Concerns about interstitial lung disease

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#1

Recently started on weekly rapamycin myself, 3mg/week with GFJ. I thought I’d covered my bases in terms of reading about side effects, but recently came across some literature suggesting interstitial lung disease as a concern for people on rapamycin. Admittedly, the folks in these studies are on daily dosing, and so presumably aren’t representative of those taking rapa for longevity, but there were a few things mentioned that I thought were worth discussing.

  1. Interstitial lung disease was present in a considerable number of patients, which increased from original estimates due to better monitoring and the recognition that many of these patients simply had subclinical, asymptomatic ILD.

“Nowadays, a much higher incidence of all-grade ILD is reported, varying from 14 to 45% for temsirolimus[18] and 3 to 54% for everolimus.”

Now, it should be noted that most of us are on sirolimus, but the incidence of ILD, according to this paper, actually may be even higher in sirolimus. There are actually cases described of sirolimus-induced ILD resolving following switching to everolimus:(Sirolimus-induced interstitial lung disease and resolution after conversion to everolimus - PMC

  1. Risk of ILD from rapamycin and other mTOR inhibitors may not be dose-dependent. This would possibly spell more risk for folks like us than one might think on the basis of lower dosing.

" Numerous studies, however, argue against a dose–effect relationship for the development of ILD. Several cases describe the development of ILD in patients with normal or even low levels of sirolimus.[53] For temsirolimus, the incidence of ILD was not increased in patients who are treated at a much higher dose for mantle cell lymphoma compared to the lower dose in mRCC patients.[39] No dose-dependent relationship in the development of ILD was seen either in a phase II study where different doses of temsirolimus were used.[34] Finally, cases of ILD have even been described following the placement of an everolimus-eluting coronary artery stent, in which systemic exposure to everolimus is very limited." (bolding mine)

Thoughts on these concerns? I have had a bit of a dry cough after 6 weeks on rapamycin which could honestly be a dozen different things, but I must admit I find this paper to be a bit concerning.

The paper is seen below:

mTOR inhibitor‐induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm - Willemsen - 2016 - International Journal of Cancer - Wiley Online Library

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#2

This is absolutely a clear and present danger, be vigilant, good of you to make a point of this important side effect. ILD and anemia are two long term high dose side effect risks.

From your paper link:

“The incidence rate of any grade pneumonitis was 0.11 and of grade 3–4 pneumonitis 0.03. For any grade and for grade 3–4 dyspnea (shortness of breath) the incidence rates were 0.15 and 0.03 and for any grade and grade 3–4 cough 0.23 and 0.01, respectively.”

But some context. The patients expressing serious ILD are very sick and on chronic high dose sirolimus.

https://sci-hub.se/10.1056/NEJM200007203430317

“We report three cases of sirolimus-induced interstitial pneumonitis in renal-transplant recipients who were receiving sirolimus as immunosuppressive therapy (trough blood concentrations, 15 to 30 ng per mL). Progressive interstitial pneumonitis developed during sirolimus therapy in three renal-transplant recipients (two women and a man). Patient 1 was also taking prednisolone, azathioprine, aspirin, acebutolol, isradipine, and gemfibrozil; Patient 2 was taking mycophenolate mofetil, prednisolone, enalapril, furosemide, and insulin; and Patient 3 was taking prednisolone, fenofibrate, and insulin. Two patients had exertional dyspnea, which gradually intensified, whereas the third patient remained asymptomatic”

But here’s the irony…ILD was associated with BETTER clinical outcome!

“Several studies point to the observation that the development of ILD can be viewed as a pharmacodynamic marker that correlates with clinical response. In a large retrospective review of 310 patients, the 36 patients who developed ILD had a significantly longer overall survival than the 274 patients without ILD (median 15.4 vs. 7.4 months). In a second study, 14 of 96 patients (15%) who developed pulmonary abnormalities compatible with ILD had a significantly better median progression-free survival (PFS) (15.0 vs. 3.0 months), and overall survival (17.4 vs. 8.2 months) compared to the patients without symptoms of ILD. When patients benefit from treatment they will be treated for a longer period and as such have a higher cumulative risk of developing ILD.”

At your 3mg/week, and presumably healthy, you are nowhere near ILD side effect risk. But do NOT dismiss it…monitor closely like any other of the known side effects.

The good thing…it typically signals progression and resolves after discontinuation of dosing.

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#3

Would there be early biomarkers? Would this be reflected by increasing CRP, WBC?

I’m concerned in that 40 years ago I was a smoker and also exposed to joint compound dust back when it contained asbestos.

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#4

Immunosuppression mediated 100%, so yes WBC components of your CBC would be leading indicators. But of course watch out for any persistent cough whilst taking Rapamycin.

I’m not a doctor. I can only surmise that if you have any compromised lung function, it may heighten the ILD risk but again you’d need to be venturing into high dose regimes I would think and you’d get an early signal.

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#5

I would also get a high quality air purifier for the room where you sleep to filter out any atmosphere particulates. I did this and it resolved a chronic dry cough I would have for months (3-6) at a time. This would be to avoid any false positives.

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#6

Just wanted to follow up on this for anyone who sees this post at a later point. My cough is totally gone. I’m pretty sure I just had a touch of a cold-turned-cough and never got additional symptoms significant enough to indicate I was actually sick. Plan is to continue with what I’m doing and of course, I’ll monitor for cough down the road.

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#7

This is my largest concern because I had Covid-pneumonia in both lungs a couple years ago

#8

I believe that Rapamycin is an effective treatment for non-small cell lung cancer.

Rapamycin inhibits lung squamous cell carcinoma growth by downregulating glypican-3/Wnt/β-catenin signaling and autophagy | SpringerLink.

#9

My girlfriend says she only ever prescribes mtor inhibitors (everolimus) sometimes for breast and kidney cancers not non small cell lung cancers. So I guess that rapamycin only works in mice not humans in that case…