Correspondence on “Native joint infections in Iceland 2003-2017: an increase in postarthroscopic infections” by Gunnlaugsdóttir et al
Similar to the periprosthetic joint infections, the diagnosis and treatment of native joint infections (NJIs) is also challenging. If not promptly recognized and adequately treated, NJIs can lead to devastating consequences, such as threatening septicemia and loss of joint function.1 The incidence of NJIs seems to be increasing but remains rare.2,3 Therefore, few studies investigated the epidemiology, clinical risk factors, and outcomes of NJIs, and a nationwide study would provide the best attainable level of evidence on this issue.2,3 With great interest, we read the article by Gunnlaugsdóttir and colleagues,4 in which they provide epidemiological, clinical, and prognostic analysis of patients with culture-proven NJI over a 15-year period. They found that the incidence of NJIs has remained stable in Iceland over the past 15 years, but the proportion of iatrogenic infections is high, especially seen a significant increase of iatrogenic infections following arthroscopic procedures. The authors should be applauded for their tremendous initiative and extensive efforts at illustrating the results. We compliment the authors for their comprehensive nationwide study, while there are a few points that we wish to raise.
First, as discussed by the authors, when compared with a previous nationwide study covering 1990–2002, there was no sig...
Correspondence on “Native joint infections in Iceland 2003-2017: an increase in postarthroscopic infections” by Gunnlaugsdóttir et al
Similar to the periprosthetic joint infections, the diagnosis and treatment of native joint infections (NJIs) is also challenging. If not promptly recognized and adequately treated, NJIs can lead to devastating consequences, such as threatening septicemia and loss of joint function.1 The incidence of NJIs seems to be increasing but remains rare.2,3 Therefore, few studies investigated the epidemiology, clinical risk factors, and outcomes of NJIs, and a nationwide study would provide the best attainable level of evidence on this issue.2,3 With great interest, we read the article by Gunnlaugsdóttir and colleagues,4 in which they provide epidemiological, clinical, and prognostic analysis of patients with culture-proven NJI over a 15-year period. They found that the incidence of NJIs has remained stable in Iceland over the past 15 years, but the proportion of iatrogenic infections is high, especially seen a significant increase of iatrogenic infections following arthroscopic procedures. The authors should be applauded for their tremendous initiative and extensive efforts at illustrating the results. We compliment the authors for their comprehensive nationwide study, while there are a few points that we wish to raise.
First, as discussed by the authors, when compared with a previous nationwide study covering 1990–2002, there was no significant change in the overall incidence of iatrogenic infections among adults, the number of infections is rising due to an increase in the number of arthroscopic procedures. However, in the previous nationwide study, there was a significant increasing trend in the annual volume of arthroscopic procedures during the 1990–2001 financial year, and since then the annals volume of arthroscopies became relatively stable (estimated by the number of arthroscopic procedures during 2010–2017 was 21342). Therefore, the markedly increased infections among adults following arthroscopic procedures may attribute to other risk factors. For instance, the increased iatrogenic infections may be associated with the hospital- or surgeon-related risk factors. Previous studies have demonstrated a volume-outcome relationship in arthroscopic rotator cuff repair, which suggested that higher surgical volume (i.e., annualized case volume or hospital volume) was associated with decreased surgical complications.5,6 For arthroscopy of the knee, a simulation study suggests that consultant-level skills are not reached until 170 procedures have been performed.7 Thus, we speculate the increased postarthroscopic infections might be associated with hospitals or surgeons with a low annual caseload, such as a hospital that adopted arthroscopy as new technology or a surgeon who was early in the learning curve.8
Second, the increased postarthroscopic infections may not only be associated with the increased number of procedures but also associated with the dramatically increased indications for arthroscopy. Over the past decades, with the rapid development of arthroscopic techniques, the application field of arthroscopy has been a breakthrough. The application of arthroscopy has extended to all major limb joints and several smaller joints, and as a minimally invasive therapeutic technology, arthroscopy is increasingly performed instead of traditional open surgeries.9 The authors have compared the frequency of arthroscopies with other Nordic countries and suggested that arthroscopic knee procedures are overused in Iceland. However, it would be more plausible if the authors analyzed the variation of the arthroscopic indications. Besides, during the dissemination of arthroscopic skills and technologies for new indications, the surgeons had to ascend the learning curve, which could also affect the incidence of NJIs.
Third, the authors adopted strict eligible criteria (culture-proven NJIs), in combination with the rather low incidence of NJIs, which led to limited power to assess the epidemiological, clinical, and prognostic characteristics of patients with NJIs. It has been well established that with a large enough sample size, a test has the power to detect any discrepancy from the null however small.10 For this reason, a statistically significant result may have limited practical implications, or we may have a statistically insignificant result, yet useful information could be obtained from the data. Therefore, the statistically significant results cannot be interpreted simply by themselves, instead, further investigation should be done to figure out whether there is practical or clinical significance.
References
1. Roerdink RL, Huijbregts HJTAM, van Lieshout AWT, et al. The difference between native septic arthritis and prosthetic joint infections: A review of literature. J Orthop Surg (Hong Kong) 2019;27(2):2309499019860468.
2. Geirsson AJ, Statkevicius S, Víkingsson A. Septic arthritis in Iceland 1990-2002: increasing incidence due to iatrogenic infections. Ann Rheum Dis 2008;67(5):638–43.
3. Kennedy N, Chambers ST, Nolan I, et al. Native Joint Septic Arthritis: Epidemiology, Clinical Features, and Microbiological Causes in a New Zealand Population. J Rheumatol 2015;42(12):2392–7.
4. Gunnlaugsdóttir SL, Erlendsdóttir H, Helgason KO, et al. Native joint infections in Iceland 2003-2017: an increase in postarthroscopic infections. Ann Rheum Dis 2021:annrheumdis-2021-220820.
5. Weinheimer KT, Smuin DM, Dhawan A. Patient Outcomes as a Function of Shoulder Surgeon Volume: A Systematic Review. Arthroscopy 2017;33(7):1273–1281.
6. Warner JJP, Higgins LD. Editorial Commentary: Volume and Outcome: 100 Years of Perspective on Value From E.A. Codman to M.E. Porter. Arthroscopy 2017;33(7):1282–1285.
7. Price AJ, Erturan G, Akhtar K, et al. Evidence-based surgical training in orthopaedics: how many arthroscopies of the knee are needed to achieve consultant level performance? Bone Joint J 2015;97-B(10):1309–15.
8. Simpson AH, Howie CR, Norrie J. Surgical trial design - learning curve and surgeon volume: Determining whether inferior results are due to the procedure itself, or delivery of the procedure by the surgeon. Bone Joint Res 2017;6(4):194–195.
9. Carr AJ, Price AJ, Glyn-Jones S, et al. Advances in arthroscopy-indications and therapeutic applications. Nat Rev Rheumatol 2015;11(2):77–85.
10. Mayo DG, Spanos A. Error statistics. In Philosophy of statistics. North-Holland, 2011:153–198.
We thank Huang and co-authors (1) for their correspondence on our work (2). We want to take the opportunity to clarify the raised issues.
The first issue raised was the question regarding the investigation of dose-dependent effects of treatments. For treatments in which dose-dependent effects are important, different doses have been studied and the relationship has been shown. This is the case with the use of glucocorticoids (GC). Using an Andersen-Gill model with inverse probability weights we found an adjusted Hazard ratio (HR) for herpes zoster (HZ) of 4.42 (2.50 to 7.83) for GC of more than 10 mg/day compared to no GC and 1.47 (1.17 to 1.85) for GCs of 5 to 10 mg/day. To answer the question about a possible effect of (different) duration of exposure on the outcome we would like to point out, that this information (exposure duration of disease-modifying anti-rheumatic drugs (DMARDs)) is naturally accommodated in the Andersen-Gill model which we used to calculate estimates.
Regarding the second issue raised, the analysis of other immunosuppressant treatments, we admit that we did not consider those treatments in our analyses due to the rare prescribing rates of these medications, except from leflunomide, especially in monotherapy. In particular, the proportion of patients with concomitant use of leflunomide with biologic DMARDs was approximately 10%, while concomitant use of cyclosporin with biologic DMARDs was below 1% and only 4 patients received mycophenol...
We thank Huang and co-authors (1) for their correspondence on our work (2). We want to take the opportunity to clarify the raised issues.
The first issue raised was the question regarding the investigation of dose-dependent effects of treatments. For treatments in which dose-dependent effects are important, different doses have been studied and the relationship has been shown. This is the case with the use of glucocorticoids (GC). Using an Andersen-Gill model with inverse probability weights we found an adjusted Hazard ratio (HR) for herpes zoster (HZ) of 4.42 (2.50 to 7.83) for GC of more than 10 mg/day compared to no GC and 1.47 (1.17 to 1.85) for GCs of 5 to 10 mg/day. To answer the question about a possible effect of (different) duration of exposure on the outcome we would like to point out, that this information (exposure duration of disease-modifying anti-rheumatic drugs (DMARDs)) is naturally accommodated in the Andersen-Gill model which we used to calculate estimates.
Regarding the second issue raised, the analysis of other immunosuppressant treatments, we admit that we did not consider those treatments in our analyses due to the rare prescribing rates of these medications, except from leflunomide, especially in monotherapy. In particular, the proportion of patients with concomitant use of leflunomide with biologic DMARDs was approximately 10%, while concomitant use of cyclosporin with biologic DMARDs was below 1% and only 4 patients received mycophenolate mofetil at baseline. Therefore, we restrained from further stratification due to the small sample sizes within some treatment groups. Other treatments are not collected regularly in the register therefore the use of CYP3A4 inhibitors/CYP2C19 could not be studied.
Information on HZ contact and previous HZ history was available only for a small proportion of patients. However, the use of an Andersen-Gill model enabled us to include recurrent events for this analysis by taking the complete follow-up time into account.
We had investigated all available information on comorbidities for this analysis. Their occurrence was equally distributed over the treatments. Therefore we only included information on relevant comorbidities (table 1).
1. Huang Y, Hsu W, Lin Y, Wei J. Correspondence on 'Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register.' Ann Rheum Dis 2021.
2. Redeker I, Albrecht K, Kekow J, Burmester GR, Braun J, Schafer M, et al. Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register. Ann Rheum Dis 2021.
We welcome the correspondence to our article, which reported results of a phase III study (NCT03502616), by James Cheng-Chung Wei and colleagues.1
Considering the primary endpoint, Assessment of SpondyloArthritis International Society (ASAS) 20 response rates at week 16, significant improvements vs placebo were evident with tofacitinib 5 mg two times per day (BID). The response rate with tofacitinib 5 mg BID did decline very slightly from week 12 to week 16, before continuing to improve through week 48 (figure 2A). A similar pattern was observed in some secondary endpoints (ASAS40 response rates [figure 2B]; change from baseline in Ankylosing Spondylitis Disease Activity Score [ΔASDAS; figure 3A] and high-sensitivity C-reactive protein [ΔhsCRP; figure 3B]; ASAS 5/6 response [supplemental figure 3B]; ASDAS low disease activity [ASDAS LDA; supplemental figure 4C]; and ASDAS inactive disease [supplemental figure 4D]), although for all other endpoints, improvements were steady or increased through week 16.
We believe that what may be perceived as a ‘dip’ in efficacy at week 16 was likely due to patient variability. Notably, this ‘dip’ was most pronounced for ASAS20 response rates, an endpoint which is often associated with variability, compared with the more conservative endpoints (ASAS40 response rates, ASAS5/6 and ASDAS LDA), for which the differences between week 12 and week 16 were numerically smaller than for ASAS20 response rates. Additionally, for hsCRP,...
We welcome the correspondence to our article, which reported results of a phase III study (NCT03502616), by James Cheng-Chung Wei and colleagues.1
Considering the primary endpoint, Assessment of SpondyloArthritis International Society (ASAS) 20 response rates at week 16, significant improvements vs placebo were evident with tofacitinib 5 mg two times per day (BID). The response rate with tofacitinib 5 mg BID did decline very slightly from week 12 to week 16, before continuing to improve through week 48 (figure 2A). A similar pattern was observed in some secondary endpoints (ASAS40 response rates [figure 2B]; change from baseline in Ankylosing Spondylitis Disease Activity Score [ΔASDAS; figure 3A] and high-sensitivity C-reactive protein [ΔhsCRP; figure 3B]; ASAS 5/6 response [supplemental figure 3B]; ASDAS low disease activity [ASDAS LDA; supplemental figure 4C]; and ASDAS inactive disease [supplemental figure 4D]), although for all other endpoints, improvements were steady or increased through week 16.
We believe that what may be perceived as a ‘dip’ in efficacy at week 16 was likely due to patient variability. Notably, this ‘dip’ was most pronounced for ASAS20 response rates, an endpoint which is often associated with variability, compared with the more conservative endpoints (ASAS40 response rates, ASAS5/6 and ASDAS LDA), for which the differences between week 12 and week 16 were numerically smaller than for ASAS20 response rates. Additionally, for hsCRP, there was a very small difference between week 12 and week 16, consistent with the natural variability observed in the measurements over time in this study. Furthermore, as ASDAS inactive disease is a very stringent outcome measure, which is challenging to achieve and maintain, some variability in the observed responses was to be expected. Of note, 15 patients had inactive disease at week 12, compared with nine patients at week 16. Finally, at week 16, all patients entered the open-label phase of the study, with those receiving placebo switching to tofacitinib 5 mg BID in a blinded manner until the final database release. It is not uncommon to see a perceived ‘dip’ in efficacy at the last visit of the blinded phase in a randomized study, ahead of the open-label extension phase. While the exact cause of this phenomenon is not known, it may be related to patients’ belief that they could have been receiving placebo when they are informed that the blinded phase is over and that they will be entering the open-label phase.
Patients in the study could indeed continue stable background non-steroidal anti-inflammatory drugs (NSAIDs), oral corticosteroids or conventional synthetic disease-modifying drugs (csDMARDs), methotrexate or sulfasalazine. As noted by Wei JC-C, et al., tofacitinib in combination with methotrexate has been shown to be efficacious and well-tolerated in previous phase II and phase III studies of patients with rheumatoid arthritis.2-4 However, methotrexate and systemic corticosteroids have not demonstrated efficacy in the axial skeleton.5 6 We therefore do not believe that methotrexate provides any additional benefits for axial symptoms in ankylosing spondylitis. Notably, in the current study, the proportion of patients using NSAIDs was balanced across treatment groups (both approximately 80%; Table 1), and while csDMARD use was not as balanced (22% of patients receiving tofacitinib 5 mg BID vs 32% of patients receiving placebo), we believe that this should not have had an effect on the results specific to signs and symptoms of axial disease. Furthermore, if there was an effect of csDMARDs, with the imbalance mentioned above, it would have gone against tofacitinib.
We agree with Wei JC-C, et al., that the ASAS Health Index (ASAS-HI) assesses the overall picture of a broad range of health aspects,7 and is therefore a reliable and comprehensive measure to include in clinical trial protocols.8 In the current study, we measured the Ankylosing Spondylitis Quality of Life score, a widely accepted measure,9 which was pre-specified in the clinical trial protocol and is used as standard in the regulatory setting (and is mandated by the Food and Drug Administration). As this study is complete and data collection has ended, we are unable to include the ASAS-HI at this stage, but we will be sensitive to survey fatigue in future clinical trials and continue to advocate for specific endpoints such as the ASAS-HI to be included.
We believe that we have addressed the queries and concerns of Wei JC-C, et al. as far as possible within the scope of this correspondence.
Acknowledgements
Medical writing support, under the guidance of the authors, was provided by
Kimberley Haines, MSc, CMC Connect, McCann Health Medical Communications, and was funded by Pfizer Inc, New York, NY, USA in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med 2015;163:461–464).
References
1. Wei JC-C, Ker A, Yang C-R, et al. Correspondence to “Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study” by “Deodhar et al.”. Ann Rheum Dis 2021. https://ard.bmj.com/content/80/8/1004.responses#correspondence-to-%E2%80....
2. Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken) 2011;63(8):1150–58. doi: 10.1002/acr.20494
3. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 2013;381(9865):451–60. doi: 10.1016/S0140-6736(12)61424-X
4. Kremer J, Li Z-G, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 2013;159(4):253–61. doi: 10.7326/0003-4819-159-4-201308200-00006
5. Haibel H, Brandt HC, Song IH, et al. No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial. Ann Rheum Dis 2007;66(3):419–21. doi: 10.1136/ard.2006.054098
6. Haibel H, Fendler C, Listing J, et al. Efficacy of oral prednisolone in active ankylosing spondylitis: results of a double-blind, randomised, placebo-controlled short-term trial. Ann Rheum Dis 2014;73(1):243–46. doi: 10.1136/annrheumdis-2012-203055
7. Assessment of SpondyloArthritis International Society. Description of ASAS Health Index 2021 [Available from: https://www.asas-group.org/instruments/asas-health-index/#:~:text=The%20....
Accessed 24 August 2021.
8. Kiltz U, van der Heijde D, Boonen A, et al. Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis. Ann Rheum Dis 2018;77(9):1311–17. doi: 10.1136/annrheumdis-2017-212076
9. Doward LC, Spoorenberg A, Cook SA, et al. Development of the ASQoL: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis 2003;62(1):20–26.
We have a great interest in the article published by Prendecki et al studying on immune response to SARS-CoV2 vaccination (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in patients receiving immunosuppression (IS) for autoimmune rheumatic and glomerular diseases.[1] They reported poor humeral and cellular responses to first-dose vaccine in IS group comparing to a cohort of healthy volunteer (HV), while the immune responses could be augmented by second dose. [1] We appreciate this important and timely study. However, we believe that some issues should be discussed in this study.
First of all, the baseline comparability between IS and HV as well as between subgroups should be balanced, not only for age, but also for interval between 2 doses and types of vaccine. According to the recommendation for use of AstraZeneca COVID-19 vaccine published by World Health Organization (WHO), they suggested an interval of 8 to 12 weeks between the two doses due to the observation that two-dose efficacy and antibody level increase with a longer inter-dose interval. [2] However, IS group patients got second-dose vaccination at a median of 30 days (IQR 28-42 days), which didn’t categorize subgroup by different types of vaccine and was much earlier than the WHO recommendation timing. Although the significantly lower seroconversion rate was noticed in patients receiving ChAdOx1 than those receiving BNT2b162, we still concerned that short interval vaccination schedule would have i...
We have a great interest in the article published by Prendecki et al studying on immune response to SARS-CoV2 vaccination (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in patients receiving immunosuppression (IS) for autoimmune rheumatic and glomerular diseases.[1] They reported poor humeral and cellular responses to first-dose vaccine in IS group comparing to a cohort of healthy volunteer (HV), while the immune responses could be augmented by second dose. [1] We appreciate this important and timely study. However, we believe that some issues should be discussed in this study.
First of all, the baseline comparability between IS and HV as well as between subgroups should be balanced, not only for age, but also for interval between 2 doses and types of vaccine. According to the recommendation for use of AstraZeneca COVID-19 vaccine published by World Health Organization (WHO), they suggested an interval of 8 to 12 weeks between the two doses due to the observation that two-dose efficacy and antibody level increase with a longer inter-dose interval. [2] However, IS group patients got second-dose vaccination at a median of 30 days (IQR 28-42 days), which didn’t categorize subgroup by different types of vaccine and was much earlier than the WHO recommendation timing. Although the significantly lower seroconversion rate was noticed in patients receiving ChAdOx1 than those receiving BNT2b162, we still concerned that short interval vaccination schedule would have impacts on the result of antibody level. Nevertheless, two-dose interval in HV (median 66 days, IQR 61-69 days) was significantly longer than IS. PITCH study had showed a higher antibody titer in long dose interval group (median 10 weeks, range 6-14) than conventional group (median 3 weeks, range 2-5). [3] Therefore, the baseline comparability between IS and HV in second dose protection should be ensured.
Second, it is believed that we could do more research in determining the most appropriate timing for vaccine. Not only in Prendecki et al study, B cell depletion was also described as a strong predictor to the failed serological response in many previous publications. [4-6] As a result, suggestion about delaying vaccination until B cell reconstitution occurred seemed to play a vital role in achieving better serological immunity. Spiera et al research mentioned the similar concept, which revealed a higher rates of seropositive responses to vaccines than B cell depletion even in a weak levels of reconstitution. [6] However, the duration to the last rituximab treatment especially administration within 6 months has a strong relation with failure seroconversion as well. Besides, it would be a considerable expense if we evaluate peripheral B cell maturation for all patients who were previous treated with rituximab. Hence, to take both duration and peripheral B-cell into consideration and reduce the cost, we proposed performing further analysis on the relation between the time to last rituximab infusion and baseline B cell counts as well as seroconversion rate to find out the best cutoff of initiating vaccine.
To sum up, we believed that the protocol of AstraZeneca COVID-19 vaccine and the two-dose interval should be modified and balanced between two groups for increasing credibility about baseline comparability. At the meanwhile, we suggested for further analysis on last rituximab duration, B cell number and seroconversion rate to find the cutoff for vaccination. But for patients living in high community transmission rates regions, we still recommended to follow the current guidelines and be vaccinated as soon as possible.
1. Prendecki, M., et al., Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression. Annals of the Rheumatic Diseases, 2021: p. annrheumdis-2021-220626.
2. WHO. Interim recommendations for use of the ChAdOx1-S [recombinant] vaccine against COVID-19. 30, July, 2021.
3. Payne, R.P., et al., Sustained T cell immunity, protection and boosting using extended dosing intervals of BNT162b2 mRNA vaccine.
4. Bonelli, M.M., et al., SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response. Annals of the Rheumatic Diseases, 2021.
5. Boyarsky, B.J., et al., Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients with rheumatic and musculoskeletal diseases. Annals of the Rheumatic Diseases, 2021. 80: p. 1098-1099.
6. Spiera, R., S. Jinich, and D. Jannat-Khah, Rituximab, but not other antirheumatic therapies, is associated with impaired serological response to SARS-CoV-2 vaccination in patients with rheumatic diseases. Annals of the Rheumatic Diseases, 2021.
We read with great interest the recent article by Laurent et al.1 which confirmed the potential role of innate lymphoid cells-2 (ILC2) in the establishment of fibrosis in human systemic sclerosis. It provided a novel idea that transforming growth factor-β (TGFβ) downregulates KLRG1 expression on ILC2 and contributes to its low interleukin 10 (IL10) production capacity, finally resulting in skin fibrosis. However, we feel confused when reading some parts of the article.
From the design of the overall experiment, we can clearly understand that the authors first determined the importance of ILC2 in fibrotic tissues, and then sought out the reason: the low IL10 production caused by TGF-β stimulation. Finally, they conducted relevent cell and animal experiments and draw the final conclusion. However, from the conclusion of the article, it is the reduction of IL10 that leads to the progression of fibrosis? It makes us confused because ILC2 is not the main cell producing IL10. As we all known, IL10 is a cytokine of multi-cell origin and almost all immune cells can synthesize IL102. Meanwhile, despite its relative increase in fibrotic tissues, the numberof Innate lymphoid cells is very rare3. With the diversification of IL10 sources, is the low IL10 production capacity of ILC2 the main cause of fibrosis?
In summary, we respect the original insight and contributions of the authors, and believe an in-depth study of the role of IL10 may be a new research direction.
We read with great interest the recent article by Laurent et al.1 which confirmed the potential role of innate lymphoid cells-2 (ILC2) in the establishment of fibrosis in human systemic sclerosis. It provided a novel idea that transforming growth factor-β (TGFβ) downregulates KLRG1 expression on ILC2 and contributes to its low interleukin 10 (IL10) production capacity, finally resulting in skin fibrosis. However, we feel confused when reading some parts of the article.
From the design of the overall experiment, we can clearly understand that the authors first determined the importance of ILC2 in fibrotic tissues, and then sought out the reason: the low IL10 production caused by TGF-β stimulation. Finally, they conducted relevent cell and animal experiments and draw the final conclusion. However, from the conclusion of the article, it is the reduction of IL10 that leads to the progression of fibrosis? It makes us confused because ILC2 is not the main cell producing IL10. As we all known, IL10 is a cytokine of multi-cell origin and almost all immune cells can synthesize IL102. Meanwhile, despite its relative increase in fibrotic tissues, the numberof Innate lymphoid cells is very rare3. With the diversification of IL10 sources, is the low IL10 production capacity of ILC2 the main cause of fibrosis?
In summary, we respect the original insight and contributions of the authors, and believe an in-depth study of the role of IL10 may be a new research direction.
References
1. Laurent P, Allard B, Manicki P, et al. TGFβ promotes low IL10-producing ILC2 with profibrotic ability involved in skin fibrosis in systemic sclerosis. Ann Rheum Dis 2021.
2. Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010;10:170-81.
3. Constantinides MG, McDonald BD, Verhoef PA, Bendelac A. A committed precursor to innate lymphoid cells. Nature 2014;508:397-401.
Correspondence on ‘Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain’ by Rahman et al
Young Ho Lee, Gwan Gyu Song
Department of Rheumatology, Korea University College of Medicine, Seoul, Korea
Corresponding author:
Young Ho Lee, MD, PhD
Department of Rheumatology
Korea University Anam Hospital, Korea University College of Medicine
73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Korea
Tel: 822-920-5645, Fax: 822-922-5974, E-mail: lyhcgh@korea.ac.kr
Acknowledgements
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors have no financial or non-financial conflict of interest to declare.
We have read with great interest the genome-wide association study (GWAS) on candidate genes for chronic widespread pain (CWP) described by Rahman and colleagues.1 This GWAS meta-analysis has shown a new association of the RNF123 locus and suggested a link of the ATP2C1 locus with CWP; however, the association between COMT locus and CWP was not replicated. Although the results were quite helpful for understanding the genetic basis of CWP, several methodological issues need to be addressed.
To begin with, both CWP and fibromyalgia appear to be a part of a pain continuum in the ge...
Correspondence on ‘Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain’ by Rahman et al
Young Ho Lee, Gwan Gyu Song
Department of Rheumatology, Korea University College of Medicine, Seoul, Korea
Corresponding author:
Young Ho Lee, MD, PhD
Department of Rheumatology
Korea University Anam Hospital, Korea University College of Medicine
73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Korea
Tel: 822-920-5645, Fax: 822-922-5974, E-mail: lyhcgh@korea.ac.kr
Acknowledgements
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors have no financial or non-financial conflict of interest to declare.
We have read with great interest the genome-wide association study (GWAS) on candidate genes for chronic widespread pain (CWP) described by Rahman and colleagues.1 This GWAS meta-analysis has shown a new association of the RNF123 locus and suggested a link of the ATP2C1 locus with CWP; however, the association between COMT locus and CWP was not replicated. Although the results were quite helpful for understanding the genetic basis of CWP, several methodological issues need to be addressed.
To begin with, both CWP and fibromyalgia appear to be a part of a pain continuum in the general population; however, they vary more in quantitative measures, rather than qualitative ones.2 Despite the absence of sensitive and specific laboratory tests, biomarkers, or pathological characteristics for CWP and fibromyalgia, fibromyalgia is associated with more severe symptoms and consequences in daily life, as well as greater pain severity, than CWP.2 Hence, until a fibromyalgia subgroup analysis of CWP is conducted, the study results might not be as significant as anticipated for better understanding the genetic basis of fibromyalgia. Second, CWP occurrence seemed to be affected by several variables, such as age, sex, and body mass index (BMI).3 The challenge of this study is the disparity in age, sex, and BMI between the case and control groups.1 These fundamental factors must be accounted for in the design or corrected for in the analysis. Inappropriate control selection in case-control research increases the variability in underlying causative variables and may reduce the power of detection of an effect.4 Studies in a meta-analysis with a high risk of bias without proper handling may invalidate the meta-analytical findings, resulting in inaccurate conclusions.5 When improper control selection is suspected, these confounders must be accounted for in the analysis.6 Although we admire the efforts of the authors, the research should be viewed with the aforementioned methodological issues in mind.
REFERENCES
1 Rahman MS, Winsvold BS, Chavez SOC, et al. Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain. Annals of the rheumatic diseases 2021
2 Staud R. Chronic widespread pain and fibromyalgia: two sides of the same coin? Current rheumatology reports 2009;11:433.
3 Mills SE, Nicolson KP, Smith BH. Chronic pain: a review of its epidemiology and associated factors in population-based studies. British journal of anaesthesia 2019;123:e273-e83.
4 Zondervan KT, Cardon LR. Designing candidate gene and genome-wide case–control association studies. Nature protocols 2007;2:2492-501.
5 Ahmed I, Sutton AJ, Riley RD. Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: a database survey. Bmj 2012;344
6 Pourhoseingholi MA, Baghestani AR, Vahedi M. How to control confounding effects by statistical analysis. Gastroenterology and hepatology from bed to bench 2012;5:79.
Dear editor:
We read with great interest the recent article titled ‘‘Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis’’ by Dr. Li and colleagues1. Authors proposed that excessive Tenascin-C (TNC) deposition at chronic inflammation entheseal site promotes pathological bone formation in ankylosing spondylitis (AS). Suppression of this aberrant pathway may have therapeutic effects in AS. This study provides valuable and innovative results, but some concerns should be taken into account.
First, the pathophysiological roles of human leukocyte antigen-B27 (HLA-B27)-mediated activation in AS has not been discussed in the study. HLA-B27 was known as a pivotal genetic predisposing factor in AS through the activation of the interleukin (IL)-17/IL-23 axis. By alternating the balance of IL-17- and IL-22-producing cells,2 3 the disruption of the gut microbiome or invasion by pathogenic bacteria might lead to inflammatory or immune-mediated diseases. The misfolding of HLA-B27 mediates the stromal activation in the pathogenesis of syndesmophyte formation of ankylosing spines via upregulating the phosphorylated -inositol-requiring 1 (IRE1)/spliced X-box–binding protein 1 (sXBP1)/retinoic acid receptor-β (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) pathway.4 The enhanced expression of TNAP is a significant factor of abnormal mineralization, and...
Dear editor:
We read with great interest the recent article titled ‘‘Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis’’ by Dr. Li and colleagues1. Authors proposed that excessive Tenascin-C (TNC) deposition at chronic inflammation entheseal site promotes pathological bone formation in ankylosing spondylitis (AS). Suppression of this aberrant pathway may have therapeutic effects in AS. This study provides valuable and innovative results, but some concerns should be taken into account.
First, the pathophysiological roles of human leukocyte antigen-B27 (HLA-B27)-mediated activation in AS has not been discussed in the study. HLA-B27 was known as a pivotal genetic predisposing factor in AS through the activation of the interleukin (IL)-17/IL-23 axis. By alternating the balance of IL-17- and IL-22-producing cells,2 3 the disruption of the gut microbiome or invasion by pathogenic bacteria might lead to inflammatory or immune-mediated diseases. The misfolding of HLA-B27 mediates the stromal activation in the pathogenesis of syndesmophyte formation of ankylosing spines via upregulating the phosphorylated -inositol-requiring 1 (IRE1)/spliced X-box–binding protein 1 (sXBP1)/retinoic acid receptor-β (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) pathway.4 The enhanced expression of TNAP is a significant factor of abnormal mineralization, and the blockade of TNAP inhibits new bony appositions. We suggest that further discussion or study will be very useful for clarifying the linkage between TNC and the genetic importance of HLA-B27 in AS.
Second, the upregulated reactivity of TNC could induce an inflammatory response and promote degeneration and fibrosis both in the cartilage of osteoarthritis (OA) and rheumatoid arthritis (RA) patients.5 This illustrates the coexisting of spondylosis or RA spinal disease amongst the AS patients may disrupt the study result. Therefore, this current study obtained tissue from late-stage AS patients whilst neither available demographic, nor disease status, nor co-existence of OA/AS and RA/AS. Hence, the interpretation of the study data should be utilized carefully.
Finally, we believe that the effect of IL-17 inhibitors and tumor necrosis factor (TNF) blockers in TNC are worth investigating in the future. Moreover, IL-17 and TNF inhibitors have been proven to be effective in preventing new bone formation in several trials.6 The immunohistochemical analysis of TNC expression after treatment of IL-17 or TNF inhibitors may shed more light in future studies.
Dear Authors, can you explain why the conclusion states "This interim analysis revealed a greater number of pts receiving APR (66%) who completed the 12-mo follow-up achieved REM or LDA, as measured by cDAPSA over 12 mos" but in the second pannel of the Figure the data for patients reaching REM/LDA cDAPSA at 12mos is 50%? Thank you.
We read with interest the article of Imke Redeker et al.1 The article not only has included large quantity of patients but also performed sensitivity analysis and subgroup analysis of. Authors concluded that glucocorticoids and JAK inhibitors were associated with risk of herpes zoster (HZ) in rheumatoid arthritis (RA) patients. However, there are some concerns that required to be taken into account in order to make the study more comprehensive.
First of all, the dosage or exposure duration of disease-modifying antirheumatic drugs treatments (DMARDs) has barely mentioned in this study. We know that the purpose of the study might simply be intent to focus on the connection between medicine exposure and the outcome of HZ. Nevertheless, it’s our opinion that dose response relationship should be analyzed to show dose-dependent effect.
Second, drug-drug interaction is an important issue on all treatment. There’s already some evidence showing certain drugs that may interact with DMARDs. In this research, CYP3A4 inhibitor together with CYP2C19 have been discussed to have a cross action with JAK inhibitors.2 Drugs may change the original medicinal effect proposed to be and thus interfere with the result we get. What’s more, apart from glucocorticoids and methotrexate mentioned in article, we suggest that more kinds of common immunosuppressants should be considered. Especially for RA patients, immunosuppressants such as cyclosporine, leflunomide and mycophenolate...
We read with interest the article of Imke Redeker et al.1 The article not only has included large quantity of patients but also performed sensitivity analysis and subgroup analysis of. Authors concluded that glucocorticoids and JAK inhibitors were associated with risk of herpes zoster (HZ) in rheumatoid arthritis (RA) patients. However, there are some concerns that required to be taken into account in order to make the study more comprehensive.
First of all, the dosage or exposure duration of disease-modifying antirheumatic drugs treatments (DMARDs) has barely mentioned in this study. We know that the purpose of the study might simply be intent to focus on the connection between medicine exposure and the outcome of HZ. Nevertheless, it’s our opinion that dose response relationship should be analyzed to show dose-dependent effect.
Second, drug-drug interaction is an important issue on all treatment. There’s already some evidence showing certain drugs that may interact with DMARDs. In this research, CYP3A4 inhibitor together with CYP2C19 have been discussed to have a cross action with JAK inhibitors.2 Drugs may change the original medicinal effect proposed to be and thus interfere with the result we get. What’s more, apart from glucocorticoids and methotrexate mentioned in article, we suggest that more kinds of common immunosuppressants should be considered. Especially for RA patients, immunosuppressants such as cyclosporine, leflunomide and mycophenolate mofetil should be taken into consideration and stratified.
Last but not least, in addition to the confounding factors listed at the baseline, we also found other residual confounders might impact on the HZ infection rate. For instance, HZ contact and previous HZ history are influential factors, which demonstrate a significant relation to the incidence of herpes zoster.3
Furthermore, more comorbidities, such as other rheumatic diseases,4 acquired immune deficiency syndrome (AIDS),5 lymphopenia, low immunoglobulin and complement level are all possible confounders and should be discussed.
References
1. Redeker I, Albrecht K, Kekow J, et alRisk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT registerAnnals of the Rheumatic Diseases Published Online First: 28 July 2021. doi: 10.1136/annrheumdis-2021-220651
2. Walton A, Paik J, Quebe A, Kannowski CL, Choong C, Anderson S, Owensby JK. Frequency of Prescription Claims for Drugs that May Interact with Janus Kinase Inhibitors Among Patients with Rheumatoid Arthritis in the US. Rheumatol Ther. 2021 Mar;8(1):599-607. doi: 10.1007/s40744-020-00275-8. Epub 2021 Jan 23. PMID: 33484433; PMCID: PMC7991043.
3. Lai YC, Yew YW. Risk of Herpes Zoster and Family History: A Meta-analysis of Case-control Studies. Indian J Dermatol. 2016 Mar-Apr;61(2):157-62. doi: 10.4103/0019-5154.177748. PMID: 27057014; PMCID: PMC4817439.
4. Wang S, Wei JC, Huang JY, Perng WT, Zhang Z. The risk of herpes zoster among patients with ankylosing spondylitis: A population-based cohort study in Taiwan. Int J Rheum Dis. 2020 Feb;23(2):181-188. doi: 10.1111/1756-185X.13650. Epub 2019 Jul 23. PMID: 31334604.
5. Jansen K, Haastert B, Michalik C, Guignard A, Esser S, Dupke S, Plettenberg A, Skaletz-Rorowski A, Brockmeyer NH. Incidence and risk factors of herpes zoster among hiv-positive patients in the german competence network for HIV/AIDS (KompNet): a cohort study analysis. BMC Infect Dis. 2013 Aug 10;13:372. doi: 10.1186/1471-2334-13-372. PMID: 23937603; PMCID: PMC3751196.
Great article on an evolving area with very limited published evidence.
I note in supplementary appendix 1 that there is no IQ range quoted for the "time from last RTX dose to first vaccination" for the Spike antibody positive (n=17) group.
It would be helpful if you could include this data, as it would give some guidance as to minimum timeframe to wait post rituximab before giving vaccination. Also including absolute minimum and maximum time in days for the "time from last RTX dose to first vaccination" for all 3 categories (total, spike AB+ and spike AB- would be useful)
Regards
Dr Richard Germann
Nephrologist
Tauranga
New Zealand.
Correspondence on “Native joint infections in Iceland 2003-2017: an increase in postarthroscopic infections” by Gunnlaugsdóttir et al
Show MoreSimilar to the periprosthetic joint infections, the diagnosis and treatment of native joint infections (NJIs) is also challenging. If not promptly recognized and adequately treated, NJIs can lead to devastating consequences, such as threatening septicemia and loss of joint function.1 The incidence of NJIs seems to be increasing but remains rare.2,3 Therefore, few studies investigated the epidemiology, clinical risk factors, and outcomes of NJIs, and a nationwide study would provide the best attainable level of evidence on this issue.2,3 With great interest, we read the article by Gunnlaugsdóttir and colleagues,4 in which they provide epidemiological, clinical, and prognostic analysis of patients with culture-proven NJI over a 15-year period. They found that the incidence of NJIs has remained stable in Iceland over the past 15 years, but the proportion of iatrogenic infections is high, especially seen a significant increase of iatrogenic infections following arthroscopic procedures. The authors should be applauded for their tremendous initiative and extensive efforts at illustrating the results. We compliment the authors for their comprehensive nationwide study, while there are a few points that we wish to raise.
First, as discussed by the authors, when compared with a previous nationwide study covering 1990–2002, there was no sig...
We thank Huang and co-authors (1) for their correspondence on our work (2). We want to take the opportunity to clarify the raised issues.
Show MoreThe first issue raised was the question regarding the investigation of dose-dependent effects of treatments. For treatments in which dose-dependent effects are important, different doses have been studied and the relationship has been shown. This is the case with the use of glucocorticoids (GC). Using an Andersen-Gill model with inverse probability weights we found an adjusted Hazard ratio (HR) for herpes zoster (HZ) of 4.42 (2.50 to 7.83) for GC of more than 10 mg/day compared to no GC and 1.47 (1.17 to 1.85) for GCs of 5 to 10 mg/day. To answer the question about a possible effect of (different) duration of exposure on the outcome we would like to point out, that this information (exposure duration of disease-modifying anti-rheumatic drugs (DMARDs)) is naturally accommodated in the Andersen-Gill model which we used to calculate estimates.
Regarding the second issue raised, the analysis of other immunosuppressant treatments, we admit that we did not consider those treatments in our analyses due to the rare prescribing rates of these medications, except from leflunomide, especially in monotherapy. In particular, the proportion of patients with concomitant use of leflunomide with biologic DMARDs was approximately 10%, while concomitant use of cyclosporin with biologic DMARDs was below 1% and only 4 patients received mycophenol...
We welcome the correspondence to our article, which reported results of a phase III study (NCT03502616), by James Cheng-Chung Wei and colleagues.1
Considering the primary endpoint, Assessment of SpondyloArthritis International Society (ASAS) 20 response rates at week 16, significant improvements vs placebo were evident with tofacitinib 5 mg two times per day (BID). The response rate with tofacitinib 5 mg BID did decline very slightly from week 12 to week 16, before continuing to improve through week 48 (figure 2A). A similar pattern was observed in some secondary endpoints (ASAS40 response rates [figure 2B]; change from baseline in Ankylosing Spondylitis Disease Activity Score [ΔASDAS; figure 3A] and high-sensitivity C-reactive protein [ΔhsCRP; figure 3B]; ASAS 5/6 response [supplemental figure 3B]; ASDAS low disease activity [ASDAS LDA; supplemental figure 4C]; and ASDAS inactive disease [supplemental figure 4D]), although for all other endpoints, improvements were steady or increased through week 16.
We believe that what may be perceived as a ‘dip’ in efficacy at week 16 was likely due to patient variability. Notably, this ‘dip’ was most pronounced for ASAS20 response rates, an endpoint which is often associated with variability, compared with the more conservative endpoints (ASAS40 response rates, ASAS5/6 and ASDAS LDA), for which the differences between week 12 and week 16 were numerically smaller than for ASAS20 response rates. Additionally, for hsCRP,...
Show MoreWe have a great interest in the article published by Prendecki et al studying on immune response to SARS-CoV2 vaccination (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in patients receiving immunosuppression (IS) for autoimmune rheumatic and glomerular diseases.[1] They reported poor humeral and cellular responses to first-dose vaccine in IS group comparing to a cohort of healthy volunteer (HV), while the immune responses could be augmented by second dose. [1] We appreciate this important and timely study. However, we believe that some issues should be discussed in this study.
Show MoreFirst of all, the baseline comparability between IS and HV as well as between subgroups should be balanced, not only for age, but also for interval between 2 doses and types of vaccine. According to the recommendation for use of AstraZeneca COVID-19 vaccine published by World Health Organization (WHO), they suggested an interval of 8 to 12 weeks between the two doses due to the observation that two-dose efficacy and antibody level increase with a longer inter-dose interval. [2] However, IS group patients got second-dose vaccination at a median of 30 days (IQR 28-42 days), which didn’t categorize subgroup by different types of vaccine and was much earlier than the WHO recommendation timing. Although the significantly lower seroconversion rate was noticed in patients receiving ChAdOx1 than those receiving BNT2b162, we still concerned that short interval vaccination schedule would have i...
We read with great interest the recent article by Laurent et al.1 which confirmed the potential role of innate lymphoid cells-2 (ILC2) in the establishment of fibrosis in human systemic sclerosis. It provided a novel idea that transforming growth factor-β (TGFβ) downregulates KLRG1 expression on ILC2 and contributes to its low interleukin 10 (IL10) production capacity, finally resulting in skin fibrosis. However, we feel confused when reading some parts of the article.
...Show MoreFrom the design of the overall experiment, we can clearly understand that the authors first determined the importance of ILC2 in fibrotic tissues, and then sought out the reason: the low IL10 production caused by TGF-β stimulation. Finally, they conducted relevent cell and animal experiments and draw the final conclusion. However, from the conclusion of the article, it is the reduction of IL10 that leads to the progression of fibrosis? It makes us confused because ILC2 is not the main cell producing IL10. As we all known, IL10 is a cytokine of multi-cell origin and almost all immune cells can synthesize IL102. Meanwhile, despite its relative increase in fibrotic tissues, the numberof Innate lymphoid cells is very rare3. With the diversification of IL10 sources, is the low IL10 production capacity of ILC2 the main cause of fibrosis?
In summary, we respect the original insight and contributions of the authors, and believe an in-depth study of the role of IL10 may be a new research direction.
Correspondence
Correspondence on ‘Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain’ by Rahman et al
Young Ho Lee, Gwan Gyu Song
Department of Rheumatology, Korea University College of Medicine, Seoul, Korea
Corresponding author:
Young Ho Lee, MD, PhD
Department of Rheumatology
Korea University Anam Hospital, Korea University College of Medicine
73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Korea
Tel: 822-920-5645, Fax: 822-922-5974, E-mail: lyhcgh@korea.ac.kr
Acknowledgements
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors have no financial or non-financial conflict of interest to declare.
We have read with great interest the genome-wide association study (GWAS) on candidate genes for chronic widespread pain (CWP) described by Rahman and colleagues.1 This GWAS meta-analysis has shown a new association of the RNF123 locus and suggested a link of the ATP2C1 locus with CWP; however, the association between COMT locus and CWP was not replicated. Although the results were quite helpful for understanding the genetic basis of CWP, several methodological issues need to be addressed.
Show MoreTo begin with, both CWP and fibromyalgia appear to be a part of a pain continuum in the ge...
Dear editor:
We read with great interest the recent article titled ‘‘Tenascin-C-mediated suppression of extracellular matrix adhesion force promotes entheseal new bone formation through activation of Hippo signalling in ankylosing spondylitis’’ by Dr. Li and colleagues1. Authors proposed that excessive Tenascin-C (TNC) deposition at chronic inflammation entheseal site promotes pathological bone formation in ankylosing spondylitis (AS). Suppression of this aberrant pathway may have therapeutic effects in AS. This study provides valuable and innovative results, but some concerns should be taken into account.
First, the pathophysiological roles of human leukocyte antigen-B27 (HLA-B27)-mediated activation in AS has not been discussed in the study. HLA-B27 was known as a pivotal genetic predisposing factor in AS through the activation of the interleukin (IL)-17/IL-23 axis. By alternating the balance of IL-17- and IL-22-producing cells,2 3 the disruption of the gut microbiome or invasion by pathogenic bacteria might lead to inflammatory or immune-mediated diseases. The misfolding of HLA-B27 mediates the stromal activation in the pathogenesis of syndesmophyte formation of ankylosing spines via upregulating the phosphorylated -inositol-requiring 1 (IRE1)/spliced X-box–binding protein 1 (sXBP1)/retinoic acid receptor-β (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) pathway.4 The enhanced expression of TNAP is a significant factor of abnormal mineralization, and...
Show MoreDear Authors, can you explain why the conclusion states "This interim analysis revealed a greater number of pts receiving APR (66%) who completed the 12-mo follow-up achieved REM or LDA, as measured by cDAPSA over 12 mos" but in the second pannel of the Figure the data for patients reaching REM/LDA cDAPSA at 12mos is 50%? Thank you.
We read with interest the article of Imke Redeker et al.1 The article not only has included large quantity of patients but also performed sensitivity analysis and subgroup analysis of. Authors concluded that glucocorticoids and JAK inhibitors were associated with risk of herpes zoster (HZ) in rheumatoid arthritis (RA) patients. However, there are some concerns that required to be taken into account in order to make the study more comprehensive.
Show MoreFirst of all, the dosage or exposure duration of disease-modifying antirheumatic drugs treatments (DMARDs) has barely mentioned in this study. We know that the purpose of the study might simply be intent to focus on the connection between medicine exposure and the outcome of HZ. Nevertheless, it’s our opinion that dose response relationship should be analyzed to show dose-dependent effect.
Second, drug-drug interaction is an important issue on all treatment. There’s already some evidence showing certain drugs that may interact with DMARDs. In this research, CYP3A4 inhibitor together with CYP2C19 have been discussed to have a cross action with JAK inhibitors.2 Drugs may change the original medicinal effect proposed to be and thus interfere with the result we get. What’s more, apart from glucocorticoids and methotrexate mentioned in article, we suggest that more kinds of common immunosuppressants should be considered. Especially for RA patients, immunosuppressants such as cyclosporine, leflunomide and mycophenolate...
Dear authors,
Great article on an evolving area with very limited published evidence.
I note in supplementary appendix 1 that there is no IQ range quoted for the "time from last RTX dose to first vaccination" for the Spike antibody positive (n=17) group.
It would be helpful if you could include this data, as it would give some guidance as to minimum timeframe to wait post rituximab before giving vaccination. Also including absolute minimum and maximum time in days for the "time from last RTX dose to first vaccination" for all 3 categories (total, spike AB+ and spike AB- would be useful)
Regards
Dr Richard Germann
Nephrologist
Tauranga
New Zealand.
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