Association between serum anti-granulocyte-macrophage colony-stimulating factor autoantibodies and nintedanib-induced diarrhea in interstitial lung disease: a retrospective study

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic interstitial lung disease (ILD) characterized by a poor prognosis and an unknown etiology (1). Nintedanib, a tyrosine kinase inhibitor, exerts its antifibrotic effects by inhibiting signaling pathways mediated by platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) receptors (2). Its efficacy in slowing disease progression in IPF has been demonstrated in large randomized controlled trials, including the INPULSIS trial (3).

Although anti-inflammatory therapies, such as corticosteroids, are effective for certain non-IPF ILDs, approximately 30% of these patients develop progressive pulmonary fibrosis (PPF), which requires antifibrotic treatment (1). Nintedanib has also shown efficacy in patients with non-IPF ILDs exhibiting PPF (4) or systemic sclerosis-associated ILD (5). Consequently, nintedanib is widely used in the management of fibrotic lung diseases and is associated with improved survival in both IPF and PPF populations (6,7). Given that sustained treatment is required to achieve these clinical benefits, appropriate management of adverse events is essential to ensure treatment continuity and optimize clinical outcomes.

Diarrhea is the most frequently reported adverse event associated with nintedanib, occurring in more than 60% of patients in the INPULSIS and INBUILD trials (3,4). Although the precise mechanism of nintedanib-induced diarrhea remains unclear, it is thought to involve intestinal epithelial injury. This injury may result directly from inhibition of PDGF and FGF signaling, which are involved in epithelial maintenance, and indirectly from mucosal ischemia secondary to VEGF pathway inhibition (2,8,9). We previously reported that higher peripheral blood monocyte counts were associated with a lower incidence of diarrhea within 3 months of nintedanib initiation, after adjustment for ILD type, nintedanib dose, and percent predicted forced vital capacity (%FVC) (10). Based on these findings, we hypothesized that monocytes may differentiate into M2 macrophages, which are known to facilitate epithelial repair (11,12). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key regulator of monocyte differentiation into macrophages, particularly the M2 phenotype (13). Conversely, anti-GM-CSF autoantibodies (GMAb) may impair this process and potentially inhibit intestinal epithelial regeneration. Notably, serum GMAb levels have been associated with disease activity and relapse in inflammatory bowel diseases (IBDs), suggesting a role in intestinal barrier dysfunction (14,15). Collectively, these observations support a potential mechanistic link between GM-CSF/GMAb-mediated pathways and susceptibility to nintedanib-induced diarrhea.

Therefore, in this retrospective study, we investigated the association between serum GMAb levels and the occurrence of diarrhea in patients with ILDs treated with nintedanib. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1130/rc).

Methods

Study design and participants

This single-center, retrospective, interview-based study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Institutional Review Board of NHO Kinki Chuo Chest Medical Center (No. Rin2023-122; approval date: March 25, 2024). Written informed consent was obtained from all participants prior to inclusion.

This study was performed as a secondary analysis of our previous study (10) for the subjects whose serum samples were available. We enrolled patients with IPF or non-IPF ILDs meeting criteria for PPF following standard management, who initiated nintedanib treatment between April 2022 and March 2024. Diarrhea was assessed using structured interviews conducted between April 2024 and August 2024. Patients were eligible if they had either (I) received nintedanib for more than 3 months or (II) developed diarrhea within 3 months of treatment initiation, allowing assessment of early-onset diarrhea. To minimize confounding, patients who developed diarrhea and had received antibiotics within 1 week prior to onset were excluded, based on our previous study (10).

A total of 79 patients were identified in whom the presence or absence of diarrhea within 3 months of nintedanib initiation could be confirmed by interview (Figure 1). Among the 79 eligible patients, 41 had available serum samples collected immediately before initiation of nintedanib and were included in the present analysis.

Figure 1 Patient flow. GMAb, anti-granulocyte-macrophage colony-stimulating factor.

Diagnosis of ILDs

IPF and PPF were diagnosed according to the 2022 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (1). Non-IPF ILDs included idiopathic interstitial pneumonias other than IPF (16), fibrotic hypersensitivity pneumonitis (17), connective tissue disease-associated ILDs (18,19), and pulmonary fibrosis associated with autoimmune pulmonary alveolar proteinosis (APAP) (20).

Baseline clinical assessments

Baseline clinical data were retrospectively obtained from medical records at the time of nintedanib initiation. These included age, sex, smoking status, concomitant medications, and modified Medical Research Council dyspnea score (21).

Pulmonary function parameters included %FVC and percent predicted diffusing capacity of carbon monoxide. Laboratory data included peripheral blood monocyte counts, surfactant protein-D (SP-D), and Krebs von den Lungen-6. Body surface area (BSA, m²) was calculated using the DuBois formula (22).

Assessment of diarrhea

Diarrhea was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (23), based on the increase in stool frequency relative to baseline:

• Grade 1: <4 stools/day increase;
• Grade 2: 4–6 stools/day increase;
• Grade 3: ≥7 stools/day increase.

The highest CTCAE grade during the observation period was recorded for each patient.

Stool consistency was categorized as watery, formless, loose, or soft, with watery stool representing the most severe form (24).

The time from nintedanib initiation to onset of diarrhea was categorized as ≤3 or >3 months.

Measurement of GMAb

Serum levels of GMAb were measured using an enzyme-linked immunosorbent assay, as previously described. A cutoff value of 3.33 µg/mL was used for the diagnosis of APAP, in accordance with a prior report (25).

Assay precision at the low levels around 0.50 µg/mL was evaluated by intra-assay and inter-assay coefficient of variation (CV), calculated by repeated measurements within a single run of a plate and three independent runs on different days, respectively. Ideal upper limits of intra-assay and inter-assay CV are 10–15% and 15–20% (26).

Statistical analysis

Continuous variables are presented as medians with interquartile ranges (IQRs), and categorical variables as counts. %FVC was categorized as normal (≥80%) or reduced (<80%) (27). Based on our previous study (10), peripheral blood monocyte counts and serum SP-D levels were dichotomized as >650 vs. ≤650/µL and >157.5 vs. ≤157.5 ng/mL, respectively. Between-group comparisons were performed using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables.

Receiver operating characteristic (ROC) curve analysis was used to determine optimal cutoff values for serum GMAb levels and nintedanib dose normalized by BSA for predicting diarrhea within 3 months. These variables were subsequently dichotomized based on the derived cutoffs.

Logistic regression analysis was performed to identify predictors of diarrhea within 3 months of nintedanib initiation. Variables included clinically relevant factors and those identified in our previous study, including ILD type (IPF vs. PPF), %FVC, nintedanib dose/BSA, and corticosteroid use (10). Multivariate models were constructed using variables selected from univariate analyses. A predictive scoring model was developed by assigning points to each variable based on β-coefficients derived from multivariate logistic regression analysis. The total score was evaluated using ROC analysis to determine its ability to predict diarrhea within 3 months. In addition, correlations between GMAb levels and clinical parameters were assessed using Spearman’s rank correlation coefficient.

As a sensitivity analysis, multivariate analysis was performed to predict diarrhea within 3 months among subjects excluding APAP patients, because markedly elevated serum GMAb levels observed in APAP compared with other ILDs could disproportionately influence the analysis.

All statistical analyses were performed using SPSS Statistics for Macintosh, version 29 (IBM Corp., Armonk, NY, USA). A two-sided P value <0.05 was considered statistically significant.

Results

Patient demographics

Of the 79 patients with ILD treated with nintedanib in our previous study, 41 patients with available serum samples collected at the initiation of nintedanib were included in the present analysis (Table 1).

The median age was 70 years (IQR, 63.5–77.0 years), and 30 patients were male. Underlying ILDs included IPF (n=26) and non-IPF ILDs (n=15). %FVC was ≥80% in 28 patients. The initial nintedanib dose was 300 mg/day in 29 patients. Corticosteroids were administered to four patients, all of whom had non-IPF ILDs. Two patients with non-IPF ILDs were diagnosed with APAP, and 26 patients developed diarrhea within 3 months of nintedanib initiation.

Compared with the 38 patients without available serum samples, the included cohort had a higher proportion of IPF (P=0.01) and less frequent use of corticosteroids (P=0.08) and immunosuppressants (P=0.002).

Distribution of serum GMAb levels

The median serum GMAb level was 0.470 µg/mL (IQR, 0.220–0.770 µg/mL; n=41). The distribution of GMAb levels is shown in Figure 2. Three patients (with APAP, rheumatoid arthritis-associated ILD, and unclassifiable ILD) had GMAb levels >3.33 µg/mL (30.60, 7.37, and 4.25 µg/mL, respectively). An additional patient with APAP had a GMAb level of 2.40 µg/mL. Among these four patients, three developed diarrhea within 3 months of nintedanib initiation.

Figure 2 The distribution of serum GMAb levels is shown. A serum GMAb level ≥3.33 μg/mL was used as the cutoff for the diagnosis of autoimmune pulmonary alveolar proteinosis. GMAb, anti-granulocyte-macrophage colony-stimulating factor autoantibody.

Correlation between GMAb and clinical parameters

Serum GMAb levels were not significantly correlated with any clinical or laboratory parameters based on Spearman’s rank correlation analysis (Table 2).

Cutoff values of nintedanib dose per BSA and GMAb

ROC curve analysis was performed to determine cutoff values for predicting diarrhea within 3 months. The optimal cutoff values were 158.0 mg/m² for nintedanib dose per BSA and 0.77 µg/mL for serum GMAb levels. Using a cutoff of 0.77 µg/mL, the positive predictive value for diarrhea within 3 months was 0.80, whereas the negative predictive value was 0.42.

Precision of GMAb measurement at low levels

To assess assay precision at low GMAb levels, a sample with GMAb levels of 0.48 µg/mL was evaluated. The intra-assay %CV was 16% and the inter-assay %CV was 8%.

Comparison of clinical parameters and biomarkers

Clinical parameters and biomarkers were compared between patients with and without diarrhea within 3 months of nintedanib initiation (Table 3). Patients with SP-D levels >157.5 ng/mL developed diarrhea more frequently than those with lower SP-D levels (P=0.009, Fisher’s exact test). Male patients tended to have a higher incidence of diarrhea than female patients; however, this difference did not reach statistical significance (P=0.06).

Predictive factors of diarrhea within 3 months

Univariate logistic regression analysis was performed to identify predictors of diarrhea within 3 months of nintedanib initiation (Table 4). Among the variables examined, male sex was a significant predictor [odds ratio (OR), 4.812; 95% confidence interval (CI), 1.105–20.952; P=0.04]. IPF showed a trend toward an association with diarrhea (P=0.10). GMAb >0.77 µg/mL was not a significant predictor in univariate analysis. However, in multivariate logistic regression analysis adjusted for ILD type, sex, and nintedanib dose per BSA, GMAb >0.77 µg/mL was identified as a significant predictor of diarrhea within 3 months (OR, 14.638; 95% CI, 1.208–177.335; P=0.03) (Table 5). As a sensitivity analysis, a similar multivariate analysis was performed after excluding the two APAP patients (n=39). Serum GMAb >0.77 µg/mL showed a trend toward association with nintedanib-induced diarrhea (OR, 10.861; 95% CI, 0.792–148.926; P=0.07; Table 6).

In addition, after adjustment for ILD type, sex, and nintedanib dose per BSA, neither SP-D >157.5 ng/mL nor peripheral monocyte count ≤650/µL was a statistically significant predictor of diarrhea within 3 months (Table 7).

Predictive models for nintedanib-induced diarrhea

A predictive scoring model (Model 1) was developed based on β-coefficients from multivariate logistic regression analysis, including GMAb >0.77 µg/mL, IPF, and male sex. Scores of 6, 4, and 5 points were assigned to GMAb, IPF, and male sex, respectively, yielding a total score range of 0–15. The area under the curve (AUC) for Model 1 was 0.800 (95% CI, 0.670–0.930; P<0.001; Table 8), with an optimal cutoff value of 7.5 (Figure 3). A second model (Model 2), excluding GMAb, included IPF and male sex. The AUC for Model 2 was 0.719 (95% CI, 0.538–0.881; P=0.008; Table 8), with a cutoff value of 7. Comparison of ROC curves demonstrated that Model 1 had a significantly higher predictive performance than Model 2 (ΔAUC =0.077; P=0.03) (Table 8; Figure 4).

Figure 3 Receiver operating characteristic curve analysis was performed to determine the optimal cutoff score for predicting NTB-induced diarrhea within 3 months using the total score of Model 1 (Table 5). Model 1 included idiopathic pulmonary fibrosis, male sex, and NTB dose normalized by body surface area >158.0 mg/m², to which 4, 5, and 6 points were assigned, respectively. The area under the curve was 0.800 (95% confidence interval, 0.670–0.930). NTB, nintedanib.

Figure 4 Receiver operating characteristic curve analysis was performed to determine the optimal cutoff scores for predicting nintedanib (NTB)-induced diarrhea within 3 months using the total scores of Models 1 and 2. Model 1 included IPF, male sex, and GMAb >0.77 μg/mL, whereas Model 2 included IPF and male sex only. The total score ranges were 0–15 points for Model 1 and 0–9 points for Model 2. The optimal cutoff values were 7.5 for Model 1 and 7 for Model 2. The AUC for Model 1 was 0.751 (95% CI, 0.609–0.894), and that for Model 2 was 0.674 (95% CI, 0.524–0.824). The difference in AUC between the two models (ΔAUC) was 0.077 (95% CI, 0.006–0.148; P=0.03). AUC, area under the curve; CI, confidence interval; GMAb, anti-granulocyte-macrophage colony-stimulating factor autoantibody; IPF, idiopathic pulmonary fibrosis.

Discussion

To our knowledge, this is the first study to examine serum GMAb as a candidate biomarker for nintedanib-induced diarrhea in patients with ILD. We showed that higher levels of serum GMAb (>0.770 µg/mL) were a significant predictive factor for nintedanib-induced diarrhea within 3 months after adjustment for clinical parameters. Higher SP-D levels and lower monocyte counts, which we previously identified as significant predictors (10), suggested a higher frequency of nintedanib-induced diarrhea. GMAb was not correlated with SP-D, monocyte counts, %FVC, or sex.

GM-CSF was originally defined as a hematopoietic factor that controls the production, differentiation, and function of granulocytes and monocytes/macrophages (28). At sites of inflammation, GM-CSF can exert proinflammatory effects through recruitment of myeloid cells and/or enhancement of their survival and activation (28). In addition, GM-CSF affects other cell types, and various conditions and diseases are regulated in complex manners (28). For example, GM-CSF has been reported to improve alveolar epithelial barrier function in rat models of acute lung injury (29) and influenza viral pneumonia (30).

GM-CSF also has various effects on intestinal epithelial cells (28,31); it suppresses apoptosis, induces proliferation of epithelial cells, and augments tight junctions between epithelial cells (32,33). As a result, GM-CSF inhibits epithelial injury, promotes repair of epithelial injury, and reduces epithelial permeability. It is therefore suggested that diarrhea could be attenuated by GM-CSF through these effects. Kudo et al. reported that GM-CSF administration reduced epithelial apoptosis, inflammation, and epithelial damage in histological specimens in a dextran-induced colitis model, and body weight loss and stool scores were also improved (32). Additionally, GM-CSF knockout mice develop more severe dextran-induced colitis than wild-type mice (34). Moreover, GM-CSF has also been reported to induce M2 macrophages (13), which can repair epithelial injury through monocyte differentiation and are thought to orchestrate wound healing in various organs (35).

In humans, the inhibitory effects of GM-CSF on diarrhea have not been sufficiently demonstrated; however, it has been reported that intestinal permeability was decreased in patients with chemotherapy-induced stomatitis treated with locally administered GM-CSF mouthwash (36). Although there are no data on the quantity of GM-CSF reaching the intestine in that study, Cartee et al. reported that plasma GM-CSF was detectable in some patients treated with GM-CSF mouthwash (37). Hence, GM-CSF may reduce intestinal permeability and diarrhea, similar to findings in animal colitis models.

Based on the inhibitory effects of GM-CSF on diarrhea, higher levels of GMAb in the serum could augment the severity and frequency of diarrhea (14,15). The findings are consistent with the results of our study. GMAb has been reported to be associated with disease activity in IBDs, including Crohn’s disease (CD) and ulcerative colitis (UC) (14). Däbritz et al. demonstrated that serum GMAb positively correlated with disease activity, with levels of 1.7 and 0.5 µg/mL predicting relapse within 2–6 months in CD and UC, respectively (14). Nylund et al. showed that patients with CD and higher serum GMAb levels (≥1.6 µg/mL) exhibited increased intestinal permeability (38). Thus, repair of intestinal epithelial injury caused by nintedanib may be impaired by GMAb, and higher serum GMAb levels may be associated with more severe and frequent diarrhea.

Uchida et al. showed that low levels of GMAb (<1 µg/mL) are detectable in the sera of healthy volunteers (39). Generally, GMAb levels >10 µg/mL suppress the function of macrophages and neutrophils, whereas levels between 1 and 10 µg/mL are also thought to suppress function to varying degrees (39). In vitro studies have demonstrated that GMAb at concentrations of 0.5 and 0.1 µg/mL can inhibit neutrophil function (39). Therefore, serum GMAb levels >0.77 µg/mL, which were identified as predictive in this study, may have biological relevance, although this requires confirmation in future in vitro and in vivo studies.

The most important ILD associated with positive GMAb was APAP. We have previously reported that the 5-HT3 receptor antagonist ramosetron is useful for managing nintedanib-induced diarrhea. One of the two patients treated with ramosetron in our initial report had APAP-related pulmonary fibrosis (8), and three of the 11 patients enrolled in prospective studies evaluating ramosetron efficacy had APAP (40). In our experience, patients with APAP-related pulmonary fibrosis treated with nintedanib frequently experienced severe diarrhea that could not be controlled with conventional therapy, such as loperamide. These findings may suggest an association between positive serum GMAb and nintedanib-induced diarrhea. However, because more than 60% of patients treated with nintedanib experienced diarrhea (3,4), the higher frequency observed in APAP-related pulmonary fibrosis should be interpreted with caution. Nevertheless, careful monitoring for diarrhea may be warranted in this population.

This study has several limitations. First, this was a single-center retrospective study, and a limited number of patients were included in this study. This is the most important problem to be mentioned. The wide CI of OR for GMAb indicated unstable estimation and the presence of sparse data bias and overfitting could have occurred. The inconsistency between univariate and multivariate significance of GMAb may be explained, at least in part, by these biases. Second, diarrhea was assessed based on interviews conducted after treatment initiation and recall bias could not be avoided. However, not all episodes of diarrhea may have been documented in medical records, and the interview approach may complement routine clinical documentation. Third, serum samples were available for only 41 of the 79 patients included in our previous study. Differences in baseline characteristics between GMAb-evaluable and non-evaluable patients may have influenced the results. Especially the former population included significantly more IPF patients and tended to have received less corticosteroid therapy than the latter. This may explain why SP-D levels and monocyte counts, previously identified as significant predictors (10), were not significant after adjustment for sex, ILD type, and nintedanib dose/BSA in this cohort (Table 7). Fourth, the presence of APAP in patients with high GMAb levels might have influenced the predictive performance of GMAb for diarrhea. However, sensitivity analysis excluding the APAP cases still suggested a trend toward an association between elevated GMAb levels and nintedanib-induced diarrhea. Thus, the possibility remains that elevated GMAb levels (>0.77 µg/mL), independent of APAP, might have been associated with the occurrence of diarrhea. Fifth, the cutoff of GMAb for predicting diarrhea should be validated in an independent cohort including more patients. With such validation, a more precise cutoff of GMAb level might be identified, and our updated predicting scoring system based on the new cutoff should be re-evaluated. Sixth, measurement variability at low GMAb concentrations remains a concern. We previously reported median GMAb levels of 0.43 (IQR, 0.16–0.85) in sarcoidosis and 0.85 (IQR, 0.52–1.06) in healthy controls (25). The median GMAb level in this study [0.470 (IQR, 0.220–0.770)] was comparable to those findings. We have also found that assay precision at the low level of GMAb, assessed by intra-assay and inter-assay CV, was acceptable.

Conclusions

Our study, including a small number of patients, suggested that GMAb might be a predictor of nintedanib-induced diarrhea. It also suggested a potential role of GM-CSF/GMAb-related pathways in nintedanib-induced diarrhea. However, considering the various limitations accompanying this study, further prospective studies with larger sample sizes and mechanistic investigations are required to make these findings helping clinical decision making in the daily clinical settings and clarify their biological significance.

Acknowledgments

We thank Dr. Koh Nakata (Division of Pioneering Advanced Therapeutics, Niigata University Medical and Dental Hospital, Niigata, Japan) for guidance on serum GMAb measurement and Mr. Kazuyoshi Hatsuda (NHO Kinki Chuo Chest Medical Center, Osaka, Japan) for performing the GMAb assays.

We also thank Ms. Natsumi Matsumura, Ms. Miho Umehara, and Ms. Chihiro Inotani (Department of Nutrition, School of Human Life and Ecology, Osaka Metropolitan University, Osaka, Japan) for conducting patient interviews.

We are grateful to Ms. Sayaka Tanaka (Clinical Research Center, NHO Kinki Chuo Chest Medical Center, Sakai, Osaka, Japan) for assistance with data collection from medical records.

We thank Editage (www.editage.jp) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1130/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1130/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1130/prf

Funding: This work was partially supported by the Study Group on Diffuse Lung Disease and Scientific Research on Intractable Diseases of the Japan Ministry of Health, Labour and Welfare (JMHLW) (Program Grant Number JPMH20FC1030 to T.A.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1130/coif). T.A. has received lecture fees from Boehringer Ingelheim, Shionogi, Sekisui Medical, AstraZeneca, Nobel Pharma, Nippon Shinyaku, and Mochida Pharmaceutical Co., Ltd. He has also received research funding unrelated to this work from Sysmex and Sekisui Medical, and funding related to this work from the Japan Ministry of Health, Labour and Welfare (JMHLW) (No. JPMH20FC1030). Masakazu Hiramatsu received funding from the Taiyo Life Welfare Foundation (No. 2025-II-11). N.T. has received lecture fees from Boehringer Ingelheim. T.T. has received lecture fees from Shionogi. M.M. has received lecture fees from Boehringer Ingelheim and Shionogi. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of NHO Kinki Chuo Chest Medical Center (No. Rin2023-122; approval date: March 25, 2024).Written informed consent was obtained from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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