantly better FVC evolution with a higher proportion of stabilization and lower proportion of FVC decrease (p= 0.024). RR above 1.5 mg/L was a predictive factor of reduced FVC decline compared with lower RR levels adjusting for MMF dose and duration of MMF exposure (p= 0.008). There was no difference regarding DLCO outcome. Conclusion: Our study suggests that optimal MPA exposure, as indicated by RR levels, may better protect against FVC decline in SSc-ILD patients treated with MMF. Routine monitoring of MPA exposure could be beneficial in optimizing treatment outcomes. Prospective, multicenter studies are needed to further explore the relationship between MPA exposure and clinical outcomes in SSc-ILD. Scleroderma Connective tissue diseases Interstitial lung disease Mycophenolic acid Pharmacology Figures Figure 1 Figure 2 Introduction Systemic Sclerosis (SSc) is a rare connective tissue disease characterized by microvascular damage and remodeling with fibroblasts activation and extra-cellular matrix synthesis ( 1 ). Organs involved can be the skin, heart, kidney, muscles, articulations and lungs ( 2 ). Lung involvement is frequent in SSc, indeed, pulmonary fibrosis had been showed in 70 to 100% in autopsy series ( 3 ). Furthermore, up to 50% of patients present significant clinical lung involvement making SSc related interstitial lung disease (SSc-ILD) a major determinant of prognosis and quality of life ( 4 – 6 ). Currently, interstitial lung disease is the most common cause of death among these patients. Immunosuppressive therapy (IS) for SSc-ILD is indicated for severe or worsening ILD based on international guidelines ( 7 , 8 ). In SSc-ILD, according to the Scleroderma lung study II, MMF can be used as first line-therapy or as maintenance therapy after Cyclophosphamide (CYC) ( 9 ). MMF belongs to the anti-metabolite family and exhibits a complex pharmacokinetics. MMF is hydrolyzed by carboxylesterases in the active component, mycophenolic acid (MPA) in the stomach and absorbed ( 10 , 11 ). It is used in several diseases such as Solid Organ Transplantation (SOT), Systemic Lupus erythematous (SLE) or chronic graft versus host disease (GvHD) ( 12 – 15 ). Plasma concentration has already been investigated in these diseases but not in SSc whereas MMF is now an established therapy. Plasma concentrations should range between 30–60 mg/h/L in SOT ( 16 ) and at least 35 and 30 mg/h/L respectively in SLE ( 17 ) and GvHD ( 18 ). In SSc, the target dose of 3 grammes of MMF has shown equivalent efficacy as CYC against ILD ( 9 , 19 ). Furthermore, in SSc there are considerable MMF inter-individual variations in drug exposure and concentration: higher concentrations are found in female patients, patients with poor renal function, low body weight, whereas lower concentrations are observed in proton pump inhibitor (PPI) users ( 20 ) or overweight patient. Gastro-intestinal disorders, frequently observed in SSc patients may also cause a variation of the MMF concentration ( 21 ). To our knowledge, only one retrospective monocentric study tried and failed to demonstrate a relationship between MMF area under the concentration-time curve (AUC) and outcomes in skin involvement using Rodnan skin score or Pulmonary Function Tests (PFTs) evolution ( 22 ). Unfortunately, no data concerning radiologic or clinical evolution was reported which are two key prognostic determinants for SSc progression. Despite of this, through their study, Legendre et al. showed large inter-individual variability in MPA AUC in SSc patients for a daily dosing of 1000 mg twice daily. This result suggests that monitoring MMF could be required in SSc. However, as there is no evidence supporting measurement of MPA exposure in SSc, such dosage is not routinely recommended in current guidelines. When practitioners do use it, they generally consider that the target of MPA should be the same as in SOT. The recommended target ranges include an AUC between 30–60 mg/h/L or an estimation with residual rate (RR) (concentration level just before the next intake of medication) ranging between 1.5-4 mg/L. ( 23 ). In this context, we conducted a retrospective study to explore the relationship between clinical, radiological, and functional ILD evolution in SSc patients and MPA-RR measured at one year of MMF treatment. Methods Study design and population We conducted a retrospective monocentric study in the department of respiratory medicine of hospital Nord in Marseille, France between January 2010 and February 2024. In our hospital, SSc-ILD patients treated with MMF are monitored by RR in routine clinical practice. To be eligible, patients had to fulfill ACR/EULAR criteria ( 24 ) for SSc with ILD assessed by an expert radiologist in Multidisciplinary Discussion (MDD), to receive MMF (Cellcept® or Myfortic®) and to have a measurement of MPA-RR. All patients included in the analysis underwent PFTs and High-resolution computed tomography (HRCT) of the lungs after MMF initiation. The Institutional Review Board of the French learned society for respiratory medicine -Société de Pneumologie de Langue Française- approved the protocol (CEPRO 2023-014), and a written information and non-objection notice was given to all participants according to French law. Parameters analyzed The aim of our study was to explore the relationship between the MPA-RR at steady state and the progression of the respiratory disease. For this purpose, we analyzed the variation of forced vital capacity (FVC), diffusing lung capacity for carbon monoxide (DLCO) and evolution of HRCT and dyspnea after one year of MMF treatment. Baseline was defined as the time of initiation of MMF. The evaluation time was defined as the closest time point to one year from MMF initiation, and included clinical, functional, radiological respiratory parameters and MPA-RR dosage. For all the subjects, we collected the following data carried out in clinical routine, before MMF initiation and at the time of RR: age, sex, BMI, smoking status, dyspnea according to the mMRC (modified Medical Research Council) scale, 6-minute walk test (6MWT), oxygen supplementation, co-morbidities, blood cell count, treatments used such as corticosteroids or immunosuppressants, HRCT patterns and evolution. All participants benefited from spirometry, plethysmography, and diffusion analysis when available (Ilmeter 1,304; Masterlab Jaeger, Wurzberg, Germany). Variations of FVC, DLCO and HRCT patterns between MMF introduction and MPA-RR measurement were pooled in three groups: improved, stable or worsened. Regarding PFTs, an absolute increase of more than 10% of FVC was considered as an improvement whereas an absolute decrease of more than 10% was considered as worsened. All other variations were considered as stable. An absolute increase of more than 15% in DLCO was classified as improved, whereas an absolute decrease of 15% of more was considered as worsened. All other variations were classified as stable ( 25 ). Concerning radiologic evolution, progression, stability or amelioration was assessed in MDD with an expert radiologist in accordance with current international guidelines. The composite criterion for SSc-ILD evolution was based on the progressive pulmonary fibrosis (PPF) guidelines: meeting two of the three following criteria indicating progression: an absolute decline of 5% in FVC and/or 10% in DLCO, clinical deterioration, or radiological progression ( 26 ). Pharmacokinetics Residual rate samplings were performed after MPA plasma concentration has reached steady state (i.e 5 half-lives) that mean at least 5 days after the first intake of MMF. We performed the samplings into 5 mL EDTA heparinized vacutainer tubes. MPA RR was defined as the concentration at 12 h +/- 2 h after the last drug intake. Analysis of MPA in plasma was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS is the gold standard method with High analytical selectivity and sensitivity. A Waters XEVO TQ-S Micro Mass spectrometer coupled to a Waters Acquity liquid chromatography system was used in positive electrospray ionization mode as previously described ( 27 ). MPA quantification was achieved using multiple reaction monitoring. MPA quantification was achieved through multiple reaction monitoring. Deuterated Mycophenolic acid was used as an internal standard. The method is linear from 0.20 to 30 µg/mL, with both accuracy and precision within 10%. Statistical analysis A descriptive analysis was performed on our population. Continuous variables were expressed in median and interquartile or mean and standard deviation, depending on the distribution (Shapiro-Wilk test), and qualitative variables were expressed in numbers and percentages. Qualitative parameters were compared using Chi-square tests. Quantitative parameters were compared using a student’s test or a Mann-Whitney-Wilcoxon non-parametric test depending on the distribution. The association between MPA-RR and MMF dose was analyzed using Pearson correlation. Predictive factors for worsened FVC in SSc-ILD patients, in relation to the MPA-RR, were analyzed using logistic regression in both univariate and multivariate models. All tests were two-sided. A p-value < 0.05 was considered significant. The analysis was performed using version 4.3.2 (2022-06-23) of the R software (R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/ ). Results Patient characteristics Over the studied period (January 2010 and February 2024), we identified 54 patients who fulfilled the ACR/EULAR criteria for SSc and treated with MMF. Eleven patients did not undergo measurement of MPA-RR. Finally, 43 patients were included in the analysis. Main population characteristics at the time of MMF treatment onset are detailed in Table 1 . Mean age was 54 years (+/-14), with 34 (79%) women. Seventeen (40%) presented with diffuse cutaneous disease, 24 (56%) with limited cutaneous disease, and 2 (4,7%) with sine scleroderma SSc. Gastrointestinal tract involvement and PPI use was reported in 38 (88%) patients. Autoimmune diseases were associated with SSc in 10 (23%) patients, mostly Sjogren disease or SLE. Six (14%) patients died during the follow-up. Table 1 Baseline characteristics of 43 systemic sclerosis treated with mycophenolate mofetil. Characteristics Total patients (N = 43) 1 RR 1,5, N = 24 1 p-value 2 Female 34 (79%) 16 (84%) 18 (75%) 0.7 Diagnostic age (y) 50 (+/-16) 46 (+/-19) 54 (+/-12) 0.3 BMI (kg/m2) 24.2 (18.0-35.7) 23.0 (18.0-32.6) 25.3 (21.6–35.7) 0.2 Comorbidities 30 (70%) 14 (74%) 16 (67%) 0.6 Other AID 10 (23%) 6 (32%) 4 (17%) 0.3 History of tobacco 17 (40%) 8 (42%) 9 (38%) 0.8 mMRC 0.11 0–1 15 (36%) 4 (22%) 11 (46%) > 1 27 (64%) 14 (78%) 13 (54%) SSc type 0.3 Diffuse 17 (40%) 6 (32%) 11 (46%) Limited 24 (56%) 13 (68%) 11 (46%) Sine scleroderma 2 (4.7%) 0 (0%) 2 (8.3%) Gastrointestinal tract involvment 38 (88%) 16 (84%) 22 (92%) 0.6 Anti-Scl70 33 (77%) 12 (63%) 21 (88%) 0.079 Anti-centromere 1 (2.3%) 1 (5.3%) 0 (0%) 0.4 HRCT Pattern 0.2 PPFE 1 (2.3%) 1 (5.3%) 0 (0%) Unclassifiable 2 (4.7%) 1 (5.3%) 1 (4.2%) UIP 9 (21%) 6 (32%) 3 (13%) NSIP 31 (72%) 11 (58%) 20 (83%) FVC (L) 2.02 (0.93–4.38) 1.91 (1.00-4.38) 2.12 (0.93–3.34) 0.2 FVC (%) 73 (27–109) 66 (27–107) 74 (37–109) 0.2 DLCO (%) 41 (8–69) 41 (8–54) 43 (20–69) 0.3 PH 15 (36%) 8 (44%) 7 (29%) 0.3 Oxygen 17 (40%) 9 (47%) 8 (33%) 0.3 Steroids 19 (44%) 8 (42%) 11 (46%) 0.8 Time before MMF onset (months) 59 (0-396) 80 (0-396) 39 (0-312) 0.085 Time between MMF and residual rate (months) 12 (0-112) 13 (3–50) 12 (0-112) 0.7 MMF dose (g) 0.032 2 12 (28%) 2 (11%) 10 (42%) Adverse event 17 (40%) 8 (42%) 9 (38%) 0.8 CYC 4 (9.3%) 1 (5.3%) 3 (13%) 0.6 Rituximab 7 (16%) 4 (21%) 3 (13%) 0.7 Antifibrotic drugs 3 (7.0%) 1 (5.3%) 2 (8.3%) > 0.9 Deaths 6 (14%) 4 (21%) 2 (8.3%) 0.4 1 n (%); Mean (+/-SD); Median (Minimum-Maximum) 2 Fisher’s exact test; Wilcoxon rank sum test; Pearson’s Chi-squared test RR = residual rate, BMI = Body mass index; AID = Auto-immune disease; mMRC = modified Medical Research council; SSc = Systemic sclerosis; HRCT = High-resolution computed tomography; PPFE = Pleuroparenchymal Fibroelastosis; FVC = forced vital capacity; DLCO = Diffusing lung capacity for carbon monoxide; PH = Pulmonary Hypertension; MMF = Mycophenolate mofetil; CYC = cyclophosphamide Patients presented SSc-ILD with non-specific interstitial pneumoniae (NSIP) pattern in 31 (72%) of cases. Other patterns were usual interstitial pneumoniae (UIP), unclassifiable and Pleuroparenchymal fibroelastosis in 9 (21%), 2 (4.7%) and 1 (2.3%) case, respectively. At time of treatment introduction, median FVC was 73% (range 27–109), and median DLCO was 41% (8–69) of predicted values. Fifteen patients had pulmonary hypertension (36%) and 17 patients needed supplemental oxygen (40%). We created two groups of patients based on their MPA-RR levels at evaluation time: 19 (44%) with RR = 1.5 mg/L. A comparison of baseline characteristics between the two groups is summarized in Table 1 . The MMF dose was the only variable with a significant difference between these groups (p-value 0.032), with a higher MMF dose in the > = 1.5 mg/L group. Seventeen (40%) patients presented adverse event, mainly digestive, without significant difference between the two groups. Treatments such as CYC, rituximab or antifibrotic drugs, as well as PFTs or duration between MMF introduction and RR measurement, were not statistically different between the two groups. MMF dose and MPA-RR relationship The median duration between MMF introduction and RR measurement was 12 months (range 0-112). The median MMF dose and MPA-RR were 1000 mg/day (0.5-3) and 1.7 mg/L (0.5–6.2), respectively. There was a significant positive correlation between MMF dose and MPA-RR using Pearson model (rho: 0.47, p-value 0.002) (Fig. 1 ). Patients evolution Table 2 compares the evolution of the PFTs, HRCT and clinical outcomes between these two groups. Concerning PFTs, the absolute evolution of FVC was significantly better in RR > = 1.5 mg/L group than in lower RR group (p-value 0.024). Indeed, a stabilization of FVC was observed in a higher proportion of patients ( n = 17; 74%) in RR > = 1.5 mg/L group compared with the RR = 1.5 mg/L group ( n = 3; 13%) versus the RR < 1.5 mg/L group ( n = 7; 47%). Figure 2 represents the evolution of mean FVC in patients depending on MPA-RR upper or lower 1.5 mg/L. Table 2 Clinical, functional and radiologic evolution of patients based on mycophenolic acid residual rate. Characteristics RR 1,5, N = 24 1 p-value 2 FVC absolute evolution 0.024 Decrease 7 (47%) 3 (13%) Increase 3 (20%) 3 (13%) Stable 5 (33%) 17 (74%) DLCO absolute evolution 0.6 Worsened 1 (9.1%) 3 (18%) Stable 9 (82%) 14 (82%) Improved 1 (9.1%) 0 (0%) HRCT evolution 0.4 Worsened 2 (11%) 3 (14%) Improved 2 (11%) 0 (0%) Stable 14 (78%) 19 (86%) mMRC evolution 0.4 Worsened 5 (29%) 5 (22%) Stable 10 (59%) 11 (48%) Improved 2 (12%) 7 (30%) SSc-ILD Evolution > 0.9 Progression 3 (16%) 3 (13%) Stable 16 (84%) 21 (88%) 1 Median (Minimum-Maximum); n (%) 2 Wilcoxon rank sum test; Fisher’s exact test RR = residual rate; FVC = forced vital capacity; DLCO = Diffusing lung capacity for carbon monoxide; HRCT = High-resolution computed tomography; mMRC = modified Medical Research council; SSc-ILD = Systemic sclerosis related interstitial lung disease. FVC = absolute increase of more than 10% was considered as an improvement whereas an absolute decrease of more than 10% was considered as worsened. All other variations were considered as stable DLCO = absolute increase of more than 15% was considered as an improvement whereas an absolute decrease of more than 15% was considered as worsened. All other variations were considered as stable Conversely, no significant results were found with DLCO between the 2 groups (p-value 0.6). Of note, data on DLCO were missing in 15 (35%) patients. Regarding HRCT, dyspnea evolution and SSc-ILD evolution based on international PPF criteria, no differences were observed between the two groups. Table 3 summarizes predictive factors for worsened FVC evolution using logistic regression in univariate and multivariate analysis. The only protective factor was MPA-RR at evaluation time in both univariate and multivariate analyses, adjusting for MMF dose, time of MMF exposure, and patient age at diagnosis. In our cohort, a MPA-RR over 1.5 mg/L independently reduced the risk of worsened FVC evolution by 95% (p-value 0.008) compared to a MPA-RR lower than 1.5 mg/L. Table 3 Predictive factors of FVC worsening in univariate and multivariate analysis. Characteristics Univariate Multivariate N OR 1 95% CI 1 p-value OR 1 95% CI 1 p-value Diagnostic age (y) 38 1.03 0.98, 1.09 0.2 1.05 0.99, 1.12 0.089 Female 38 0.51 0.10, 2.96 0.4 BMI (kg/m2) 38 0.97 0.80, 1.17 0.8 Comorbidities 38 1.30 0.29, 7.05 0.7 Other AID 38 0.41 0.02, 2.89 0.4 Tobacco 38 1.55 0.35, 6.82 0.6 mMRC 38 0.8 0–1 1.00 — > 1 0.83 0.19, 3.92 0.8 SSc type 38 0.8 Diffuse 1.00 — Limitée 1.00 0.22, 4.83 > 0.9 Sine scleroderma 3.00 0.10, 89.1 0.5 Gastrointestinal tract involvement 38 0.18 0.02, 1.28 0.085 Anti-Scl70 38 0.64 0.13, 3.62 0.6 Anti-centromere 38 0.00 0.4 FVC (L) 38 2.00 0.78, 5.80 0.15 FVC (%) 38 1.01 0.98, 1.06 0.4 DLCO (%) 32 1.01 0.96, 1.07 0.6 PH 38 0.53 0.07, 2.67 0.5 Oxygen 38 0.66 0.12, 2.97 0.6 Steroids 38 0.57 0.11, 2.54 0.5 Time before MMF onset (months) 38 0.99 0.98, 1.00 0.2 MMF dose (g) 38 0.7 0.8 2 0.44 0.04, 4.80 0.5 1.00 0.03, 48.2 > 0.9 Time between MMF and residual rate (months) 38 0.89 0.75, 1.00 0.058 0.85 0.69, 1.00 0.053 MPA Residual rate 38 0.022 0.008 1,5 0.17 0.03, 0.78 0.029 0.05 0.00, 0.49 0.021 CYC 38 0.00 0.2 Rituximab 38 1.15 0.14, 6.62 0.9 Antifibrotics 38 6.75 0.58, 157 0.12 1 OR = Odds Ratio, CI = Confidence Interval BMI = Body mass index; AID = Auto-immune disease; mMRC = modified Medical Research council; SSc = Systemic sclerosis; FVC = forced vital capacity; DLCO = Diffusing lung capacity for carbon monoxide; PH = Pulmonary Hypertension; MMF = Mycophenolate mofetil; CYC = cyclophosphamide. Discussion In this study, we observed that patients with MPA-RR above 1.5 mg/L had a preserved FVC overtime compared to patients with MPA-RR under 1.5 mg/L. Additionally, our findings failed to reveal significant associations between DLCO, HRCT or SSc-ILD evolution using PPF criteria and the MPA-RR values. However, approximately 80% of patients in both groups showed stability concerning these three criteria. Without a placebo control group, we cannot definitively conclude that MMF allowed for stability in our cohort. Nonetheless, these findings are in accordance with previous multicentric studies demonstrating the efficacy of MMF in improving both FVC and DLCO in SSc-ILD patients ( 9 , 28 – 30 ). Indeed, MMF is established as a first-line therapy for SSc-ILD with fibrosis extent exceeding 20% ( 7 , 8 ). We believe that the lack of power in our study may have contributed to the non-significant results for DLCO, HRCT, or PPF criteria. This suggests that our sample size or the duration of MMF exposure might have been insufficient to detect significant differences. Moreover, as approximately 35% of our patients had missing DLCO data, we did not conduct further analyses comparing DLCO and MPA-RR to avoid the risk of misinterpretation of our data. Of note, our patient cohort exhibited more severe disease manifestations with compromised PFTs compared to previous studies. Specifically, our median FVC and DLCO values were lower (73% and 41%, respectively) compared to those reported by Legendre et al ( 22 ). Consequently, the rate of FVC improvement in our cohort (21%) was lower than that reported in other studies ( 9 , 31 – 33 ). Tashkin et al. demonstrated FVC improvement in 71% of cases in Scleroderma Lung Study (SLS) II. It is noteworthy that our patients received lower MMF doses compared to those received in previous trials. Indeed, the median MMF dose in our study was 1000 mg/day, whereas patients in controlled studies such as SLS II received 3000 mg/day ( 9 ) or 2000 mg/day for most patients in Legendre et al study ( 22 ). This discrepancy in MMF dosage may suggest an undertreatment in our cohort, especially considering that only 56% of subjects had MPA-RR levels above 1.5 mg/L. All these differences may have contributed to the absence of a significant association between DLCO, HRCT and SSc-ILD evolution and RR measurements in our cohort. In clinical practice, we advocate for the necessity of measuring MPA exposure and emphasize the importance of further investigation in this area. Our findings revealed that a MPA-RR level above 1.5 mg/L was the only protective factor against FVC worsening in multivariate analysis, with a remarkable 95% reduction in the risk of progression. Interestingly, this analysis was adjusted on MMF dose and time of exposure, underscoring the significance of inter- and intra-individual variability in MMF pharmacokinetics. This variability is also highlighted by the moderate correlation of MMF dose and MPA-RR observed in our study. However, it is worth mentioning that we employed MPA target ranges established in other conditions, and optimal ranges specific to SSc may differ. Prior research has demonstrated a correlation between MPA exposure and disease activity with recommended target ranges for MPA plasma exposure typically expressed as AUC values ranging from 30 to 60 mg/L.h or residual rate concentrations between 1.5 to 4 mg/L ( 23 ). Moreover, considerable inter-individual variability in MPA plasma exposure has been observed ( 34 , 35 ), which may also be extended to SSc due to factors such as PPI use or gastrointestinal tract involvement ( 21 ). However to the best of our knowledge, Legendre et al were the only investigators to explore the relationship between MMF treatment and skin or lung involvement, as assessed by Rodnan skin score and PFT variation, respectively ( 22 ). Our findings are consistent with previous research indicating significant inter-individual variability in MPA plasma exposure, supporting the importance of documenting MPA plasma exposure in patients with SSc. MPA concentrations in our cohort ranged widely from 0.5 to 6.2 mg/L, with daily MMF doses varying from 500 to 3000 mg. Our study boasts several strengths. We present the largest cohort of SSc-ILD investigating MPA exposure to date. Contrary to previous findings by Legendre et al, our study demonstrated the beneficial impact of RR measurements on FVC progression ( 22 ). FVC has been identified as a critical determinant of mortality in ILD, underscoring the clinical relevance of this association ( 36 ). Moreover, the simultaneous assessment of RR and PFTs is noteworthy, given the wide variability in MPA blood concentration. The comparable baseline characteristics of our two patient groups facilitated a more precise comparison of the effect of MMF exposure. The AUC is more difficult to measure in real life because of the need of multiple blood samples. Indeed, our results are easier to generalize in routine clinical practice as it only requires one sample for RR measurement. Several limitations of our study should be acknowledged. First, due to the retrospective nature, we could only report RR of MPA, as there were significant missing data regarding AUC. Additionally, being monocentric with a relatively sample size, our study may be subject to inherent biases. Notably, skin involvement, a major outcome and an indication for MMF therapy in SSc patients, was not consistently reported. As a result, we could not assess usefulness of monitoring MPA on the skin progression of SSc. Furthermore, patients in our cohort could have been treated with either Cellcept® or Myfortic®, potentially introducing pharmacokinetic or pharmacodynamic variations. Moreover, measurements of residual rate or AUC do not guarantee consistent MPA exposure throughout the follow-up period, as fluctuations in concentration may occur due to factors such as changes in medication or infections ( 21 , 34 , 35 ). Despite its importance as a prognostic determinant in SSc-ILD, we were unable to draw conclusions regarding DLCO probably due to missing data. Conclusion We have identified for the first time, an association between MPA exposure and outcomes in SSc-ILD. Optimal MMF exposure, as indicated by MPA-RR above 1.5 mg/L appears to be a protective factor against FVC worsening. Thus, the routine monitoring of MPA exposure, for a better adaptation of MMF dose, may offer clinical benefits to patients. Future prospective, multicenter studies with larger sample sizes are warranted to further explore pharmacokinetic/pharmacodynamic relationships in SSc and to optimize methods for measuring MPA plasma exposure. Abbreviations SSc Systemic sclerosis SSc-ILD = SSc related interstitial lung disease IS = Immunosuppressive therapy ILD = interstitial lung disease MMF = Mycophenolate Mofetil CYC = Cyclophosphamide MPA = mycophenolic acid SOT = Solid Organ Transplantation SLE = Systemic Lupus erythematous GvHD = chronic graft versus host disease PPI = Proton pump inhibitor AUC = area under the concentration-time curve PFTs = pulmonary function tests RR = MPA residual rate MDD = Multidisciplinary Discussion HRCT = High resolution computed-tomography FVC = forced vital capacity DLCO = diffusing lung capacity for carbon monoxide mMRC = modified Medical Research Council PPF = Pulmonary Progressive Fibrosis NSIP = interstitial pneumoniae UIP = usual interstitial pneumoniae SLS = Scleroderma Lung Study Declarations Statement of Ethics The Institutional Review Board of the French learned society for respiratory medicine -Société de Pneumologie de Langue Française- approved the protocol (CEPRO 2023-014), and a written information and non-objection notice was given to all participants according to French law. Data Availability Statement The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Conflict of interest Statement The authors declare that they have no competing interests. Funding Sources The authors report no targeted funding. Author Contributions JM, JB, ES design the study and methods. Clinical data were provided by ES, JB, BC, AN, BG, MR. Statistical analyses were done by JM, SD. JM wrote the original draft. ES, JB, BG, MR reviewed and edited the manuscript. Figures were created by JM, SD, BC. Supervision by JB, AB, BG, MR. Guarantor of the study is JB. All authors read and approved the manuscript. Aknowledgements Not applicable References Tamby MC, Chanseaud Y, Guillevin L, Mouthon L. New insights into the pathogenesis of systemic sclerosis. Autoimmun Rev. mai 2003,2(3):152‑7. Ranque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev. mars 2010,9(5):A311-318. 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Mycophenolate mofetil: what is its place in the treatment of autoimmune rheumatic diseases? Autoimmun Rev. janv 2007,6(3):190‑5. Eskin-Schwartz M, David M, Mimouni D. Mycophenolate mofetil for the management of autoimmune bullous diseases. Dermatol Clin. oct 2011,29(4):555‑9. Chaigne B, Gatault P, Darrouzain F, Barbet C, Degenne D, François M, et al. Mycophenolate mofetil in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a prospective pharmacokinetics and clinical study. Clin Exp Immunol. mai 2014,176(2):172‑9. van Gelder T, Le Meur Y, Shaw LM, Oellerich M, DeNofrio D, Holt C, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit. avr 2006,28(2):145‑54. Zahr N, Arnaud L, Marquet P, Haroche J, Costedoat-Chalumeau N, Hulot JS, et al. Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil. Arthritis Rheum. juill 2010,62(7):2047‑54. Wakahashi K, Yamamori M, Minagawa K, Ishii S, Nishikawa S, Shimoyama M, et al. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation. Int J Hematol. août 2011,94(2):193‑202. Fernández-Codina A, Walker KM, Pope JE, Scleroderma Algorithm Group. Treatment Algorithms for Systemic Sclerosis According to Experts. Arthritis Rheumatol. nov 2018,70(11):1820‑8. Alex G, Shanoj KC, Varghese DR, Sageer Babu AS, Reji R, Shenoy PD. Co prescription of anti-acid therapy reduces the bioavailability of mycophenolate mofetil in systemic sclerosis patients: A crossover trial. Semin Arthritis Rheum. déc 2023,63:152270. Andréasson K, Neringer K, Wuttge DM, Henrohn D, Marsal J, Hesselstrand R. Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation-a prospective, observational study. Arthritis Res Ther. 6 oct 2020,22(1):230. Legendre P, Blanchet B, Porcher R, Bérezné A, Allard M, London J, et al. Mycophenolic acid drug monitoring in patients with systemic sclerosis associated with diffuse skin and/or pulmonary involvement: A monocentric and retrospective French study. J Scleroderma Relat Disord. févr 2021,6(1):87‑95. Le Meur Y, Büchler M, Thierry A, Caillard S, Villemain F, Lavaud S, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. nov 2007,7(11):2496‑503. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. nov 2013,72(11):1747‑55. Wells AU, Margaritopoulos GA, Antoniou KM, Denton C. Interstitial lung disease in systemic sclerosis. Semin Respir Crit Care Med. avr 2014,35(2):213‑21. Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 1 mai 2022,205(9):e18‑47. Streit F, Shipkova M, Armstrong VW, Oellerich M. Validation of a rapid and sensitive liquid chromatography-tandem mass spectrometry method for free and total mycophenolic acid. Clin Chem. janv 2004,50(1):152‑9. Liossis SNC, Bounas A, Andonopoulos AP. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford). août 2006,45(8):1005‑8. Vanthuyne M, Blockmans D, Westhovens R, Roufosse F, Cogan E, Coche E, et al. A pilot study of mycophenolate mofetil combined to intravenous methylprednisolone pulses and oral low-dose glucocorticoids in severe early systemic sclerosis. Clin Exp Rheumatol. 2007,25(2):287‑92. Herman D, Ghazipura M, Barnes H, Macrea M, Knight SL, Silver RM, et al. Mycophenolate in Patients with Systemic Sclerosis-associated Interstitial Lung Disease: A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. janv 2024,21(1):136‑50. Mendoza FA, Nagle SJ, Lee JB, Jimenez SA. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol. juin 2012,39(6):1241‑7. Le EN, Wigley FM, Shah AA, Boin F, Hummers LK. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis. juin 2011,70(6):1104‑7. Derk CT, Grace E, Shenin M, Naik M, Schulz S, Xiong W. A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis. Rheumatology (Oxford). déc 2009,48(12):1595‑9. Streicher C, Djabarouti S, Xuereb F, Lazaro E, Legeron R, Bouchet S, et al. Pre-dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases. Br J Clin Pharmacol. déc 2014,78(6):1419‑25. Schaier M, Scholl C, Scharpf D, Schmitt WH, Schwenger V, Zeier M, et al. High interpatient variability in response to mycophenolic acid maintenance therapy in patients with ANCA-associated vasculitis. Nephrol Dial Transplant. avr 2015,30 Suppl 1:i138-145. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 31 oct 2019,381(18):1718‑27. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 28 Oct, 2024 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Revision requested 22 Aug, 2024 Editor assigned by journal 21 Aug, 2024 Submission checks completed at journal 21 Aug, 2024 First submitted to journal 15 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4919161","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":343583675,"identity":"43ffd964-5109-4354-918f-fa5ad9767fcc","order_by":0,"name":"Jules Milesi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYBACxgbmBhDNwwckDnwAEgZA/AG/FkaIFjYgcXAGRAvjDEL2gCmQFmYeYrQwz0hsfPiDYZsMG3v7w8M2NXcYzMUOMDZX4LNjRmKzMQ/DbR42njMGh3OOPWOwnJ3A2HgGv5Y2aQaQFokchsM5bIfrN9xOYH/YgF9L+88fIC3yzx8ctvh3mMHgNtAWAlraGMAOk2AwOMzYRoyWnofN0jwGIL/kGBzs7XsG1JLYiFeLYXvywY8/Km7b87Mff/zhx7c7QC3JB/FrAUsawPkHGOAxhQvIo/EP4FU9CkbBKBgFIxMAAMcJUZ34JgW9AAAAAElFTkSuQmCC","orcid":"","institution":"Aix Marseille Univ","correspondingAuthor":true,"prefix":"","firstName":"Jules","middleName":"","lastName":"Milesi","suffix":""},{"id":343583676,"identity":"044b888d-ab9b-45f3-8552-c4ece3881cd2","order_by":1,"name":"Emmanuelle Sampol","email":"","orcid":"","institution":"Aix Marseille Univ, APHM","correspondingAuthor":false,"prefix":"","firstName":"Emmanuelle","middleName":"","lastName":"Sampol","suffix":""},{"id":343583677,"identity":"75179d78-aa2e-4fa0-9e01-7894a018177b","order_by":2,"name":"Audrey Benyamine","email":"","orcid":"","institution":"Aix-Marseille Univ, APHM, North Hospital","correspondingAuthor":false,"prefix":"","firstName":"Audrey","middleName":"","lastName":"Benyamine","suffix":""},{"id":343583678,"identity":"5ea5600f-7f87-47cc-b568-856c8ab3b274","order_by":3,"name":"Shani Diai","email":"","orcid":"","institution":"University Hospital of Marseille (APHM)","correspondingAuthor":false,"prefix":"","firstName":"Shani","middleName":"","lastName":"Diai","suffix":""},{"id":343583679,"identity":"1862e150-a1c6-47d0-8f8c-a9fa66d36d6f","order_by":4,"name":"Benjamin Coiffard","email":"","orcid":"","institution":"Aix Marseille Univ","correspondingAuthor":false,"prefix":"","firstName":"Benjamin","middleName":"","lastName":"Coiffard","suffix":""},{"id":343583680,"identity":"f47cdea2-0508-42e2-ac15-9b78826cfa71","order_by":5,"name":"Ana Nieves","email":"","orcid":"","institution":"Aix Marseille Univ","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"Nieves","suffix":""},{"id":343583681,"identity":"921fec53-8b2d-4f7c-a06f-9a8ede2d320f","order_by":6,"name":"Brigitte Granel","email":"","orcid":"","institution":"Aix-Marseille Univ, APHM, North Hospital","correspondingAuthor":false,"prefix":"","firstName":"Brigitte","middleName":"","lastName":"Granel","suffix":""},{"id":343583682,"identity":"5591c853-2584-410a-b33a-2a142d0b09ac","order_by":7,"name":"Martine Reynaud-Gaubert","email":"","orcid":"","institution":"Aix Marseille Univ","correspondingAuthor":false,"prefix":"","firstName":"Martine","middleName":"","lastName":"Reynaud-Gaubert","suffix":""},{"id":343583683,"identity":"46e17ac9-4513-496b-a0df-f279c589c1ed","order_by":8,"name":"Julien Bermudez","email":"","orcid":"","institution":"Aix Marseille Univ","correspondingAuthor":false,"prefix":"","firstName":"Julien","middleName":"","lastName":"Bermudez","suffix":""}],"badges":[],"createdAt":"2024-08-15 12:02:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4919161/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4919161/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-024-03361-7","type":"published","date":"2024-10-28T15:57:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66656636,"identity":"25bd0a47-0f13-43bb-9ec8-0e610f009a94","added_by":"auto","created_at":"2024-10-15 08:22:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":154069,"visible":true,"origin":"","legend":"\u003cp\u003ePearson correlation between mycophenolic acid residual (MPA) rate and Mycophenolate Mofetil (MMF) dose\u003c/p\u003e","description":"","filename":"Fig1.CorrelationResidualrateMMFdose.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4919161/v1/c16afbc6c9b82bf50afd0c71.jpg"},{"id":66656637,"identity":"820d0a64-a797-483f-9985-64f9d0eb384f","added_by":"auto","created_at":"2024-10-15 08:22:33","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":219231,"visible":true,"origin":"","legend":"\u003cp\u003eLongitudinal Plot of mean FVC evolution depending on mycophenolic acid residual rate.\u003c/p\u003e","description":"","filename":"Fig2.LongitudinalPlot.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4919161/v1/3cccb226e86c15f5b118ba05.jpg"},{"id":68206986,"identity":"fadac10b-f020-43f6-b0b7-0a76c9217ad3","added_by":"auto","created_at":"2024-11-04 16:34:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1244114,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4919161/v1/744172b6-6388-4eb4-bcc7-1ce09bdfad8b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Usefulness of monitoring Mycophenolic Acid Exposure in Systemic Sclerosis- Related Interstitial Lung Disease: A Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSystemic Sclerosis (SSc) is a rare connective tissue disease characterized by microvascular damage and remodeling with fibroblasts activation and extra-cellular matrix synthesis (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Organs involved can be the skin, heart, kidney, muscles, articulations and lungs (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Lung involvement is frequent in SSc, indeed, pulmonary fibrosis had been showed in 70 to 100% in autopsy series (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Furthermore, up to 50% of patients present significant clinical lung involvement making SSc related interstitial lung disease (SSc-ILD) a major determinant of prognosis and quality of life (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Currently, interstitial lung disease is the most common cause of death among these patients.\u003c/p\u003e \u003cp\u003eImmunosuppressive therapy (IS) for SSc-ILD is indicated for severe or worsening ILD based on international guidelines (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In SSc-ILD, according to the Scleroderma lung study II, MMF can be used as first line-therapy or as maintenance therapy after Cyclophosphamide (CYC) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). MMF belongs to the anti-metabolite family and exhibits a complex pharmacokinetics. MMF is hydrolyzed by carboxylesterases in the active component, mycophenolic acid (MPA) in the stomach and absorbed (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). It is used in several diseases such as Solid Organ Transplantation (SOT), Systemic Lupus erythematous (SLE) or chronic graft versus host disease (GvHD) (\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Plasma concentration has already been investigated in these diseases but not in SSc whereas MMF is now an established therapy. Plasma concentrations should range between 30\u0026ndash;60 mg/h/L in SOT (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and at least 35 and 30 mg/h/L respectively in SLE (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and GvHD (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In SSc, the target dose of 3 grammes of MMF has shown equivalent efficacy as CYC against ILD (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Furthermore, in SSc there are considerable MMF inter-individual variations in drug exposure and concentration: higher concentrations are found in female patients, patients with poor renal function, low body weight, whereas lower concentrations are observed in proton pump inhibitor (PPI) users (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) or overweight patient. Gastro-intestinal disorders, frequently observed in SSc patients may also cause a variation of the MMF concentration (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo our knowledge, only one retrospective monocentric study tried and failed to demonstrate a relationship between MMF area under the concentration-time curve (AUC) and outcomes in skin involvement using Rodnan skin score or Pulmonary Function Tests (PFTs) evolution (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Unfortunately, no data concerning radiologic or clinical evolution was reported which are two key prognostic determinants for SSc progression. Despite of this, through their study, Legendre et al. showed large inter-individual variability in MPA AUC in SSc patients for a daily dosing of 1000 mg twice daily. This result suggests that monitoring MMF could be required in SSc. However, as there is no evidence supporting measurement of MPA exposure in SSc, such dosage is not routinely recommended in current guidelines. When practitioners do use it, they generally consider that the target of MPA should be the same as in SOT. The recommended target ranges include an AUC between 30\u0026ndash;60 mg/h/L or an estimation with residual rate (RR) (concentration level just before the next intake of medication) ranging between 1.5-4 mg/L. (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this context, we conducted a retrospective study to explore the relationship between clinical, radiological, and functional ILD evolution in SSc patients and MPA-RR measured at one year of MMF treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective monocentric study in the department of respiratory medicine of hospital Nord in Marseille, France between January 2010 and February 2024. In our hospital, SSc-ILD patients treated with MMF are monitored by RR in routine clinical practice. To be eligible, patients had to fulfill ACR/EULAR criteria (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) for SSc with ILD assessed by an expert radiologist in Multidisciplinary Discussion (MDD), to receive MMF (Cellcept\u0026reg; or Myfortic\u0026reg;) and to have a measurement of MPA-RR. All patients included in the analysis underwent PFTs and High-resolution computed tomography (HRCT) of the lungs after MMF initiation.\u003c/p\u003e \u003cp\u003e The Institutional Review Board of the French learned society for respiratory medicine -Soci\u0026eacute;t\u0026eacute; de Pneumologie de Langue Fran\u0026ccedil;aise- approved the protocol (CEPRO 2023-014), and a written information and non-objection notice was given to all participants according to French law.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eParameters analyzed\u003c/h2\u003e \u003cp\u003eThe aim of our study was to explore the relationship between the MPA-RR at steady state and the progression of the respiratory disease. For this purpose, we analyzed the variation of forced vital capacity (FVC), diffusing lung capacity for carbon monoxide (DLCO) and evolution of HRCT and dyspnea after one year of MMF treatment. Baseline was defined as the time of initiation of MMF. The evaluation time was defined as the closest time point to one year from MMF initiation, and included clinical, functional, radiological respiratory parameters and MPA-RR dosage.\u003c/p\u003e \u003cp\u003eFor all the subjects, we collected the following data carried out in clinical routine, before MMF initiation and at the time of RR: age, sex, BMI, smoking status, dyspnea according to the mMRC (modified Medical Research Council) scale, 6-minute walk test (6MWT), oxygen supplementation, co-morbidities, blood cell count, treatments used such as corticosteroids or immunosuppressants, HRCT patterns and evolution. All participants benefited from spirometry, plethysmography, and diffusion analysis when available (Ilmeter 1,304; Masterlab Jaeger, Wurzberg, Germany).\u003c/p\u003e \u003cp\u003eVariations of FVC, DLCO and HRCT patterns between MMF introduction and MPA-RR measurement were pooled in three groups: improved, stable or worsened. Regarding PFTs, an absolute increase of more than 10% of FVC was considered as an improvement whereas an absolute decrease of more than 10% was considered as worsened. All other variations were considered as stable. An absolute increase of more than 15% in DLCO was classified as improved, whereas an absolute decrease of 15% of more was considered as worsened. All other variations were classified as stable (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Concerning radiologic evolution, progression, stability or amelioration was assessed in MDD with an expert radiologist in accordance with current international guidelines. The composite criterion for SSc-ILD evolution was based on the progressive pulmonary fibrosis (PPF) guidelines: meeting two of the three following criteria indicating progression: an absolute decline of 5% in FVC and/or 10% in DLCO, clinical deterioration, or radiological progression (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetics\u003c/h2\u003e \u003cp\u003eResidual rate samplings were performed after MPA plasma concentration has reached steady state (i.e 5 half-lives) that mean at least 5 days after the first intake of MMF. We performed the samplings into 5 mL EDTA heparinized vacutainer tubes.\u003c/p\u003e \u003cp\u003eMPA RR was defined as the concentration at 12 h +/- 2 h after the last drug intake. Analysis of MPA in plasma was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS is the gold standard method with High analytical selectivity and sensitivity. A Waters XEVO TQ-S Micro Mass spectrometer coupled to a Waters Acquity liquid chromatography system was used in positive electrospray ionization mode as previously described (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). MPA quantification was achieved using multiple reaction monitoring. MPA quantification was achieved through multiple reaction monitoring. Deuterated Mycophenolic acid was used as an internal standard. The method is linear from 0.20 to 30 \u0026micro;g/mL, with both accuracy and precision within 10%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eA descriptive analysis was performed on our population. Continuous variables were expressed in median and interquartile or mean and standard deviation, depending on the distribution (Shapiro-Wilk test), and qualitative variables were expressed in numbers and percentages. Qualitative parameters were compared using Chi-square tests. Quantitative parameters were compared using a student\u0026rsquo;s test or a Mann-Whitney-Wilcoxon non-parametric test depending on the distribution. The association between MPA-RR and MMF dose was analyzed using Pearson correlation. Predictive factors for worsened FVC in SSc-ILD patients, in relation to the MPA-RR, were analyzed using logistic regression in both univariate and multivariate models.\u003c/p\u003e \u003cp\u003eAll tests were two-sided. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. The analysis was performed using version 4.3.2 (2022-06-23) of the R software (R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.R-project.org/\u003c/span\u003e\u003cspan address=\"https://www.R-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eOver the studied period (January 2010 and February 2024), we identified 54 patients who fulfilled the ACR/EULAR criteria for SSc and treated with MMF. Eleven patients did not undergo measurement of MPA-RR. Finally, 43 patients were included in the analysis. Main population characteristics at the time of MMF treatment onset are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Mean age was 54 years (+/-14), with 34 (79%) women. Seventeen (40%) presented with diffuse cutaneous disease, 24 (56%) with limited cutaneous disease, and 2 (4,7%) with \u003cem\u003esine scleroderma\u003c/em\u003e SSc. Gastrointestinal tract involvement and PPI use was reported in 38 (88%) patients. Autoimmune diseases were associated with SSc in 10 (23%) patients, mostly Sjogren disease or SLE. Six (14%) patients died during the follow-up.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of 43 systemic sclerosis treated with mycophenolate mofetil.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal patients (N\u0026thinsp;=\u0026thinsp;43)\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;\u0026lt;\u0026thinsp;1,5, N\u0026thinsp;=\u0026thinsp;19\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRR\u0026thinsp;\u0026gt;\u0026thinsp;1,5, N\u0026thinsp;=\u0026thinsp;24\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (79%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnostic age (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (+/-16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (+/-19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (+/-12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.2 (18.0-35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.0 (18.0-32.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.3 (21.6\u0026ndash;35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther AID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of tobacco\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emMRC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt; 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSc type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiffuse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLimited\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (56%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (68%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSine scleroderma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal tract involvment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-Scl70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.079\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-centromere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRCT Pattern\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPFE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnclassifiable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (4.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC (L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.02 (0.93\u0026ndash;4.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.91 (1.00-4.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.12 (0.93\u0026ndash;3.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (27\u0026ndash;109)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (27\u0026ndash;107)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (37\u0026ndash;109)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLCO (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (8\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (8\u0026ndash;54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43 (20\u0026ndash;69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSteroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime before MMF onset (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (0-396)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 (0-396)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39 (0-312)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime between MMF and residual rate (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (0-112)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (3\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (0-112)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMMF dose (g)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt; 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRituximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntifibrotic drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeaths\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e n (%); Mean (+/-SD); Median (Minimum-Maximum)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e Fisher\u0026rsquo;s exact test; Wilcoxon rank sum test; Pearson\u0026rsquo;s Chi-squared test\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eRR\u0026thinsp;=\u0026thinsp;residual rate, BMI\u0026thinsp;=\u0026thinsp;Body mass index; AID\u0026thinsp;=\u0026thinsp;Auto-immune disease; mMRC\u0026thinsp;=\u0026thinsp;modified Medical Research council; SSc\u0026thinsp;=\u0026thinsp;Systemic sclerosis; HRCT\u0026thinsp;=\u0026thinsp;High-resolution computed tomography; PPFE\u0026thinsp;=\u0026thinsp;Pleuroparenchymal Fibroelastosis; FVC\u0026thinsp;=\u0026thinsp;forced vital capacity; DLCO\u0026thinsp;=\u0026thinsp;Diffusing lung capacity for carbon monoxide; PH\u0026thinsp;=\u0026thinsp;Pulmonary Hypertension; MMF\u0026thinsp;=\u0026thinsp;Mycophenolate mofetil; CYC\u0026thinsp;=\u0026thinsp;cyclophosphamide\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePatients presented SSc-ILD with non-specific interstitial pneumoniae (NSIP) pattern in 31 (72%) of cases. Other patterns were usual interstitial pneumoniae (UIP), unclassifiable and Pleuroparenchymal fibroelastosis in 9 (21%), 2 (4.7%) and 1 (2.3%) case, respectively. At time of treatment introduction, median FVC was 73% (range 27\u0026ndash;109), and median DLCO was 41% (8\u0026ndash;69) of predicted values. Fifteen patients had pulmonary hypertension (36%) and 17 patients needed supplemental oxygen (40%).\u003c/p\u003e \u003cp\u003eWe created two groups of patients based on their MPA-RR levels at evaluation time: 19 (44%) with RR\u0026thinsp;\u0026lt;\u0026thinsp;1.5 mg/L and 24 (56%) with RR\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;1.5 mg/L. A comparison of baseline characteristics between the two groups is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The MMF dose was the only variable with a significant difference between these groups (p-value 0.032), with a higher MMF dose in the \u0026gt;\u0026thinsp;=\u0026thinsp;1.5 mg/L group. Seventeen (40%) patients presented adverse event, mainly digestive, without significant difference between the two groups. Treatments such as CYC, rituximab or antifibrotic drugs, as well as PFTs or duration between MMF introduction and RR measurement, were not statistically different between the two groups.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eMMF dose and MPA-RR relationship\u003c/h2\u003e \u003cp\u003eThe median duration between MMF introduction and RR measurement was 12 months (range 0-112). The median MMF dose and MPA-RR were 1000 mg/day (0.5-3) and 1.7 mg/L (0.5\u0026ndash;6.2), respectively. There was a significant positive correlation between MMF dose and MPA-RR using Pearson model (rho: 0.47, p-value 0.002) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatients evolution\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e compares the evolution of the PFTs, HRCT and clinical outcomes between these two groups. Concerning PFTs, the absolute evolution of FVC was significantly better in RR\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;1.5 mg/L group than in lower RR group (p-value 0.024). Indeed, a stabilization of FVC was observed in a higher proportion of patients (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;17; 74%) in RR\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;1.5 mg/L group compared with the RR\u0026thinsp;\u0026lt;\u0026thinsp;1.5 mg/L group (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5; 33%). In addition, a lower proportion of patients experienced a decrease of FVC in the RR\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;1.5 mg/L group (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3; 13%) \u003cem\u003eversus\u003c/em\u003e the RR\u0026thinsp;\u0026lt;\u0026thinsp;1.5 mg/L group (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7; 47%). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e represents the evolution of mean FVC in patients depending on MPA-RR upper or lower 1.5 mg/L.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical, functional and radiologic evolution of patients based on mycophenolic acid residual rate.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRR\u0026thinsp;\u0026lt;\u0026thinsp;1,5, N\u0026thinsp;=\u0026thinsp;19\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRR\u0026thinsp;\u0026gt;\u0026thinsp;1,5, N\u0026thinsp;=\u0026thinsp;24\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC absolute evolution\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecrease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncrease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLCO absolute evolution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorsened\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRCT evolution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorsened\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (86%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emMRC evolution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorsened\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (48%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSc-ILD Evolution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e Median (Minimum-Maximum); n (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e Wilcoxon rank sum test; Fisher\u0026rsquo;s exact test\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eRR\u0026thinsp;=\u0026thinsp;residual rate; FVC\u0026thinsp;=\u0026thinsp;forced vital capacity; DLCO\u0026thinsp;=\u0026thinsp;Diffusing lung capacity for carbon monoxide; HRCT\u0026thinsp;=\u0026thinsp;High-resolution computed tomography; mMRC\u0026thinsp;=\u0026thinsp;modified Medical Research council; SSc-ILD\u0026thinsp;=\u0026thinsp;Systemic sclerosis related interstitial lung disease.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eFVC\u0026thinsp;=\u0026thinsp;absolute increase of more than 10% was considered as an improvement whereas an absolute decrease of more than 10% was considered as worsened. All other variations were considered as stable\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDLCO\u0026thinsp;=\u0026thinsp;absolute increase of more than 15% was considered as an improvement whereas an absolute decrease of more than 15% was considered as worsened. All other variations were considered as stable\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eConversely, no significant results were found with DLCO between the 2 groups (p-value 0.6). Of note, data on DLCO were missing in 15 (35%) patients. Regarding HRCT, dyspnea evolution and SSc-ILD evolution based on international PPF criteria, no differences were observed between the two groups.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e summarizes predictive factors for worsened FVC evolution using logistic regression in univariate and multivariate analysis. The only protective factor was MPA-RR at evaluation time in both univariate and multivariate analyses, adjusting for MMF dose, time of MMF exposure, and patient age at diagnosis. In our cohort, a MPA-RR over 1.5 mg/L independently reduced the risk of worsened FVC evolution by 95% (p-value 0.008) compared to a MPA-RR lower than 1.5 mg/L.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePredictive factors of FVC worsening in univariate and multivariate analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOR\u003c/b\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e95% CI\u003c/b\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003ep-value\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eOR\u003c/b\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e95% CI\u003c/b\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003ep-value\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnostic age (y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98, 1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.99, 1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10, 2.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.80, 1.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29, 7.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther AID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02, 2.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTobacco\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35, 6.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emMRC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt; 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19, 3.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSc type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiffuse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLimit\u0026eacute;e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.22, 4.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSine scleroderma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10, 89.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal tract involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.02, 1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.085\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-Scl70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.13, 3.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-centromere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC (L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78, 5.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98, 1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLCO (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96, 1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07, 2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.12, 2.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSteroids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11, 2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime before MMF onset (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98, 1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMF dose (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.12, 6.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.02, 12.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt; 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04, 4.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.03, 48.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime between MMF and residual rate (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.75, 1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.69, 1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMPA Residual rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e38\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt; 1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt; 1,5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.03, 0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.00, 0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCYC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRituximab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14, 6.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntifibrotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58, 157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e OR\u0026thinsp;=\u0026thinsp;Odds Ratio, CI\u0026thinsp;=\u0026thinsp;Confidence Interval\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eBMI\u0026thinsp;=\u0026thinsp;Body mass index; AID\u0026thinsp;=\u0026thinsp;Auto-immune disease; mMRC\u0026thinsp;=\u0026thinsp;modified Medical Research council; SSc\u0026thinsp;=\u0026thinsp;Systemic sclerosis; FVC\u0026thinsp;=\u0026thinsp;forced vital capacity; DLCO\u0026thinsp;=\u0026thinsp;Diffusing lung capacity for carbon monoxide; PH\u0026thinsp;=\u0026thinsp;Pulmonary Hypertension; MMF\u0026thinsp;=\u0026thinsp;Mycophenolate mofetil; CYC\u0026thinsp;=\u0026thinsp;cyclophosphamide.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we observed that patients with MPA-RR above 1.5 mg/L had a preserved FVC overtime compared to patients with MPA-RR under 1.5 mg/L. Additionally, our findings failed to reveal significant associations between DLCO, HRCT or SSc-ILD evolution using PPF criteria and the MPA-RR values. However, approximately 80% of patients in both groups showed stability concerning these three criteria. Without a placebo control group, we cannot definitively conclude that MMF allowed for stability in our cohort. Nonetheless, these findings are in accordance with previous multicentric studies demonstrating the efficacy of MMF in improving both FVC and DLCO in SSc-ILD patients (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Indeed, MMF is established as a first-line therapy for SSc-ILD with fibrosis extent exceeding 20% (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). We believe that the lack of power in our study may have contributed to the non-significant results for DLCO, HRCT, or PPF criteria. This suggests that our sample size or the duration of MMF exposure might have been insufficient to detect significant differences. Moreover, as approximately 35% of our patients had missing DLCO data, we did not conduct further analyses comparing DLCO and MPA-RR to avoid the risk of misinterpretation of our data.\u003c/p\u003e \u003cp\u003eOf note, our patient cohort exhibited more severe disease manifestations with compromised PFTs compared to previous studies. Specifically, our median FVC and DLCO values were lower (73% and 41%, respectively) compared to those reported by Legendre et al (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Consequently, the rate of FVC improvement in our cohort (21%) was lower than that reported in other studies (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Tashkin et al. demonstrated FVC improvement in 71% of cases in Scleroderma Lung Study (SLS) II. It is noteworthy that our patients received lower MMF doses compared to those received in previous trials. Indeed, the median MMF dose in our study was 1000 mg/day, whereas patients in controlled studies such as SLS II received 3000 mg/day (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) or 2000 mg/day for most patients in Legendre et al study (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). This discrepancy in MMF dosage may suggest an undertreatment in our cohort, especially considering that only 56% of subjects had MPA-RR levels above 1.5 mg/L. All these differences may have contributed to the absence of a significant association between DLCO, HRCT and SSc-ILD evolution and RR measurements in our cohort.\u003c/p\u003e \u003cp\u003eIn clinical practice, we advocate for the necessity of measuring MPA exposure and emphasize the importance of further investigation in this area. Our findings revealed that a MPA-RR level above 1.5 mg/L was the only protective factor against FVC worsening in multivariate analysis, with a remarkable 95% reduction in the risk of progression. Interestingly, this analysis was adjusted on MMF dose and time of exposure, underscoring the significance of inter- and intra-individual variability in MMF pharmacokinetics. This variability is also highlighted by the moderate correlation of MMF dose and MPA-RR observed in our study. However, it is worth mentioning that we employed MPA target ranges established in other conditions, and optimal ranges specific to SSc may differ.\u003c/p\u003e \u003cp\u003ePrior research has demonstrated a correlation between MPA exposure and disease activity with recommended target ranges for MPA plasma exposure typically expressed as AUC values ranging from 30 to 60 mg/L.h or residual rate concentrations between 1.5 to 4 mg/L (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Moreover, considerable inter-individual variability in MPA plasma exposure has been observed (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e), which may also be extended to SSc due to factors such as PPI use or gastrointestinal tract involvement (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). However to the best of our knowledge, Legendre et al were the only investigators to explore the relationship between MMF treatment and skin or lung involvement, as assessed by Rodnan skin score and PFT variation, respectively (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Our findings are consistent with previous research indicating significant inter-individual variability in MPA plasma exposure, supporting the importance of documenting MPA plasma exposure in patients with SSc. MPA concentrations in our cohort ranged widely from 0.5 to 6.2 mg/L, with daily MMF doses varying from 500 to 3000 mg.\u003c/p\u003e \u003cp\u003eOur study boasts several strengths. We present the largest cohort of SSc-ILD investigating MPA exposure to date. Contrary to previous findings by Legendre et al, our study demonstrated the beneficial impact of RR measurements on FVC progression (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). FVC has been identified as a critical determinant of mortality in ILD, underscoring the clinical relevance of this association (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Moreover, the simultaneous assessment of RR and PFTs is noteworthy, given the wide variability in MPA blood concentration. The comparable baseline characteristics of our two patient groups facilitated a more precise comparison of the effect of MMF exposure. The AUC is more difficult to measure in real life because of the need of multiple blood samples. Indeed, our results are easier to generalize in routine clinical practice as it only requires one sample for RR measurement.\u003c/p\u003e \u003cp\u003eSeveral limitations of our study should be acknowledged. First, due to the retrospective nature, we could only report RR of MPA, as there were significant missing data regarding AUC. Additionally, being monocentric with a relatively sample size, our study may be subject to inherent biases. Notably, skin involvement, a major outcome and an indication for MMF therapy in SSc patients, was not consistently reported. As a result, we could not assess usefulness of monitoring MPA on the skin progression of SSc. Furthermore, patients in our cohort could have been treated with either Cellcept\u0026reg; or Myfortic\u0026reg;, potentially introducing pharmacokinetic or pharmacodynamic variations. Moreover, measurements of residual rate or AUC do not guarantee consistent MPA exposure throughout the follow-up period, as fluctuations in concentration may occur due to factors such as changes in medication or infections (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Despite its importance as a prognostic determinant in SSc-ILD, we were unable to draw conclusions regarding DLCO probably due to missing data.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe have identified for the first time, an association between MPA exposure and outcomes in SSc-ILD. Optimal MMF exposure, as indicated by MPA-RR above 1.5 mg/L appears to be a protective factor against FVC worsening. Thus, the routine monitoring of MPA exposure, for a better adaptation of MMF dose, may offer clinical benefits to patients. Future prospective, multicenter studies with larger sample sizes are warranted to further explore pharmacokinetic/pharmacodynamic relationships in SSc and to optimize methods for measuring MPA plasma exposure.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSSc\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSystemic sclerosis\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSSc-ILD\u0026thinsp;=\u0026thinsp;SSc related interstitial lung disease\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIS\u0026thinsp;=\u0026thinsp;Immunosuppressive therapy\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eILD\u0026thinsp;=\u0026thinsp;interstitial lung disease\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMMF\u0026thinsp;=\u0026thinsp;Mycophenolate Mofetil\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCYC\u0026thinsp;=\u0026thinsp;Cyclophosphamide\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMPA\u0026thinsp;=\u0026thinsp;mycophenolic acid\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSOT\u0026thinsp;=\u0026thinsp;Solid Organ Transplantation\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSLE\u0026thinsp;=\u0026thinsp;Systemic Lupus erythematous\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGvHD\u0026thinsp;=\u0026thinsp;chronic graft versus host disease\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePPI\u0026thinsp;=\u0026thinsp;Proton pump inhibitor\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAUC\u0026thinsp;=\u0026thinsp;area under the concentration-time curve\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePFTs\u0026thinsp;=\u0026thinsp;pulmonary function tests\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRR\u0026thinsp;=\u0026thinsp;MPA residual rate\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMDD\u0026thinsp;=\u0026thinsp;Multidisciplinary Discussion\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHRCT\u0026thinsp;=\u0026thinsp;High resolution computed-tomography\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFVC\u0026thinsp;=\u0026thinsp;forced vital capacity\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDLCO\u0026thinsp;=\u0026thinsp;diffusing lung capacity for carbon monoxide\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emMRC\u0026thinsp;=\u0026thinsp;modified Medical Research Council\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePPF\u0026thinsp;=\u0026thinsp;Pulmonary Progressive Fibrosis\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNSIP\u0026thinsp;=\u0026thinsp;interstitial pneumoniae\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUIP\u0026thinsp;=\u0026thinsp;usual interstitial pneumoniae\u003c/p\u003e \u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSLS\u0026thinsp;=\u0026thinsp;Scleroderma Lung Study\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp skip=\"true\"\u003e\u003cstrong\u003eStatement of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp skip=\"true\"\u003eThe Institutional Review Board of the French learned society for respiratory medicine -Soci\u0026eacute;t\u0026eacute; de Pneumologie de Langue Fran\u0026ccedil;aise- approved the protocol (CEPRO 2023-014), and a written information and non-objection notice was given to all participants according to French law.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no targeted funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJM, JB, ES design the study and methods. Clinical data were provided by ES, JB, BC, AN, BG, MR. Statistical analyses were done by JM, SD. JM wrote the original draft. ES, JB, BG, MR reviewed and edited the manuscript. Figures were created by JM, SD, BC. Supervision by JB, AB, BG, MR. Guarantor of the study is JB. All authors read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTamby MC, Chanseaud Y, Guillevin L, Mouthon L. New insights into the pathogenesis of systemic sclerosis. Autoimmun Rev. mai 2003,2(3):152‑7. \u003c/li\u003e\n\u003cli\u003eRanque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev. mars 2010,9(5):A311-318. \u003c/li\u003e\n\u003cli\u003eD\u0026rsquo;Angelo WA, Fries JF, Masi AT, Shulman LE. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med. mars 1969,46(3):428‑40. \u003c/li\u003e\n\u003cli\u003eSolomon JJ, Olson AL, Fischer A, Bull T, Brown KK, Raghu G. Scleroderma lung disease. Eur Respir Rev. 1 mars 2013,22(127):6‑19. \u003c/li\u003e\n\u003cli\u003eSteen VD, Conte C, Owens GR, Medsger TA. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. sept 1994,37(9):1283‑9. \u003c/li\u003e\n\u003cli\u003eElhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. nov 2017,76(11):1897‑905. \u003c/li\u003e\n\u003cli\u003eKowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. ao\u0026ucirc;t 2017,76(8):1327‑39. \u003c/li\u003e\n\u003cli\u003eHachulla E, Agard C, Allanore Y, Avouac J, Bader-Meunier B, Belot A, et al. French recommendations for the management of systemic sclerosis. Orphanet J Rare Dis. 26 juill 2021,16(Suppl 2):322. \u003c/li\u003e\n\u003cli\u003eTashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. sept 2016,4(9):708‑19. \u003c/li\u003e\n\u003cli\u003eDong M, Fukuda T, Vinks AA. Optimization of mycophenolic acid therapy using clinical pharmacometrics. Drug Metab Pharmacokinet. 2014,29(1):4‑11. \u003c/li\u003e\n\u003cli\u003eBenjanuwattra J, Pruksakorn D, Koonrungsesomboon N. Mycophenolic Acid and Its Pharmacokinetic Drug-Drug Interactions in Humans: Review of the Evidence and Clinical Implications. J Clin Pharmacol. mars 2020,60(3):295‑311. \u003c/li\u003e\n\u003cli\u003eGinzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 24 nov 2005,353(21):2219‑28. \u003c/li\u003e\n\u003cli\u003eIaccarino L, Rampudda M, Canova M, Della Libera S, Sarzi-Puttinic P, Doria A. Mycophenolate mofetil: what is its place in the treatment of autoimmune rheumatic diseases? Autoimmun Rev. janv 2007,6(3):190‑5. \u003c/li\u003e\n\u003cli\u003eEskin-Schwartz M, David M, Mimouni D. Mycophenolate mofetil for the management of autoimmune bullous diseases. Dermatol Clin. oct 2011,29(4):555‑9. \u003c/li\u003e\n\u003cli\u003eChaigne B, Gatault P, Darrouzain F, Barbet C, Degenne D, Fran\u0026ccedil;ois M, et al. Mycophenolate mofetil in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a prospective pharmacokinetics and clinical study. Clin Exp Immunol. mai 2014,176(2):172‑9. \u003c/li\u003e\n\u003cli\u003evan Gelder T, Le Meur Y, Shaw LM, Oellerich M, DeNofrio D, Holt C, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit. avr 2006,28(2):145‑54. \u003c/li\u003e\n\u003cli\u003eZahr N, Arnaud L, Marquet P, Haroche J, Costedoat-Chalumeau N, Hulot JS, et al. Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil. Arthritis Rheum. juill 2010,62(7):2047‑54. \u003c/li\u003e\n\u003cli\u003eWakahashi K, Yamamori M, Minagawa K, Ishii S, Nishikawa S, Shimoyama M, et al. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation. Int J Hematol. ao\u0026ucirc;t 2011,94(2):193‑202. \u003c/li\u003e\n\u003cli\u003eFern\u0026aacute;ndez-Codina A, Walker KM, Pope JE, Scleroderma Algorithm Group. Treatment Algorithms for Systemic Sclerosis According to Experts. Arthritis Rheumatol. nov 2018,70(11):1820‑8. \u003c/li\u003e\n\u003cli\u003eAlex G, Shanoj KC, Varghese DR, Sageer Babu AS, Reji R, Shenoy PD. Co prescription of anti-acid therapy reduces the bioavailability of mycophenolate mofetil in systemic sclerosis patients: A crossover trial. Semin Arthritis Rheum. d\u0026eacute;c 2023,63:152270. \u003c/li\u003e\n\u003cli\u003eAndr\u0026eacute;asson K, Neringer K, Wuttge DM, Henrohn D, Marsal J, Hesselstrand R. Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation-a prospective, observational study. Arthritis Res Ther. 6 oct 2020,22(1):230. \u003c/li\u003e\n\u003cli\u003eLegendre P, Blanchet B, Porcher R, B\u0026eacute;rezn\u0026eacute; A, Allard M, London J, et al. Mycophenolic acid drug monitoring in patients with systemic sclerosis associated with diffuse skin and/or pulmonary involvement: A monocentric and retrospective French study. J Scleroderma Relat Disord. f\u0026eacute;vr 2021,6(1):87‑95. \u003c/li\u003e\n\u003cli\u003eLe Meur Y, B\u0026uuml;chler M, Thierry A, Caillard S, Villemain F, Lavaud S, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. nov 2007,7(11):2496‑503. \u003c/li\u003e\n\u003cli\u003evan den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. nov 2013,72(11):1747‑55. \u003c/li\u003e\n\u003cli\u003eWells AU, Margaritopoulos GA, Antoniou KM, Denton C. Interstitial lung disease in systemic sclerosis. Semin Respir Crit Care Med. avr 2014,35(2):213‑21. \u003c/li\u003e\n\u003cli\u003eRaghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 1 mai 2022,205(9):e18‑47. \u003c/li\u003e\n\u003cli\u003eStreit F, Shipkova M, Armstrong VW, Oellerich M. Validation of a rapid and sensitive liquid chromatography-tandem mass spectrometry method for free and total mycophenolic acid. Clin Chem. janv 2004,50(1):152‑9. \u003c/li\u003e\n\u003cli\u003eLiossis SNC, Bounas A, Andonopoulos AP. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford). ao\u0026ucirc;t 2006,45(8):1005‑8. \u003c/li\u003e\n\u003cli\u003eVanthuyne M, Blockmans D, Westhovens R, Roufosse F, Cogan E, Coche E, et al. A pilot study of mycophenolate mofetil combined to intravenous methylprednisolone pulses and oral low-dose glucocorticoids in severe early systemic sclerosis. Clin Exp Rheumatol. 2007,25(2):287‑92. \u003c/li\u003e\n\u003cli\u003eHerman D, Ghazipura M, Barnes H, Macrea M, Knight SL, Silver RM, et al. Mycophenolate in Patients with Systemic Sclerosis-associated Interstitial Lung Disease: A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. janv 2024,21(1):136‑50. \u003c/li\u003e\n\u003cli\u003eMendoza FA, Nagle SJ, Lee JB, Jimenez SA. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol. juin 2012,39(6):1241‑7. \u003c/li\u003e\n\u003cli\u003eLe EN, Wigley FM, Shah AA, Boin F, Hummers LK. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis. juin 2011,70(6):1104‑7. \u003c/li\u003e\n\u003cli\u003eDerk CT, Grace E, Shenin M, Naik M, Schulz S, Xiong W. A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis. Rheumatology (Oxford). d\u0026eacute;c 2009,48(12):1595‑9. \u003c/li\u003e\n\u003cli\u003eStreicher C, Djabarouti S, Xuereb F, Lazaro E, Legeron R, Bouchet S, et al. Pre-dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases. Br J Clin Pharmacol. d\u0026eacute;c 2014,78(6):1419‑25. \u003c/li\u003e\n\u003cli\u003eSchaier M, Scholl C, Scharpf D, Schmitt WH, Schwenger V, Zeier M, et al. High interpatient variability in response to mycophenolic acid maintenance therapy in patients with ANCA-associated vasculitis. Nephrol Dial Transplant. avr 2015,30 Suppl 1:i138-145. \u003c/li\u003e\n\u003cli\u003eFlaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 31 oct 2019,381(18):1718‑27.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Scleroderma, Connective tissue diseases, Interstitial lung disease, Mycophenolic acid, Pharmacology","lastPublishedDoi":"10.21203/rs.3.rs-4919161/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4919161/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Systemic sclerosis-related interstitial lung disease (SSc-ILD) represents a significant cause of morbidity and mortality in Systemic Sclerosis (SSc). Mycophenolate mofetil (MMF) is currently the first line treatment for SSc-ILD. There is no recommendation on the dosage of mycophenolic acid (MPA) blood concentrations, so we aimed to study the correlation between MPA exposure and respiratory outcomes in this population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We conducted a retrospective cohort study of SSc-ILD patients treated with MMF in our center. According to our policy, a complete patient evaluation was performed approximately one year after MMF initiation, during which the mycophenolic acid (MPA) residual rate (RR) was measured. We analyzed the association between RR and changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Forty-three SSc-ILD patients were included. Patients with higher RR levels (1.5 mg/L) had a significantly better FVC evolution with a higher proportion of stabilization and lower proportion of FVC decrease (p= 0.024). RR above 1.5 mg/L was a predictive factor of reduced FVC decline compared with lower RR levels adjusting for MMF dose and duration of MMF exposure (p= 0.008). There was no difference regarding DLCO outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Our study suggests that optimal MPA exposure, as indicated by RR levels, may better protect against FVC decline in SSc-ILD patients treated with MMF. Routine monitoring of MPA exposure could be beneficial in optimizing treatment outcomes. Prospective, multicenter studies are needed to further explore the relationship between MPA exposure and clinical outcomes in SSc-ILD.\u003c/p\u003e","manuscriptTitle":"Usefulness of monitoring Mycophenolic Acid Exposure in Systemic Sclerosis- Related Interstitial Lung Disease: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-15 08:22:28","doi":"10.21203/rs.3.rs-4919161/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-22T08:34:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-21T04:51:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-21T04:50:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2024-08-15T12:00:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"91c9d1d1-c7f4-4d57-a6f0-908834d66902","owner":[],"postedDate":"October 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-04T16:23:38+00:00","versionOfRecord":{"articleIdentity":"rs-4919161","link":"https://doi.org/10.1186/s12890-024-03361-7","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2024-10-28 15:57:15","publishedOnDateReadable":"October 28th, 2024"},"versionCreatedAt":"2024-10-15 08:22:28","video":"","vorDoi":"10.1186/s12890-024-03361-7","vorDoiUrl":"https://doi.org/10.1186/s12890-024-03361-7","workflowStages":[]},"version":"v1","identity":"rs-4919161","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4919161","identity":"rs-4919161","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}