Infection Risk, Mortality, and Hypogammaglobulinemia Prevalence and Associated Factors in Adults Treated with Rituximab: A Tertiary Care Center Experience
, Thamer S. Alhowaish 2,3, Alaa Mathkour 4, Bayan Altamimi 2,5, Shahd Alheijani 6 and Abdulrahman Alrashid 1,2,5Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors describe a retrospective observational study investigating the associated factors with infection and mortality among 137 receiving rituximab for various indications. Their methods are well described. The following details need to be addressed prior to publication:
Major: - As the authors point out in the discussion, time of infection relative to rituximab initiation was not reported. Why was this not addressed?
- Please explain the rationale behind dividing the dosing groups as 375 mg/m2, 500 mg and 1000 mg. Why was 750 mg/m2 dosing not included? Many of the patients who received the 375 mg/m2 dosing likely received doses of 500 or 1000 mg (which is typically the maximum single dose for this medication). As such, comparing these groups may not be as relevant as comparing the cumulative doses, which the authors report had no significant differences in regards to infection or mortality risk. Furthermore, the group of 500 mg dosing is very small. In addition, the authors should review the labels throughout the paper and ensure that 375 mg/m2, and fixed doses of 500 mg and 1000 mg are correctly labeled, as there are some sections were a dose of 500 mg/m2 or 1000 mg/m2 are listed, which is likely incorrect.
- Did the authors encounter any difference in mortality pre and post pandemic? Since COVID-19 was one of the most common causes of infection related mortality.
- The authors should attempt to discuss mortality rates with hematologic malignancies with other treatment modalities vs rituximab. This could add value as to how much of the mortality risk can be attributed to the primary disease vs the drug itself, although a different study designs would be needed to truly address this.
- The authors should try to emphasize the results of their multivariate analysis, as these account for confounding and interactions with other variables. The univariate analysis results can be included in tables but should not be a major part of the discussion or text of the results section.
- The authors analyze the use of steroids as a risk factor of mortality and infection, but the dose is not addressed. It is well known that the immunosuppressive effect of steroids is much stronger beyond the 20 mg threshold and beyond the 2 week duration of use, thus these are important factors that should be analyzed if possible.
- Did any patient receive IVIG replacement therapy? This could have influenced infectious and mortality outcomes and should be analyzed.
- As the authors point out, blood group is likely irrelevant. Furthermore, about 25% of the patients did not have a reported blood type. Thus, this variable should be removed from the analysis.
- The authors should emphasize that given the retrospective nature of the study, no clear causative relation can be established between the use of rituximab and infection/mortality in this study.
Minor:
- In the abstract - methods, the sample size is included, this should be moved to results.
- In Figure 1, does “malignancies” refer to non-hematologic cancers? As hematologic malignancies are listed under primary reason for rituximab?
- The authors claim that theirs was a relatively healthy population in the discussion, but the primary diagnoses argue against that; suggest this phrase be removed or changed.
Author Response
On behalf of the team, I would like to thank the reviewers for their honest work and time.
I hope we addressed the comments in the best way possible.
All the changes in the manuscript were highlighted in yellow.
Moustafa Alhamadh
Major: - As the authors point out in the discussion, time of infection relative to rituximab initiation was not reported. Why was this not addressed?
Thank you for asking. Initially, we were planning to calculate the time of infection relative to RTX. However, we a long discussion and since the diagnoses are heterogenous and the dose of RTX is not unified and since some patients are taking multiple immunosuppressants in addition to RTX, we think that calculating the time may not accurately depict the risk of infection in RTX in particular. We agreed on only calculating the time of COVID-19 infection relative to RTX, and found that those who died of COVID-19 had an average time of 2.1 months since last RTX dose compared 7.1 months in the survivors although the difference was not statistically significant. Then, we separated the data of those who were infected with COVID-19, collected and analyzed further data, and wrote and published a paper about that a month ago (Alhowaish TS, Alhamadh MS, Mathkour A, Alamoudi M, Alqahtani HA, Alrashid A. Clinical Course and Outcomes of COVID-19 Infection in Patients Treated with Rituximab: A Tertiary Care Center Experience. Open Access Rheumatol. 2023;15:145-159. Published 2023 Aug 28. doi:10.2147/OARRR.S424316).
- Please explain the rationale behind dividing the dosing groups as 375 mg/m2, 500 mg and 1000 mg. Why was 750 mg/m2 dosing not included? Many of the patients who received the 375 mg/m2 dosing likely received doses of 500 or 1000 mg (which is typically the maximum single dose for this medication). As such, comparing these groups may not be as relevant as comparing the cumulative doses, which the authors report had no significant differences in regards to infection or mortality risk. Furthermore, the group of 500 mg dosing is very small. In addition, the authors should review the labels throughout the paper and ensure that 375 mg/m2, and fixed doses of 500 mg and 1000 mg are correctly labeled, as there are some sections were a dose of 500 mg/m2 or 1000 mg/m2 are listed, which is likely incorrect.
Thank you for your valuable comment. I modified the fixed doses throughout the manuscript. Regarding the rationale behind dividing the dose, the common RTX protocols are 1 gm either single or 2 doses, 500 mg either single or 2 doses, and 375mg/m2 every week for 4 weeks. For example a patient with a height of 170 cm and weight of 60 kg 375 mg/m2 equal to 635 every week which is almost 2.5 gm.
- Did the authors encounter any difference in mortality pre and post pandemic? Since COVID-19 was one of the most common causes of infection related mortality.
Although we did not cluster the data into pre- and post- pandemic, I would say yes. Apparently, RTX seems to be a potential risk factor for unfavorable outcomes in COVID-19 patients. Therefore, it should be used with caution or avoided unless the benefit clearly outweighs the risk. In addition, immunoglobulin testing should be performed in all patients started on RTX to know the baseline level of the patients. We did write and publish a paper about COVID-19 outcomes among RTX receivers.
- The authors should attempt to discuss mortality rates with hematologic malignancies with other treatment modalities vs rituximab. This could add value as to how much of the mortality risk can be attributed to the primary disease vs the drug itself, although a different study designs would be needed to truly address this.
Thank you for sharing the idea with us. Actually, the team is currently working on a similar idea. We hope to finish it and publish it soon.
- The authors should try to emphasize the results of their multivariate analysis, as these account for confounding and interactions with other variables. The univariate analysis results can be included in tables but should not be a major part of the discussion or text of the results section.
Noted. We modified the result section accordingly.
- The authors analyze the use of steroids as a risk factor of mortality and infection, but the dose is not addressed. It is well known that the immunosuppressive effect of steroids is much stronger beyond the 20 mg threshold and beyond the 2 week duration of use, thus these are important factors that should be analyzed if possible.
We totally agree with your comment. However, it was not one of this study objectives and because of that It would be difficult giving the time frame for the revision. To access the patients’ file and collect new data for a new objective, we will have to obtain a new IRB approval. Regardless, we would definitely include steroid dose and cumulative dose in our upcoming papers. Thank you.
- Did any patient receive IVIG replacement therapy? This could have influenced infectious and mortality outcomes and should be analyzed.
Unfortunately, immunoglobulin replacement was not part of the study objective, and because of that, we did not look at it in this paper. As a side note, only a few patients needed immunoglobulin replacement, but thank you for bringing this up, it might be beneficial to look at it in the future.
- As the authors point out, blood group is likely irrelevant. Furthermore, about 25% of the patients did not have a reported blood type. Thus, this variable should be removed from the analysis.
Although it is likely irrelevant, this finding is interesting. Although we do not know the cause, we believe it might attract other researchers’ attention to investigate the cause or prove this association.
- The authors should emphasize that given the retrospective nature of the study, no clear causative relation can be established between the use of rituximab and infection/mortality in this study.
We totally agree with your comment. In addition to what you mentioned, the infection/mortality might also be affected by the primary disease itself and the other immunosuppressants. We tried to point this out multiple times in the discussion.
Minor:
- In the abstract - methods, the sample size is included, this should be moved to results.
Noted. The method and results were modified accordingly.
- In Figure 1, does “malignancies” refer to non-hematologic cancers? As hematologic malignancies are listed under primary reason for rituximab?
Yes, other than hematological cancers.
- The authors claim that theirs was a relatively healthy population in the discussion, but the primary diagnoses argue against that; suggest this phrase be removed or changed.
Noted. The phrase has been removed.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors evaluate the rate and predictors of hypogammaglobulinemia and assess morbidity, in the form of severe infection requiring intensive care unit (ICU) admission, and mortality associated with RTX use in one of the largest medical cities in Saudi Arabia.
Some comments are:
- The authors should specify the years of inclusion (2016-until 2022, 2023?)
- It is important to include the cumulative glucocorticoid dose because secondary immunodeficiency could be related as well
- Data regarding the hypogammaglobulinemia should be included: when was the hypogammaglobulinemia diagnosed, after how many RTX cycles/ months or years since the start of RTX treatment
- I think it's important to compare the two groups (yes hypogammaglobulinemia/no hypogammaglobulinemia) regarding the presence of comorbidities because they can be a confusing factor. Not only RTX is a cause of hypogammaglobulinemia.
- Is the sample age and sex-matched? Because it is important to consider immunosenescence as a cause of hypogammaglobulinemia. In case they aren't, I suggest changing that.
- The authors find that patients who received RTX in the 1000 mg/m2 dose had a significantly lower risk of mortality compared to those who received the 375 mg/m2 however, they don't discuss this properly in the discussion.
- Tables and figures: present infection rates and mortality rates for different patient groups in order to make it easier compare and understand
- Do you have any explanation for blood types B and AB being associated with a higher mortality?
Author Response
Thank you very much for your time and valuable comments. Please see the attached document for the response letter.
Author Response File: 
Author Response.docx
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThank you for addressing the comments
Comments on the Quality of English LanguageMinor editing needed
Reviewer 2 Report
Comments and Suggestions for AuthorsI am satisfied with the author's comments
Comments on the Quality of English LanguageI am satisfied with the english
