Comparing the safety and efficacy of nintedanib starting dose in patients with connective tissue disease-associated interstitial lung diseases

Objective This study aimed to analyse whether initiating nintedanib treatment at a reduced dose could improve the treatment continuation rate while maintaining efficacy in patients with connective tissue disease (CTD)-associated interstitial lung disease. Method In total, 51 patients (age 61.6 ± 13.2 years; 38 women, 13 men) were retrospectively analysed. The primary endpoint was the cumulative discontinuation rate due to adverse events. Secondary endpoints included changes in drug dosage, efficacy evaluated based on annual changes in forced vital capacity (FVC), and safety assessed based on the frequency of adverse events. Results Eighteen patients who started treatment at the standard dose of 300 mg (standard dosage group) were compared with 33 patients who started treatment at a reduced dose (reduced dosage group). Systemic sclerosis was the most common CTD (n = 32), followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis. Both groups exhibited comparable cumulative discontinuation rates due to adverse events and similar frequencies of adverse events. No significant differences were observed in maintenance doses between the two groups; however, patients in the reduced dosage group had a lower cumulative dose for up to 52 weeks than those in the standard dosage group. No significant differences were observed in changes in FVC between the two groups. Conclusion There was no evidence for a difference between the two groups in terms of discontinuation rates, efficacy, and safety. To provide further evidence, future studies using more precise dose-escalation protocols are warranted.

Interstitial lung disease (ILD) is a common manifestation associated with various connective tissue diseases (CTDs) (1,2).The current treatment for progressive ILD involves a combination of glucocorticoids and immunosuppressive agents (1)(2)(3)(4)(5), which is insufficient to prevent progression or flares of ILD (6,7).Thus, ILD is the primary cause of death in patients with systemic sclerosis (SSc) and idiopathic inflammatory myopathies (8)(9)(10).Furthermore, ILD is a major prognostic factor for mortality in many patients with CTDs (11).Therefore, establishing new treatment strategies for connective tissue disease-associated ILD (CTD-ILD) is important to improve the outcomes of patients with CTDs.
The concept of progressive fibrosing interstitial lung disease (PF-ILD) and progressive pulmonary fibrosis has recently been introduced as a category for ILD, characterized by progressive pulmonary fibrosis that is independent of standard care treatment based on immunosuppressive regimens (7,12,13).Antifibrotic agents have emerged as a novel treatment for this group of diseases (3,6,14,15).Nintedanib (NTD), a tyrosine kinase inhibitor, is effective in preventing decreases in forced vital capacity (FVC) in patients with SSc and PF-ILD (16)(17)(18)(19)(20), making it a potent agent for the treatment of CTD-ILD.The results of clinical trials suggest that to optimize treatment efficacy, it is important to prolong the use of the drug at an adequate dose (21,22).However, many patients in clinical practice require dose reduction or discontinuation of NTD due to adverse events, including gastrointestinal symptoms and elevated levels of hepatic enzymes (16)(17)(18)(19)(20), with realworld post-marketing surveillance data in Japan showing that approximately 50% of patients were forced to discontinue the drug (23).Therefore, strategies to minimize discontinuation due to adverse events and allow long-term maintenance treatment with NTD must be considered.
NTD is associated with a high frequency of adverse events during the initial phase of treatment (21)(22)(23)(24)(25)(26), and the frequency of these adverse events and drug discontinuations increases in a dose-dependent manner (27).A proposed strategy to minimize adverse events for drugs with similar characteristics is to initiate treatment at a reduced dose and then gradually increase the dose.This approach has helped to lower the discontinuation rate due to adverse events in the early phase of treatment initiation for pirfenidone, an antifibrotic agent, and methotrexate and apremilast, drugs used in rheumatology, and has improved the continuation rate of these drugs.
In this context, the present study aimed to analyse whether initiating NTD at a reduced dose and then increasing it could improve the treatment continuation rate while maintaining efficacy compared to the standard regimen in patients with CTD-ILD.

Patients
This retrospective study included Japanese patients with CTD-ILD who were administered NTD treatment in the Department of Rheumatology or Respirology of Kyushu University Hospital (Fukuoka, Japan) from December 2019 to December 2022.Patients who had received new immunosuppressive agents within 3 months before the study were excluded, whereas those who had received concomitant doses of glucocorticoid or immunosuppressive agents were not excluded.ILD was diagnosed based on high-resolution computed tomography (CT) findings, CTD was diagnosed based on commonly used classification criteria (28)(29)(30)(31)(32)(33)(34), and interstitial pneumonia with autoimmune features was diagnosed based on the classification criteria proposed by the Task Force of the European Respiratory Society and the American Thoracic Society (35).The standard starting dose of NTD used in this study was 300 mg (150 mg twice daily); however, lower starting doses, i.e. 200 mg (100 mg twice daily), 150 mg (once daily), and 100 mg (once daily), were allowed at physicians' discretion.The optimal NTD dose was adjusted based on the patients' tolerability, with no established drug adjustment protocol in place.
This study was approved by the Ethics Committee of Kyushu University Hospital (Fukuoka, Japan; approval number, 23180-00) and was conducted according to the principles of the Declaration of Helsinki.Owing to the retrospective study design, all study information was disclosed at the site of related facilities.The requirement for patient consent was waived in accordance with the ethical committee guidelines.

Clinical and laboratory evaluation
Information retrieved from medical records included demographic data, information on ILD and CTDs, organ manifestations, medications, adverse events, and outcomes.The body surface area was calculated using the DuBois formula.Disease duration was defined as the time from the first diagnosis of ILD to NTD treatment initiation.PF-ILD and a usual interstitial pneumonia (UIP)-like fibrotic pattern on CT scans were evaluated using the definitions applied in the INBUILD trial (18).Pulmonary function tests were used to investigate FVC and diffusing capacity of the lungs for carbon monoxide.The percentage of predicted FVC was expressed as the percentage of predicted values in accordance with the prediction equations of the Japanese Respiratory Society (36).

Outcomes
The primary endpoint was the cumulative discontinuation rate due to adverse events, defined as the time from treatment initiation to discontinuation due to adverse events.Secondary endpoints included changes in drug dosage, efficacy, and safety.Dosages were recorded for up to 1 year after treatment initiation and cumulative doses were calculated for up to 52 weeks.Efficacy was evaluated using the absolute changes from baseline in FVC over 1 year.FVC results obtained 9-15 months after NTD treatment initiation were used.Safety was assessed based on the frequency of adverse events.Serious adverse events were defined as those resulting in death, life-threatening conditions, hospitalization, disability, or permanent damage.

Statistical analysis
Continuous variables are presented as means ± standard deviations or medians with interquartile ranges, whereas categorical variables are presented as frequencies and percentages.Differences between the two groups were analysed using the Student's t-test for normally distributed continuous variables, the Mann-Whitney U test for non-normally distributed continuous variables, and Fisher's exact test for categorical variables.Correlations between the two groups were analysed using Spearman's correlation coefficient.The cumulative discontinuation rate was analysed using Kaplan-Meier survival curves, and logrank statistics were used for group comparisons.Hazard ratios were estimated using the Cox proportional model.All tests were two tailed, and p-values of < 0.05 were considered significant.All analyses were performed using Stata version 16.0 (StataCorp, College Station, TX, USA), and parallel plots were generated using JMP Pro 16 (SAS Institute, Cary, NC, USA).

Patients
During the observation period, 58 patients with CTD-ILD were treated with NTD.After excluding seven patients from this study, 51 patients were analysed.Of these patients, 18 received a starting dose of 300 mg, 11 received 200 mg, four received 150 mg, and 18 received 100 mg.Thus, the 18 patients who started treatment at the standard dose of 300 mg (the standard dosage group) were compared with the remaining 33 patients who started treatment at a reduced dose (the reduced dosage group).SSc was the most common CTD, followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis (Table 1).The standard dosage group had a lower incidence of SSc than the reduced dosage group.Approximately 70% of patients with ILD presented a UIP-like fibrotic pattern on CT scans, and many presented with an FVC of < 80%.In particular, the majority of patients received NTD in combination with immunosuppressive agents, such as tacrolimus and cyclophosphamide, as well as mycophenolate mofetil, the use of which was allowed in a clinical trial (16).The use of concomitant immunosuppressive agents was identical between the two groups, except for a higher prevalence of mycophenolate mofetil and/or tacrolimus use in the reduced dosage group compared to the standard dosage group.

Cumulative discontinuation rate due to adverse events
Seven patients (38.9%) in the standard dosage group and 11 patients (33.3%) in the reduced dosage group discontinued NTD owing to adverse events.Although adverse events appeared to occur earlier in the reduced dosage group, both groups presented comparable cumulative discontinuation rates due to adverse events (Figure 1).The five patients who discontinued NTD in the early phase of treatment initiation were elderly, with a mean age of 74.2 ± 3.3 years.Similar results were obtained after adjusting for the presence or absence of SSc in multivariate Cox proportional hazard analysis, and the adjusted hazard ratio was 0.88 (95% confidence interval 0.32-2.43).

Changes in drug dosage
Figure 2 presents a parallel plot comparing the doses of NTD administered during the first year of drug initiation.After 2-3 months, both groups typically reached the maintenance dose; the time to reach the maintenance dose was significantly longer in the reduced dosage group than in the standard dosage group (Table 1).The most frequent dose was 200 mg in patients who continued NTD treatment.Although no significant differences in the maintenance doses were observed between the two groups, the patients in the reduced dosage group received a significantly lower cumulative dose for up to 52 weeks, which was equivalent to approximately 85% of that used in the standard dosage group (Table 1).

Efficacy
Efficacy was evaluated based on changes in FVC in 23 patients who underwent pulmonary function tests at 1 year: 18 and five patients in the reduced and standard dosage groups, respectively.Despite the small number of patients in the standard dosage group and an imbalance between the two groups, there were no significant differences in the changes in FVC (Figure 3(A)).Furthermore, no association was observed between changes in FVC and cumulative doses over 52 weeks (Figure 3(A)) or the maintenance dose.

Safety
Table 2 lists the adverse events reported by patients.The most common adverse events included gastrointestinal symptoms, such as diarrhoea and vomiting, followed by elevated levels of hepatic enzymes and general fatigue.Four serious adverse events, all of which resulted in hospitalization, occurred in patients in the reduced dosage group.Over 50% of the patients experienced adverse events requiring NTD dose reduction or discontinuation, with no significant differences observed between the reduced and standard dosage groups.At the 300 mg dose, the reduced dosage group showed fewer adverse events requiring NTD discontinuation (two of 13 patients) compared to the standard dosage group (seven of 18 patients), although the difference was not statistically significant.

Sensitivity analysis
We conducted a sensitivity analysis to compare the outcomes of patients who received a starting dose of 200 mg with those who received a starting dose of 300 mg.In total, 29 patients were analysed: 11 and 18 in the 200 mg and 300 mg groups, respectively.Patients in the 200 mg group had lower body weight and surface area, a lower incidence of SSc, and a higher usage of mycophenolate mofetil than those in the 300 mg group (Supplementary Table 1).The cumulative discontinuation rates due to adverse events were identical between the two groups (log-rank test: p = 0.96).In addition, changes in FVC, evaluated in seven patients in the 200 mg group and five patients in the 300 mg group, were comparable between the two groups (Table 3).No differences in adverse events were observed between the two groups (Table 3).

Discussion
This study demonstrated that when comparing patients who started NTD treatment at a standard dose of 300 mg with those who started treatment at a reduced dose, no differences in the cumulative discontinuation rate due to adverse events or in efficacy, as evaluated based on changes in FVC, were observed.The primary endpoint of this study was the cumulative discontinuation rate due to adverse events, because reducing discontinuation due to adverse events when initiating NTD treatment and maintaining treatment for as long as possible are vital to maximize treatment efficacy and improve results (21,22,37).The findings 0.69 Elevated levels of hepatic enzymes 4 ( of this study, indicating that fewer adverse events occurred after dose escalation to 300 mg in the reduced dosage group than when starting at 300 mg in the standard dosage group, suggest that the dose-escalating approach may reduce adverse events at the 300 mg dose.However, a high frequency of adverse events requiring discontinuation of the drug occurred at a low dose in the reduced dosage group.Older age was associated with early discontinuation of the drug, which aligns with findings from previous reports (23,26).The present study showed that discontinuation rates due to adverse events were identical between the two groups.These results deviate from those of a phase II trial reporting that adverse events associated with NTD and its discontinuation increased dose dependently in patients with idiopathic pulmonary fibrosis (IPF) (27).
Our study included CTD-ILDs, with SSc being the most common disease.Therefore, the results may have been influenced by differences in the nature of the diseases, given that the time to NTD dose reduction or discontinuation was reported to be shorter in patients with SSc than in those with IPF (25).In addition, the choice of the starting dose and adjustment of the optimal dose in this study were at physicians' discretion, potentially leading to different results from those reported in the aforementioned phase II trial, in which a fixed dose was continued for a certain period (27).The low incidence of SSc in the standard dosage group in this study suggests that treating physicians may have started NTD at a reduced dose owing to concerns over the potential risk of gastrointestinal symptoms and other adverse events, as patients with SSc frequently experience gastrointestinal complications.A planned short-term doseescalation approach was not performed and the dose was adjusted according to the patient's condition, and consequently, the time to reach the maintenance dose varied widely.Furthermore, because this study was not randomized, the unmeasured characteristics of the patients may have influenced the results, although there were no marked differences in baseline clinical characteristics in this study.No clear concerns were raised in the reduced dosage group; therefore, it would be worthwhile to investigate this issue in planned doseescalation studies or in future randomized controlled trials.This study compared the change in FVC in the first year of NTD treatment to assess its efficacy.Although pulmonary function tests could not be performed in all patients because of the coronavirus disease 2019 (COVID-19) pandemic during the observation period, no significant differences were observed in FVC between the two groups.In addition, the change in FVC was not associated with cumulative doses or the maintenance dose.In a phase II trial involving patients with IPF, only patients treated with 300 mg of NTD showed a reduction in FVC (27), whereas findings reported in Japanese patients with IPF showed no significant differences in changes in FVC between patients initiated at 200 mg and those initiated at 300 mg (24).Our results and the previously reported findings suggest that 200 mg of NTD is effective in Japanese patients with lower body weight and smaller surface area.
This study has several limitations.First, this was a small, retrospective study conducted at a single centre in Japan.Given that body surface area can influence NTD-associated adverse events (23,37), the results of this study, obtained in Japanese patients with smaller body surface area, must be validated through multicentre, multiracial studies.Secondly, this study did not have a defined protocol for NTD administration, nor was it randomized; therefore, the intention of treating physicians could have influenced the assessments, leading to potential bias and involvement of other unknown factors.Thirdly, although treating physicians ensured appropriate coordination for continuing NTD in clinical practice, we did not collect information on their multidisciplinary approach with antidiarrhoeal drugs, probiotics, and nutritional adjustments, which is critical for preventing NTD discontinuation (25,(38)(39)(40).Finally, owing to the COVID-19 pandemic, the pulmonary function tests necessary to assess efficacy were inadequately performed and not well balanced between the two groups.Although the results of the cumulative discontinuation rate and safety analyses, which were the main objectives of this study, can be considered reliable, further validation of the results of the efficacy analysis is warranted.

Conclusion
This study assessed the clinical significance of a reduced starting dose and a dose-escalation approach for NTD treatment.The discontinuation rates due to adverse events, efficacy, and safety of this approach were comparable to those of the standard protocol, showing no evidence for a difference.The findings indicate that a reduced starting dose alone is not enough to obtain a final adequate NTD intake.Future studies may be necessary, employing additional precise doseescalation protocols and a combined multidisciplinary approach.

Figure 3 .
Figure 3. Changes in forced vital capacity (FVC) in 23 patients who underwent pulmonary function tests at 1 year.Data are presented as box plots and whiskers.(B) Correlation between changes in FVC and cumulative doses over 52 weeks.

Table 1 .
Baseline clinical characteristics of patients with connective tissue disease-associated interstitial lung disease.

Table 3 .
Efficacy and safety outcomes of patients who received a starting dose of 200 mg compared to those who received a starting dose of 300 mg.Data are presented as median (interquartile range) or n (%).FVC, forced vital capacity; NTD, nintedanib.