Treatment of Refractory Checkpoint-Inhibitor-Induced Hepatitis with Tacrolimus: A Case and Review of the Literature
Round 1
Reviewer 1 Report
This case report reported that tacrolimus has improved hepatitis following immunotherapy by tacrolimus in a patient with metastatic melanoma. However, there is a novelty issue. In a previous report, the use of tacrolimus was suggested as a treatment for a multiple metastatic melanoma patient who developed hepatitis following combination immunotherapy with nivolumab and ipilimumab (Volume 52, Issue 1, J R Coll Physicians Edinb, 2022). Since tacrolimus has been suggested for the management of hepatitis in the same way for the same indication, the author should be able to emphasize what other clinical implications it presents compared to the previous report. This reviewer strongly recommends that this issue should be addressed in a discussion section.
No specific comment.
Author Response
We thank reviewer 1 for the comments. Indeed, tacrolimus has been proposed in earlier reports (as described in the case) and our case adds body to the evidence, which is scarce on this subject. Yet, our case also illustrates the caveats of multiple immunosuppressive agents to mitigate immune-related adverse events in cancer patients treated with IO, namely the (1) the risk of infectious complications and (2) the risk of disease progression. We believe that this clinical implication is of utmost importance, and elaborated these caveats in our discussion.
Reviewer 2 Report
This case can contribute to have more options in the treatment of hepatitis induced by immune checkpoint inhibitors.
As a case report I consider that the discussion should be shorter
Quality of Figure 2 should be improved, as is very difficult to read
Author Response
Response 1: We thank reviewer 2 for contributing. Combining the suggestions of all reviewers, we cut some parts of our discussion and focussed merely on the caveats of the use of tacrolimus as an additional immunsuppressant.
Response 2: We adapted figure 2.
Reviewer 3 Report
The manuscript "Treatment of refractory checkpoint-inhibitor induced hepatitis with tacrolimus: a case and review of the literature." describe a case of hepatitis and then provides a review of the state-of-the art.
The article is a compilation of information, with few opinions of the expert. I would appreciate if the authors would go more into controversy regarding the treatments available and to offer an opinion based in scientific evidence.
As a minor comment, Figure 2 is not readable, it is too small.
English is understandable.
Author Response
Response 1: We thank reviewer 3 for this contribution. Indeed, the body of evidence on handling steroid-refractory immune-related hepatitis is scarce. Randomized controlled trials to address these questions would be very difficult to undertake and, as such, fo now we will be stuck with low quality evidence for a while. Current treatment decisions are based solely on case reports, retrospective data and (in daily practice) on expert opinions.
Our case also illustrates the caveats of multiple immunosuppressive agents, namely the (1) the risk of infectious complications and (2) the risk of disease progression. As such, we strongly believe treatment discussions should be made on a case-by-case basis in a multidisciplinary team. Hepatologist have a lot of insight in immunosuppressive strategies for liver pathology and should alwyas be consulted in a case of steroid refractory IrH.
If we have to take a statement, we must say that the choice of treatment depends on
- Severity of the hepatitis
- Urgency for treatment
- Performance status of the patient
- Comorbidities of the patient
- Availbaility of drugs
- Expected adverse events of the optional drugs.
To our opinion MMF is a good first choice in steroid-refractory irH and tacrolimus should be considered thereafter. We tried to adresse these opinions more profoundly in the revised version of the text. In our discussion, we proposed an algorithm and our opinion how to aid clinicians in treatment decision making and expand the evidence on this matter.
Response 2: We adapted figure 2.
Reviewer 4 Report
This is a well written case report with extensive literature review in regards to drug induced live injury in patients receiving ICI. I think the paper will contribute to the current knowledge on this topic. I do have few comments that I would like to ask authors to address before publication:
1. please report BMI. If patient was obese, possibility of fatty liver contributing to development of DILI should be described.
2. Figure 2 is too busy and it is very difficult to understand it. please enlarge and simplify
3. Please report values of INR and albumin, as markers of synthetic liver function
4. " septic thrombophlebitis" of which vein? Portal vein, hepatic veins or elsewhere? if patient developed septic portal vein thrombosis this would be relevant to further discuss given temporal association to development of DILI
5. Figure 3- also needs to be enlarged. Again it is difficult to see
6. I would like authors to describe either in introduction or in the first paragraph of discussion why do they call this hepatitis instead of DILI? I did not read that patient had fever, RUQ abdominal pain, nausea and vomiting which are symptoms of hepatitis. As such, this is DILI not hepatitis, as hepatitis is a clinical diagnosis.
7. Please discuss differences between ICI DILI and DILI from other medication classes , for example antibiotics.
N/A
Author Response
Response 1: We thank reviewer 4 for his comments. BMI has been added in the manuscript; 20 kg/m2 (67 kg, 183 cm).
Response 2: We adapted figure 2.
Response 3: INR was 1,18 on day 0. It normalized (<1,1) on day 10. And only rose again to 1,24 on day 95. Albumin always remained within normal limits (34-51 g/l). We added this information to the manuscript.
Response 4: Thank you for pointing out this vague description. The patient developed a thrombophlebitis of the left cephalic vein as was clinically noted on the entry site of the peripheral infusion, which turned out to be surinfected 10 days later. We elaborated this in the case.
Response 5: We also made changes to this figure.
Response 6: We thank the reviewer for this important remark. There are differences in the terminology of immune-related adverse events among different international guidelines. However, the term “hepatitis” has been used through all major international societies (ESMO, ASCO, SITC and NCCN) in their guidelines to adress the issue of hepatotoxicity associated with immune-checkpoint inhibitors. Furthermore, the EASL guideline on drug-induced liver injury (Drug-induced liver injury. J Hepatol (2019), https://doi.org/10.1016/j.jhep.2019.02.014) describes in detail the subject of “Liver injury associated with immunotherapy for cancer” and the term “immune-mediated hepatitis” is used interchangeably in this paragraph. Futhermore, the SITC guideline also defines immune-related hepatitis for asymptomatic AST/ALT rises, in exclusion of other causes.
Response 7: This manuscript mainly focusses on the treatment issues associated with steroid-refractory immune related hepatitis. We highlighted the importance of a pathologic diagnosis, and do believe that a detailed discussion on DILI from other medication classes is beyond the scope of this manuscript. As the patient did not take any other hepatotoxic medication at the time of diagnosis, these were not addressed in detail.
Round 2
Reviewer 1 Report
The issues have been well addressed. There is no additional issue to raise.
It needs minor language polishing.
Author Response
We conducted a few language-specific check-ups of the manuscript and made the minor revisions as is seen through track changes in the Word file that we submitted now.
We would like to thank the reviewers for their comments.
Reviewer 4 Report
I would like to thank the authors for detailed responses to my concerns. I think the paper has been improved. However, I would like to point out that Figure 2 appears distorted. In its current form it is impossible to see the timeline. I believe this might be due to conversion from word to PDF but in any case this must be addressed before publication. Liver biopsy slide still does not contain pointers towards pathology being described.
English is ok, minor spelling and syntax changes that can be polished in editorial phase
Author Response
We conducted a few language-specific check-ups of the manuscript and made the minor revisions as is seen through track changes in the Word file that we submitted now.
For the figures, there seems to be a technical issue. We have no distorsion on the time line and also the pointers in the pathology picture are there. We think this might have been caused by transformation from word to pdf. We therefore changed the application which we were using for this action and uploaded a pdf version the document after cleaning out the track changes. Also we provided the figures again separately. If somehow this is not sufficient, we are off course prepared to sent the figures through an another route, for example email.
We would like to thank the reviewers for their comments.
