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  1. Anastasia Krompa
  1. Acute Medicine, London North West Healthcare NHS Trust, London, UK
  1. Correspondence to Dr Anastasia Krompa, Acute Medicine, London North West Healthcare NHS Trust, London, UK; krompa.anastasia{at}gmail.com

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Decreased telomere length and interstitial lung changes: more than just association?

The association of telomere dysfunction with idiopathic pulmonary fibrosis (IPF) is well recognised in existing data. Putman et al (Eur Respir J 2022;60:2101814) reported that telomere shortening is not associated only with progressive fibrosis, but also with early interstitial lung abnormalities (ILA), including ground glass opacities, reticular abnormalities, centrilobular nodularity, non-emphysematous cysts and traction bronchiectasis. Telomere length (TL) measurements and ILA identification derived from 5.389 participants in three existing large cohorts representative of the general population with a smoking exposure: Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene), Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) and Framingham Heart Study (FHS). In both COPDGene and AGES-Reykjavik, shortest mean TL quartile was significantly associated with 2–3 fold risk for ILA occurrence after adjustment for confounders (OR 2.2, 95% CI 1.5 to 3.4, p=0.0001 and OR 2.6, 95% CI 1.4 to 4.9, p=0.003, respectively). A similar relationship with ILA and TL was found in the FHS but using a different measurement technique (p=0.03). The authors also demonstrated relationships between TL and both quantitative and qualitative features of ILA but the relationship with mortality appeared less clear without consistency between cohorts. While ILA was unequivocally associated with reduced TL, further studies are required to establish a possible aetiological relationship and define the clinical significance of TL shortening.

TL in acute-exacerbation-IPF: marker of increased risk of mortality

The role of TL among different interstitial lung diseases (ILDs) with fibrotic usual interstitial pneumonia (UIP) pattern and the association with acute-exacerbation of IPF (AE-IPF) was reported in a Greek case–control study by Tomos et al (Pulmonology 2022;28:254). This prospective study included 79 subjects with stable IPF, AE-IPF, combined pulmonary fibrosis and emphysema, rheumatoid arthritis related UIP-ILD and age-matched healthy controls. TL was expressed as the ratio of telomeric DNA product (T) to the reference single copy gene (S). A statistically significant association was identified between patients with fibrotic UIP-ILD and TL shortening with each UIP subgroup exhibiting shorter TL compared with healthy controls (mean T/S ratio±SE 0.77±0.05 vs 2.26±0.36, p<0.001). Among the various UIP subsets studied, no significant variation in TL was identified apart from the IPF-AE participants. The IPF-AE group demonstrated consistently more compromised TL when compared with stable IPF patients (mean T/S ratio±SE 0.87±0.07 vs 0.66±0.10, p=0.029). Regarding the overall survival, reduced TL was shown to be an independent risk of death for all UIP-ILD (HR 0.174, 95% CI 0.036 to 0.846, p=0.030), while inversely, 0.01 increase of TL was associated with 17.4% decrease in mortality. Specifically, for IPF, patients with shorter TL also had significantly reduced survival compared with the those with longer TL (13.26±1.62 months vs 29.7±5.6, p=0.004), while the mortality risk was expectedly highest for the IPF-AE group. Larger-scale studies are required to confirm these findings and further evaluate the role and predictive value of TL in UIP-ILD and AE-IPF.

Tocilizumab in early systemic sclerosis-associated ILD: maintains lung function

Systemic sclerosis-associated ILD (SSc-ILD) has a poor prognosis but given the putative role of IL-6 in the pathophysiology of the disease it offers the potential for targeted therapy. Encouraging data derived from a randomised controlled trial (RCT) with an open-label extension presented by Khanna et al (Am J Respir Crit Care Med 2022;205:674) providing efficacy and safety data on tocilizumab in SSc-ILD. FocuSSced was a 48-week phase III RCT that studied the efficacy of tocilizumab, an anti-IL-6 receptor-a antibody, in 212 patients with early SSc with active skin disease, randomly assigned 1:1 to placebo or weekly 162 mg tocilizumab. Although not able to reach the predefined threshold of statistical significance for skin sclerosis improvement, preservation of lung function was observed on the tocilizumab group. The open-label extension: 89 (out of 107) patients from the previous placebo arm and 92 (out of 105) patients from the tocilizumab arm, received tocilizumab for another 48 weeks. While SSc-ILD was not an inclusion prerequisite, the majority of the subjects had normal or mildly impaired lung function, and approximately two-thirds had evidence of baseline fibrotic lung parenchyma involvement. Confirming the initial 48 weeks observation, efficacy analyses in the intention-to-treat population in 96 weeks, showed favourable outcomes of tocilizumab over placebo regarding the preservation of lung function and maintenance of carbon monoxide diffusion capacity. A milder drop in absolute forced vital capacity (FVC) was observed under the continuous tocilizumab group from baseline to week 48 (change in FVC: −11.1 mL, 95% CI −83.8 to 61.6) and from week 48 to week 96 (change in FVC: −15.3 mL, 95% CI −80.1 to 49.5. In contrast, in the placebo-tocilizumab arm, the initial 48-week lung function decline (change in FVC: −197.2 mL, 95% CI −301.6 to −92.8) was followed by relative plateau following tocilizumab to week 96 (change in FVC: 39.6 mL, 95% CI −28.3 to 107.5). Tocilizumab efficacy was also verified by post hoc analysis for patients with baseline SSc-ILD. No concerns were raised on tocilizumab’s long-term safety profile. These data provide sufficient optimism that IL-6 targeted therapy may offer potential in this difficult to treat area.

Carboplatin and nab-paclitaxel in non-small cell lung cancer and ILD: evidence of efficacy and safety

While it is not uncommon for lung cancer to complicate lung fibrosis, no standard treatment protocol is followed, mainly due to the chemotherapy associated morbidity in these already frail patients. A phase II study by Sakashita et al (Thorac Cancer 2022;13:1267) reported the role of carboplatin and nab-paclitaxel as first-line chemotherapy in patients with ILD with advanced non-small cell lung cancer (NSCLC) in a phase II clinical trial. A total of 25 NSCLC ILD patients with NSCLC stage≥IIIA, and performance status 0 or 1 received 4-weekly treatment for 4–6 cycles. The primary endpoint, set as completion of at least four cycles, was successfully reached by more than three quarters of the participants (76%, 95 CI 56.2% to 88.8%). Response (disease control rate 88%, 95% CI 69.2% to 96.7%), toxicity rates, as well as progression-free and overall survival (15.8 months, 95% CI 11.0 to 26.5 months) were similar to published data in patients with NSCLC but without ILD. A single patient (4%) fulfilled the criteria for acute ILD exacerbation related to chemotherapy, again similar to the published event rate with other chemotherapy regimens in NSCLC. While further data are required, the study indicated that the combination of carboplatin and nab-paclitaxel may be an efficient and safe therapeutic option for NSCLC ILD patients.

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Footnotes

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.