Dear Authors,
We have read “Definition of rheumatoid arthritis flare based on SDAI and CDAI” by “Konzett V. et al.” with great interest.[1] This article defined the “flare” as the number of disease activity score changes calculated from two large cohort datasets. The definition presented a clear division of disease activity, functional capacities, patient-oriented outcomes, and joint deformity progression after the flare.
We have made another flare definition and evaluated the validity of the definition using our small cohort dataset. Patients with rheumatoid arthritis (RA) who met the 2010 EULAR/ACR classification criteria [2] and followed up for more than three consecutive years were recruited. The flare was defined as a change of disease activity score represented by simplified disease activity index (SDAI) and clinical disease activity index (CDAI) corresponding to the shift in functional capacities represented with Health Assessment Questionnaire Disability Index (HAQ) no less than 0.125 compared to three months ago was calculated using a receiver operating characteristic analysis (ROC). Changes of components of the SDAI and CDAI score, HAQ score, patient’s pain score and fatigue score using a visual analog scale (PS-VAS and Fatigue-VAS), quality of life score calculated with EuroQol-5th dimensions -5L (QOLS) from 3 months before, and change of annual joint deformity progress represented with modified Sharp/van der Heijde score (dTSS) from before to afte...
Dear Authors,
We have read “Definition of rheumatoid arthritis flare based on SDAI and CDAI” by “Konzett V. et al.” with great interest.[1] This article defined the “flare” as the number of disease activity score changes calculated from two large cohort datasets. The definition presented a clear division of disease activity, functional capacities, patient-oriented outcomes, and joint deformity progression after the flare.
We have made another flare definition and evaluated the validity of the definition using our small cohort dataset. Patients with rheumatoid arthritis (RA) who met the 2010 EULAR/ACR classification criteria [2] and followed up for more than three consecutive years were recruited. The flare was defined as a change of disease activity score represented by simplified disease activity index (SDAI) and clinical disease activity index (CDAI) corresponding to the shift in functional capacities represented with Health Assessment Questionnaire Disability Index (HAQ) no less than 0.125 compared to three months ago was calculated using a receiver operating characteristic analysis (ROC). Changes of components of the SDAI and CDAI score, HAQ score, patient’s pain score and fatigue score using a visual analog scale (PS-VAS and Fatigue-VAS), quality of life score calculated with EuroQol-5th dimensions -5L (QOLS) from 3 months before, and change of annual joint deformity progress represented with modified Sharp/van der Heijde score (dTSS) from before to after were calculated. The values in the flare-recognized group (G-Flare) at the flare were compared to those that recognized no flare (G-nonFlare) at the time of the maximum SDAI or CDAI score value using ANOVA T-tests.
Surprisingly, the cutoff index of the SDAI score was > 4.63, and the CDAI score was > 4.48 with 0.794 and 0.765 of the area under the curve; these values were very close to the definition presented in the article.[1] Therefore, the flare was divided according to the same criteria defined in the article, a total of 634 patients, whom 432 of G-Flare and 202 of G-nonFlare on SDAI-based criteria, or 433 of G-Flare and 201 of G-nonFlare on CDAI-based criteria were included. All components of SDAI/CDAI, PS-VAS, modified total Sharp score (mTSS), and methotrexate/biological or targeted-synthetic disease-modifying anti-rheumatic drug administration rate at baseline were significantly higher in the G-Flare than in the G-nonFlare on whichever based criteria. The changes of all components of CDAI, dTSS, PS-VAS, Fatigue-VAS, and HAQ score were significantly greater, and QOLS was significantly lower in the G-Flare compared to the G-nonFlare group on whichever based criteria.
The G-flare group was classified by the treating protocol change after the flare, such as biological or targeted synthetic disease-modifying anti-rheumatic drug addition or switch. The change of SDAI or CDAI score on each based criteria every other three months, and the latest observation was picked up and compared between groups divided whether protocol change was done (G-cProtocol and G-sProtocol). Results revealed the disease activity in the G-cProtocol was significantly reduced on whichever based criteria, whereas no significant reduction was shown in the G-sProtocol. We examined the HAQ score in the same test manner; however, a significant decrease of the HAQ score in the G-cProtocol than in the G-sProtocol was presented only in the latest observation.
The association between flare rate and an annual increase in TSS was examined using linear regression analysis. However, no significant correlation was shown.
The definition of flare proposes a timing for re-constructing the treating protocol. Flare tends to be a more severe disease status leading to a deterioration of quality of life; therefore, once a patient recognizes flare, we should suggest protocol change. The definition of the flare in the article gives an important key.
References
1. Konzett V, Kerschbaumer A, Smolen JS, et al. Definition of rheumatoid arthritis flare based on SDAI and CDAI. Ann Rheum Dis 2024;83:169-76.
2. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.
I read the report by Zonozoi et al. with great interest (1). It is of particular importance to note that while the intent of this trial was to compare biomarker-driven strategies for maintenance of remission in ANCA-associated vasculitis, the design of the trial resulted in a much different outcome. Given the result that more than seven times as much rituximab was given to patients in the B-cell biomarker arm relative to the autoantibody biomarker arm, the practical and main result of this trial is a comparison of continuing or discontinuing rituximab after ~2 years of remission on rituximab. Since the MAINRITSAN3 trial has shown that discontinuing rituximab after ~2 years of remission has a large impact on relapse rates, a trial that effectively compares biomarkers would need to have similar amounts of rituximab in each arm in order to prevent the result from being dominated by excess or lack of rituximab (2). In concordance, the results of the current trial are nearly identical to those of MAINRITSAN3, with a 4% relapse rate in the heavily treated arms of both trials, and 21% and 26% relapse rate with little or no treatment, respectively. As it turns out, since doses of rituximab were 1000 mg in the current trial and 500 mg in MAINRITSAN3, the total dose of rituximab during the maintenance phase of the heavily treated arms were almost identical for both trials as well.
In this study, only a minority of clinical relapses (no more than 6 of 20 patients with potent...
I read the report by Zonozoi et al. with great interest (1). It is of particular importance to note that while the intent of this trial was to compare biomarker-driven strategies for maintenance of remission in ANCA-associated vasculitis, the design of the trial resulted in a much different outcome. Given the result that more than seven times as much rituximab was given to patients in the B-cell biomarker arm relative to the autoantibody biomarker arm, the practical and main result of this trial is a comparison of continuing or discontinuing rituximab after ~2 years of remission on rituximab. Since the MAINRITSAN3 trial has shown that discontinuing rituximab after ~2 years of remission has a large impact on relapse rates, a trial that effectively compares biomarkers would need to have similar amounts of rituximab in each arm in order to prevent the result from being dominated by excess or lack of rituximab (2). In concordance, the results of the current trial are nearly identical to those of MAINRITSAN3, with a 4% relapse rate in the heavily treated arms of both trials, and 21% and 26% relapse rate with little or no treatment, respectively. As it turns out, since doses of rituximab were 1000 mg in the current trial and 500 mg in MAINRITSAN3, the total dose of rituximab during the maintenance phase of the heavily treated arms were almost identical for both trials as well.
In this study, only a minority of clinical relapses (no more than 6 of 20 patients with potential relapse; assuming the six who did receive rituximab would have otherwise relapsed) were detected in advance by serological relapse, as indicated by a four- or five-fold increase in ANCA level. Boomsma et al. has shown that low antibody titers had much better sensitivity for predicting relapse without significant loss of specificity (3). A look back at data from the current study may provide insight into whether a lower threshold for an increase in ANCA level might be useful to predict relapses in time for effective intervention.
References:
1. Zonozi R, Cortazar FB, Jeyabalan A, et al. Maintenance of remission of ANCA vasculitis by rituximab based on B cell repopulation versus serological flare: a randomised trial. Ann Rheum Dis 2024;83:351-359. doi: 10.1136/ard-2023-224489
2. Charles P, Perrodeau É, Samson M, et al. Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Trial. Ann Intern Med 2020;173:179-187. doi: 10.7326/M19-3827
3. Boomsma MM, Stegeman CA, Van Der Leij MJ, et al. Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis & Rheumatism 2000;43:2025–33. doi: 10.1002/1529-0131(200009)43:9<2025::AID-ANR13>3.0.CO;2-O.
With regard to the article on ‘2023 ACR/EULAR antiphospholipid syndrome classification criteria’ by ‘Medha et al’, we believe that it contains substantial inadequacies in the obstetric domain, which weakens the application of this guideline in the antiphospholipid syndrome classification.
Firstly, on the clinical criteria obstetric domain, the classification arbitrarily divides fetal death into two categories------pregnancy loss between 10 weeks 0 days and 15 weeks 6 days gestation (early fetal death), or between 16 weeks 0 days and 34 weeks 0 days gestation, which has no support from previous consensus to set 16 weeks as a cutoff point1,2. In addition, since the author bestow the same weigh on these two categories, makes the dividing line even more unnecessary. And on top of that, in terms of fetal death, the classification slights to take pregnancy loss beyond 34 weeks of gestation into account. In our dataset of the past 7 years, the incidence of pregnancy loss beyond 34 gestational weeks in all diagnosed obstetric antiphospholipid syndrome associated fetal loss cases is 4.3% (3/70). Also, it is in accordance with other datasets in which include fetal loss beyond 34 gestational weeks as bona fide OAPS patients3. Hence, this particular classification serves no purpose in increasing its specificity, while jeopardizing its sensitivity.
Secondly, the preeclampsia with severe features column fails to include placental abruption4, heart failure5 and He...
With regard to the article on ‘2023 ACR/EULAR antiphospholipid syndrome classification criteria’ by ‘Medha et al’, we believe that it contains substantial inadequacies in the obstetric domain, which weakens the application of this guideline in the antiphospholipid syndrome classification.
Firstly, on the clinical criteria obstetric domain, the classification arbitrarily divides fetal death into two categories------pregnancy loss between 10 weeks 0 days and 15 weeks 6 days gestation (early fetal death), or between 16 weeks 0 days and 34 weeks 0 days gestation, which has no support from previous consensus to set 16 weeks as a cutoff point1,2. In addition, since the author bestow the same weigh on these two categories, makes the dividing line even more unnecessary. And on top of that, in terms of fetal death, the classification slights to take pregnancy loss beyond 34 weeks of gestation into account. In our dataset of the past 7 years, the incidence of pregnancy loss beyond 34 gestational weeks in all diagnosed obstetric antiphospholipid syndrome associated fetal loss cases is 4.3% (3/70). Also, it is in accordance with other datasets in which include fetal loss beyond 34 gestational weeks as bona fide OAPS patients3. Hence, this particular classification serves no purpose in increasing its specificity, while jeopardizing its sensitivity.
Secondly, the preeclampsia with severe features column fails to include placental abruption4, heart failure5 and Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome6 as severe complications in line with other features like pulmonary oedema. Take placental abruption as an example, it has been reported to be a severe feature for OAPS7,8. Also, it is a consensus that eclampsia is a vital manifestation of placental insufficiency1,9, but this article leaves it out in the obstetric domain.
Lastly, the definition of fetal growth restriction (FGR) is mixed up with that of small for gestational age (SGA). FGR is a pathologic condition in which the fetus fails to reach its biologically based growth potential, while SGA a physiological condition in which infants with birthweights less than 10th percentile for gestational age10. This equivocation could undermine the fidelity and specificity of this classification.
Contributors Concept and writing: CZ, TC and XF. Revising: XF.
Competing interests: None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval This study was approved by the Ethics Committee of West China Second University Hospital.
REFERENCES:
1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of Thrombosis and Haemostasis. 2006 Feb;4(2):295–306.
2. Silver RM. Fetal Death. Obstetrics & Gynecology. 2007 Jan;109(1):153–67.
3. Belhocine M, Coutte L, Martin Silva N, Morel N, Guettrot-Imbert G, Paule R, et al. Intrauterine fetal deaths related to antiphospholipid syndrome: a descriptive study of 65 women. Arthritis Research & Therapy. 2018 Nov 6;20(1).
4. Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G, Mercier E, Marchetti T, Balducchi JP ., et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood. 2013 Nov 7;123(3):404–13.
5. Atsushi S, Hiroshi S, Yasuyuki T, Chikara M Hidenori Y, Seibu M, et al. [Peripartum cardiomyopathy with antiphospholipid antibody: a case report]. J Cardiol. 2006 May; 47(5): 261-6.
6. Clark CA, Davidovits J, Spitzer KA, Laskin CA. The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic. Blood [Internet]. 2013 Jul 18 [cited 2023 Apr 9];122(3):341–7; quiz 466.
7. Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, Sáez-Comet L, Lefkou E, Mekinian A, et al. Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry. Rheumatology. 2019 Oct 3;
8. Soh MC, Pasupathy D, Gray G, Nelson-Piercy C. Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes. Rheumatology. 2013 May 16;52(9):1642–7.
9. Wang Y, Niu J, Wang J, Ye R, Zhao Y. Patient with antiphospholipid syndrome accompanied by pre-eclampsia who developed hellp syndrome and eclampsia after abortion. Chinese Medical Journal [Internet]. 2012 Nov 1 [cited 2024 Feb 22];125(22):4142
10. ACOG Practice Bulletin No. 204. Obstetrics & Gynecology. 2019 Feb;133(2):e97–109.
Dear Editors:
We read with interest the article by Moulin et al. entitled ‘Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis’.1 Alterations in tryptophan (Trp) metabolism have been documented in the context of rheumatoid arthritis (RA). The aim of this study was to ascertain whether these alterations contribute to the development of RA and can be regarded as potential therapeutic targets. Based on the authors' findings, both preclinical and clinical data suggest that modifications in Trp metabolism actively contribute to the pathogenesis of RA and may represent a novel therapeutic approach.
Following a comprehensive analysis of the article, we have identified an error that requires further investigation and rectification. According to the data presented in Table 1, it is apparent that within the ESPOIR cohort, 45 individuals (77.5%) out of the 574 patients are identified as female. However, it is imperative to acknowledge that the accurate representation should indicate that a total of 445 individuals (77.5%) out of the 574 patients are indeed female.
Nevertheless, we would like to express our gratitude to the authors for shedding light on the involvement of Trp metabolism alterations in the pathogenesis of RA and proposing it as a potential novel therapeutic avenue.
Reference
1. Moulin D, Millard M, Taïeb M, et al. Counteracting tryptophan metabolism alterations as a new therapeutic s...
Dear Editors:
We read with interest the article by Moulin et al. entitled ‘Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis’.1 Alterations in tryptophan (Trp) metabolism have been documented in the context of rheumatoid arthritis (RA). The aim of this study was to ascertain whether these alterations contribute to the development of RA and can be regarded as potential therapeutic targets. Based on the authors' findings, both preclinical and clinical data suggest that modifications in Trp metabolism actively contribute to the pathogenesis of RA and may represent a novel therapeutic approach.
Following a comprehensive analysis of the article, we have identified an error that requires further investigation and rectification. According to the data presented in Table 1, it is apparent that within the ESPOIR cohort, 45 individuals (77.5%) out of the 574 patients are identified as female. However, it is imperative to acknowledge that the accurate representation should indicate that a total of 445 individuals (77.5%) out of the 574 patients are indeed female.
Nevertheless, we would like to express our gratitude to the authors for shedding light on the involvement of Trp metabolism alterations in the pathogenesis of RA and proposing it as a potential novel therapeutic avenue.
Reference
1. Moulin D, Millard M, Taïeb M, et al. Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis. Ann Rheum Dis 2023;Epub ahead of print.
We read with great interest the study by Zonozi and colleagues, which presented the outcomes of a randomized trial comparing rituximab dosing strategies for maintaining remission in ANCA vasculitis [1]. The study proposed that rituximab dosed for B-cell repopulation results in fewer clinical relapses than when dosed for a rise in ANCA level. While acknowledging the valuable contribution of this study, we would like to express a few concerns related to methodology.
First, the authors chose to evaluate B-cell repopulation by assessing CD20-positive B-cell levels in peripheral blood. This deviation from the conventional approach of assessing CD19-positive B-cell levels, as seen in prior studies [2,3], prompts inquiries about the reasoning behind selecting CD20 as a marker for repopulation. This is particularly important considering its role in the rituximab dosing strategy within the B-cell arm.
Second, the study design suggests a dosage of 1gm in the B-cell arm for B-cell repopulation and 2gm, typically a remission induction dose in the ANCA arm, for serological flare. This differs from the usual practise of 500mg observed in MAINRITSAN2 and MAINRITSAN3 trials for maintenance of remission, and it would be beneficial to understand the reasoning behind this choice within the context of this study [2,3].
Third, a study by Thiel and colleagues demonstrated a significantly prolonged duration of B-cell depletion following rituximab treatmen...
We read with great interest the study by Zonozi and colleagues, which presented the outcomes of a randomized trial comparing rituximab dosing strategies for maintaining remission in ANCA vasculitis [1]. The study proposed that rituximab dosed for B-cell repopulation results in fewer clinical relapses than when dosed for a rise in ANCA level. While acknowledging the valuable contribution of this study, we would like to express a few concerns related to methodology.
First, the authors chose to evaluate B-cell repopulation by assessing CD20-positive B-cell levels in peripheral blood. This deviation from the conventional approach of assessing CD19-positive B-cell levels, as seen in prior studies [2,3], prompts inquiries about the reasoning behind selecting CD20 as a marker for repopulation. This is particularly important considering its role in the rituximab dosing strategy within the B-cell arm.
Second, the study design suggests a dosage of 1gm in the B-cell arm for B-cell repopulation and 2gm, typically a remission induction dose in the ANCA arm, for serological flare. This differs from the usual practise of 500mg observed in MAINRITSAN2 and MAINRITSAN3 trials for maintenance of remission, and it would be beneficial to understand the reasoning behind this choice within the context of this study [2,3].
Third, a study by Thiel and colleagues demonstrated a significantly prolonged duration of B-cell depletion following rituximab treatment in ANCA vasculitis, specifically around 21 months in GPA/MPA compared to rheumatoid arthritis and connective tissue diseases, as measured by CD19 positive B-cells [4]. This contrasts with the current study's findings, where the median time to B-cell repopulation was reported as 9.44 months using CD20-positive B-cells measured every 3 months. This approach resulted in a higher mean cumulative dose of 3.6gm per person in the B-cell arm compared to a mean of 0.5gm per person in the ANCA arm. Considering these differences, whether the lower relapse rate observed in the B-cell arm could be attributed to the higher cumulative dose?
Moreover, study conducted by Delestre et al. indicated that the extension of rituximab maintenance to 36 months did not demonstrate a reduction in the relapse rate when compared to an 18-month fixed rituximab regimen [5]. This observation was derived from a pooled analysis of the MAINRITSAN2 and MAINRITSAN3 trials [2,3].
Given these findings, it prompts consideration of whether this study design could be deemed applicable for patients who have undergone 18 months of fixed rituximab maintenance and we agree with the authors, that further exploration is required for an effective and safe remission maintenance strategy.
Conflict of Interest: None
References:
1. Zonozi R, Cortazar FB, Jeyabalan A, Sauvage G, Nithagon P, Huizenga NR, Rosenthal JM, Sipilief A, Cosgrove K, Laliberte KA, Rhee EP, Pendergraft WF 3rd, Niles JL. Maintenance of remission of ANCA vasculitis by rituximab based on B cell repopulation versus serological flare: a randomised trial. Ann Rheum Dis. 2023, PMID: 38123922
2. Charles P, Terrier B, Perrodeau É, Cohen P, Faguer S, Huart A, et al. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis. 2018 ;77(8):1143–9
3. Charles P, Perrodeau É, Samson M, Bonnotte B, Néel A, Agard C, et al. Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Trial. Ann Intern Med. 2020 ;173(3):179–87
4. Thiel J, Rizzi M, Engesser M, Dufner AK, Troilo A, Lorenzetti R, et al. B-cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. Arthritis Res Ther. 2017 ;19(1):101
5. Delestre F, Charles P, Karras A, Pagnoux C, Néel A, Cohen P, et al. Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials. Ann Rheum Dis. 2024 ;83(2):233–41
We read the article “Maintenance of remission of ANCA vasculitis by rituximab based on B cell repopulation versus serological flare: a randomised trial” with interest as we believe that this may cause a paradigm shift in the way that these patients are managed. However, as Immunologists, we have some reservations with regards to the impact that these changes may have.
The authors report administering much higher doses of rituximab to patients enrolled in the B cell arm of the study, compared to the ANCA arm (mean 3.6g vs 0.5g per person), and the decision to re-introduce rituximab was based on a very low cutoff of ≥10 cells/mm3 (=0.01 x109/L; local reference range >0.1 x109/L). As such, we would expect a much more pronounced immunosuppressive effect in those patients and, not surprisingly, a higher rate of serious infectious adverse events were reported in the B cell arm. More importantly, 2 patient deaths due to COVID-19 were noted in this group, while none in the ANCA arm.
Several similar cases of persistent or fatal COVID-19 infection in patients treated with rituximab have been reported in the literature[1,2]. Severe infectious sequalae due to multiple other viruses have also been reported, including hepatitis B, VZV, CMV, enterovirus, adenovirus, JC virus, BK virus, HPV, HSV and others[3]. A similar pattern emerges in patients with absent B cells due to any other cause, which suggests a key role for peripheral B cells in their development[4].
We read the article “Maintenance of remission of ANCA vasculitis by rituximab based on B cell repopulation versus serological flare: a randomised trial” with interest as we believe that this may cause a paradigm shift in the way that these patients are managed. However, as Immunologists, we have some reservations with regards to the impact that these changes may have.
The authors report administering much higher doses of rituximab to patients enrolled in the B cell arm of the study, compared to the ANCA arm (mean 3.6g vs 0.5g per person), and the decision to re-introduce rituximab was based on a very low cutoff of ≥10 cells/mm3 (=0.01 x109/L; local reference range >0.1 x109/L). As such, we would expect a much more pronounced immunosuppressive effect in those patients and, not surprisingly, a higher rate of serious infectious adverse events were reported in the B cell arm. More importantly, 2 patient deaths due to COVID-19 were noted in this group, while none in the ANCA arm.
Several similar cases of persistent or fatal COVID-19 infection in patients treated with rituximab have been reported in the literature[1,2]. Severe infectious sequalae due to multiple other viruses have also been reported, including hepatitis B, VZV, CMV, enterovirus, adenovirus, JC virus, BK virus, HPV, HSV and others[3]. A similar pattern emerges in patients with absent B cells due to any other cause, which suggests a key role for peripheral B cells in their development[4].
In this study data on the time to B cell repopulation (≥10 cells/mm3) after rituximab are only given for all patients (9.44 months). However, our and others’ experience is that this can take much longer and that patients can end up requiring lifelong immunoglobulin replacement[5,6].
Patients were reported to have stable serum IgG in the B cell arm of this study, but this was improved
in the ANCA arm. However previous studies have identified that up to 38.54% of patients can have hypogammaglobulinaemia post rituximab use[7], and that this is persistent in a significant proportion[8,9]. Even in patients that retain normal IgG levels, poor responses to vaccination may remain due to low peripheral B cell numbers.
We would recommend, as a minimum, to carefully monitor the infection history and the immunoglobulin levels of patients that receive this treatment, in order to prevent these problems.
References
1 Choi B, Choudhary MC, Regan J, et al. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. New England Journal of Medicine. 2020;383:2291–3.
2 Furlan A, Forner G, Cipriani L, et al. COVID-19 in B Cell-Depleted Patients After Rituximab: A Diagnostic and Therapeutic Challenge. Front Immunol. 2021;12:763412.
3 Grammatikos A, Donati M, Johnston SL, et al. Peripheral B Cell Deficiency and Predisposition to Viral Infections: The Paradigm of Immune Deficiencies . Frontiers in Immunology . 2021;12:3454. https://www.frontiersin.org/article/10.3389/fimmu.2021.731643
4 Grammatikos A, Moghaddas F, Reeve H, et al. Low circulating B cells in immunocompromised individuals are linked to poorer antibody responses to vaccines and a predisposition to viral infections. Journal of Allergy and Clinical Immunology: Global. Published Online First: 22 September 2022. doi: 10.1016/J.JACIG.2022.07.008
5 Patel PD, Rubinstein A. B Cell Reconstitution Following Rituximab in Autoimmune Disorders. Journal of Allergy and Clinical Immunology. 2012;129:AB215.
6 Sarantopoulos S, Stevenson KE, Kim HT, et al. Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood. 2011;117:2275.
7 Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk. 2013;13:106–11.
8 Makatsori M, Kiani-Alikhan S, Manson AL, et al. Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. QJM. 2014;107:821–8.
9 Labrosse R, Barmettler S, Derfalvi B, et al. Rituximab-induced hypogammaglobulinemia and infection risk in pediatric patients. J Allergy Clin Immunol. 2021;148:523-532.e8.
The authors report that AS is associated with an increased mortality, more so among the females (1). Their observations further strengthen the recent understanding that women are not so lucky (2) after all, when they acquire AS. However, we would like to point out to a neglected point in the current report, an issue related to the proposed sex differences in the risk of death.
The mean age of entry of AS patients into this work was 44 years. On the other hand, we know that AS usually starts well before age 30 and according to one study, at a median age of 25 for males and 28 for females (3). Thus, most of the patients in the current report had AS years before entering this study. Therefore, the current report really concerns the fate of AS patients after quite a number of years of disease duration. A previous study about mortality in AS had shown that males and females had a similar survival after disease onset for about a decade after which the decrease in male survival became apparent. On the other hand, it took 35 years from disease onset when the female survival began to decrease (4). It follows that the design of the current work does not allow us to assess the survival of AS from the time of disease onset.
Finally, we surely agree with the authors that more work is needed to assess the proposed increased mortality among women with AS.
Dear Editor,
I am writing to draw your attention to the profound implications of the article by Baraliakos et al. (1). This study is a beacon of hope for individuals living with axial spondyloarthritis (axSpA) and underscores the potential of Bimekizumab (BKZ) as a transformative treatment.
The study's findings reveal that BKZ, a monoclonal antibody inhibiting interleukin (IL)-17A and IL-17F, has exhibited unparalleled efficacy in patients with both non-radiographic (nr-) and radiographic (r-) axSpA. These results are not just promising; they are monumental. The study demonstrates that improvements achieved with BKZ at Week 16 persist to Week 52. Key metrics, including Assessment of SpondyloArthritis International Society ≥40% response, Ankylosing Spondylitis Disease Activity Score, high-sensitivity C-reactive protein levels, and MRI inflammation of the sacroiliac joints/spine, continued to improve in patients who received BKZ.
Of equal significance is the fact that patients who transitioned from a placebo to BKZ at Week 16 experienced comparable results to those who received BKZ from the outset. This underlines the sustained efficacy of BKZ and its potential to improve the quality of life for axSpA patients. Furthermore, BKZ demonstrated the ability to reduce objective measures of inflammation, such as MRI scores and hs-CRP levels, consistently across treatment groups. These reductions correlate with improvements in patient-reported outcomes, includ...
Dear Editor,
I am writing to draw your attention to the profound implications of the article by Baraliakos et al. (1). This study is a beacon of hope for individuals living with axial spondyloarthritis (axSpA) and underscores the potential of Bimekizumab (BKZ) as a transformative treatment.
The study's findings reveal that BKZ, a monoclonal antibody inhibiting interleukin (IL)-17A and IL-17F, has exhibited unparalleled efficacy in patients with both non-radiographic (nr-) and radiographic (r-) axSpA. These results are not just promising; they are monumental. The study demonstrates that improvements achieved with BKZ at Week 16 persist to Week 52. Key metrics, including Assessment of SpondyloArthritis International Society ≥40% response, Ankylosing Spondylitis Disease Activity Score, high-sensitivity C-reactive protein levels, and MRI inflammation of the sacroiliac joints/spine, continued to improve in patients who received BKZ.
Of equal significance is the fact that patients who transitioned from a placebo to BKZ at Week 16 experienced comparable results to those who received BKZ from the outset. This underlines the sustained efficacy of BKZ and its potential to improve the quality of life for axSpA patients. Furthermore, BKZ demonstrated the ability to reduce objective measures of inflammation, such as MRI scores and hs-CRP levels, consistently across treatment groups. These reductions correlate with improvements in patient-reported outcomes, including pain, morning stiffness, fatigue, and physical function. The impact of BKZ extends to peripheral manifestations of axSpA, with many patients achieving resolution of enthesitis and peripheral arthritis.
What is particularly striking is the consistency of the ASAS40 responses in patients with radiographic axSpA (r-axSpA), irrespective of prior exposure to TNF inhibitors (TNFi). This observation aligns with findings from phase 3 studies in patients with psoriatic arthritis. While there were variations in TNFi subgroups in patients with non-radiographic axSpA (nr-axSpA), the data from preclinical and clinical studies strongly suggest the importance of IL-17F in spondyloarthritis pathogenesis. This dual inhibition of IL-17A and IL-17F offers a promising avenue for research and further head-to-head studies comparing BKZ to IL-17Ai alone.
The article also highlights the favorable safety profile of BKZ over 52 weeks, consistent with previous evidence in axSpA and psoriatic arthritis studies. Notably, while fungal infections, especially oral candidiasis, were more common in the BKZ group compared to the placebo group, they were predominantly mild or moderate and did not result in treatment discontinuation. Furthermore, the incidence of inflammatory bowel disease (IBD) was similar to that observed in studies of IL-17Ai alone, offering a reassuring perspective on the potential effect of dual IL-17A and IL-17F inhibition on IBD rates in axSpA. Uveitis, a common extra-musculoskeletal manifestation of axSpA, was notably lower in BKZ-treated patients compared to those receiving a placebo.
In conclusion, the 52-week results of the BE MOBILE studies represent a significant stride in understanding the potential of BKZ in axSpA treatment. These findings hold the promise of transforming the lives of those affected by this challenging condition. As we eagerly await the 3-year and upcoming 5-year results from the BE AGILE study, we anticipate even deeper insights into the long-term safety and efficacy of BKZ. This research signals hope for the future of axSpA treatment, providing patients and healthcare professionals alike with renewed optimism.
Reference:
1. Baraliakos X, Deodhar A, van der Heijde D, et alBimekizumab treatment in patients with active axial spondyloarthritis: 52-week efficacy and safety from the randomised parallel phase 3 BE MOBILE 1 and BE MOBILE 2 studiesAnnals of the Rheumatic Diseases Published Online First: 04 October 2023.
We read with great interest the pooled analysis of the MAINRITSAN trials and believe that certain study conclusions and inferences warrant further discussion and clarification (1).
Since the MAINRITSAN trials represent the largest body of Class I evidence regarding rituximab maintenance in AAV, any inference drawn from them needs to be carefully worded since it is likely to be translated into clinical practice as standard-of-care with immediate effect. In this light, we believe that the authors’ conclusion that “extending RTX to 36 months does not appear to reduce the long- term relapse rate compared with 18 months of fixed- dose RTX and should probably only be considered in patients at high risk of relapse” should be a bit guarded for the following reasons.
As pointed out previously by us after the publication of MAINRITSAN-3, ANCA-associated vasculitides warrant long-term maintenance therapy with rituximab (at least for 4 years as opined by the MAINRITSAN-3 authors in response) (2,3). However, the conclusions of the current pooled analysis seem rather contradictory and in fact, counterintuitive. A closer look at the Kaplan-Meier survival curve for overall relapses (Figure 2B of the pooled analysis) shows that the plot of the 36-month fixed/fixed RTX seems to clearly diverge from the other groups including the 18-month fixed RTX after month 30 (when the effect of the last dose of RTX is expected to have worn off), a fact which is reinforced by the obtained...
We read with great interest the pooled analysis of the MAINRITSAN trials and believe that certain study conclusions and inferences warrant further discussion and clarification (1).
Since the MAINRITSAN trials represent the largest body of Class I evidence regarding rituximab maintenance in AAV, any inference drawn from them needs to be carefully worded since it is likely to be translated into clinical practice as standard-of-care with immediate effect. In this light, we believe that the authors’ conclusion that “extending RTX to 36 months does not appear to reduce the long- term relapse rate compared with 18 months of fixed- dose RTX and should probably only be considered in patients at high risk of relapse” should be a bit guarded for the following reasons.
As pointed out previously by us after the publication of MAINRITSAN-3, ANCA-associated vasculitides warrant long-term maintenance therapy with rituximab (at least for 4 years as opined by the MAINRITSAN-3 authors in response) (2,3). However, the conclusions of the current pooled analysis seem rather contradictory and in fact, counterintuitive. A closer look at the Kaplan-Meier survival curve for overall relapses (Figure 2B of the pooled analysis) shows that the plot of the 36-month fixed/fixed RTX seems to clearly diverge from the other groups including the 18-month fixed RTX after month 30 (when the effect of the last dose of RTX is expected to have worn off), a fact which is reinforced by the obtained pooled hazard ratio of 0.69, although statistical significance could not be achieved due to less patient numbers per group since the studies were not powered to detect this difference (1).
In the discussion, the authors try to explain the apparent discrepancy with the results of MAINRITSAN-3 as being due to the placebo group of MAINRITSAN-3 being selectively enriched with patients receiving individually tailored RTX in MAINRITSAN-2; however, the proportion of such patients was equally distributed in the two arms (placebo and extended RTX) of MAINRITSAN-3 and thus unlikely to explain the inter-group differences observed in the trial (4). The unequivocal results of the MAINRITSAN-3 trial, the high relapse rates observed in the long-term follow up of all MAINRITSAN trials, and the numerically significant (but statistically insignificant) difference in overall relapses between 18-month and 36-month fixed rituximab maintenance in the pooled analysis without any increase in incidence of adverse events with longer use of RTX reaffirm the probable need for longer RTX maintenance in AAV rather than going against it.
The premise of pooling in this study per se is also not very clear, since it involves quite a lot of statistical modelling including cloning, weighting and controlling for immortality bias. Using cloning and weighting to decide the final group disposition of MAINRITSAN 2 patients not randomized to MAINRITSAN 3 seems rather artificial and probably unnecessary- instead, using the long-term follow-up data of these MAINRITSAN-2 patients not randomized to MAINRITSAN-3, directly as it were, would have been more informative (and less arbitrary).
That said, the jury is still out regarding the precise duration of rituximab maintenance therapy in AAV, and this pooled analysis, rather than being inferential on underpowered data, should instead serve as an impetus for urgent, adequately powered studies to guide this decision.
References
1. Delestre F, Charles P, Karras A, Pagnoux C, Néel A, Cohen P, et al. Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials. Ann Rheum Dis. 2023:ard-2023-224623. doi: 10.1136/ard-2023-224623.
2. Charles P, Guillevin L. Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Ann Intern Med. 2020;173(11):948. doi: 10.7326/L20-1199.
3. Jain S, Chattopadhyay A, Sharma A. Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Ann Intern Med. 2020;173(11):947. doi: 10.7326/L20-1197.
4. Charles P, Perrodeau É, Samson M, Bonnotte B, Néel A, Agard C, et al. Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Trial. Ann Intern Med. 2020;173(3):179-187. doi: 10.7326/M19-3827.
I am writing to express our particular interest in the article "Rheuma-VOR study: optimising healthcare of rheumatic diseases by multiprofessional coordinating centres" by Dreher et al (1), where a prospective multicenter study was conducted with the implementation of an early referral strategy that succeeded in reducing the rheumatological medical care waiting time to 6.6 months, compared to the usual reference time of 27.7 months.
It is undeniable that the delay in referring patients with suspected rheumatoid arthritis remains a challenge. In a report conducted at a second-level hospital in Mexico, we evaluated 206 referrals to the rheumatology service from the primary level of care. We found an average of 28.2 (SD 46.9) months elapsed from the onset of symptoms to rheumatological evaluation (2).
In contrast, the study by van Nies et al conducted in the Netherlands established an early referral clinic, which managed to reduce the referral time from the general practitioner to 2 weeks and the total time elapsed from the onset of symptoms to rheumatological care to 10.6 weeks. 59% (n=162) received attention within the first 12 weeks after the onset of symptoms (3).
Within the referral system at the Mexican Social Security Institute in Monterrey, Mexico, we implemented an early referral program with the aim of reducing referral times. The program was applied to patients evaluated at the primary level who presented hand arth...
I am writing to express our particular interest in the article "Rheuma-VOR study: optimising healthcare of rheumatic diseases by multiprofessional coordinating centres" by Dreher et al (1), where a prospective multicenter study was conducted with the implementation of an early referral strategy that succeeded in reducing the rheumatological medical care waiting time to 6.6 months, compared to the usual reference time of 27.7 months.
It is undeniable that the delay in referring patients with suspected rheumatoid arthritis remains a challenge. In a report conducted at a second-level hospital in Mexico, we evaluated 206 referrals to the rheumatology service from the primary level of care. We found an average of 28.2 (SD 46.9) months elapsed from the onset of symptoms to rheumatological evaluation (2).
In contrast, the study by van Nies et al conducted in the Netherlands established an early referral clinic, which managed to reduce the referral time from the general practitioner to 2 weeks and the total time elapsed from the onset of symptoms to rheumatological care to 10.6 weeks. 59% (n=162) received attention within the first 12 weeks after the onset of symptoms (3).
Within the referral system at the Mexican Social Security Institute in Monterrey, Mexico, we implemented an early referral program with the aim of reducing referral times. The program was applied to patients evaluated at the primary level who presented hand arthralgia. Subsequently, we applied an instrument based on the EULAR criteria for clinically suspected arthralgia progressing to rheumatoid arthritis. Those with a score of 4 points or more were scheduled for an appointment with a rheumatologist in the following two weeks, along with laboratory tests and hand X-rays. We compared the time elapsed from symptom onset to rheumatology consultation and the final diagnoses between patients in the early referral program vs. the usual referral.
During the period from April to October 2023, with the implementation of the early referral program, we referred 64 patients, of whom 41 (66%) passed the criteria filter mentioned. Of these patients, 97,6 % (n=40) were women with an average age of 49,9 (SD 9,4) years. In this group, 34,1 % (n=14) of the patients received a diagnosis of rheumatoid arthritis, and the time elapsed from symptom onset to consultation was 5,4 (SD 8,9) months. In the same period, 200 patients referred to rheumatology and evaluated by primary care physicians through the usual referral; only 25 (12,5%) received a diagnosis of rheumatoid arthritis. In this group, 31 (79,4 %) were women with an average age of 50,4 (SD 10,8) years. The time elapsed from symptom onset to specialized consultation was 28,5 (SD 35.07) months.
Dreher et al (1) managed to reduce secondary care time with the implementation of a multidisciplinary coordination center responsible for assessing the likelihood of rheumatic disease through questionnaires conducted by other physicians. In contrast, we directly referred to rheumatology with the implementation of screening carried out by trained personnel, eliminating the initial screening in primary care and the associated waiting times for consultation with the internist.
This work highlights the importance of implementing early referral programs in the care of patients with suspected rheumatoid arthritis, which have been shown to significantly reduce diagnosis and care times.
REFERENCES:
1. Dreher M, Witte T, Hoeper K, et alRheuma-VOR study: optimising healthcare of rheumatic diseases by multiprofessional coordinating centresAnnals of the Rheumatic Diseases Published Online First: 27 October 2023. doi: 10.1136/ard-2023-224205
2. Vega-Morales D, Covarrubias-Castañeda Y, Arana-Guajardo AC, Esquivel-Valerio JA. Time Delay to Rheumatology Consultation: Rheumatoid Arthritis Diagnostic Concordance Between Primary Care Physician and Rheumatologist. Am J Med Qual. 2016;31(6):603. doi:10.1177/1062860616646446
3. van Nies JA, Brouwer E, van Gaalen FA, et al. Improved early identification of arthritis: evaluating the efficacy of Early Arthritis Recognition Clinics. Ann Rheum Dis. 2013;72(8):1295-1301. doi:10.1136/annrheumdis-2012-202289
Dear Authors,
Show MoreWe have read “Definition of rheumatoid arthritis flare based on SDAI and CDAI” by “Konzett V. et al.” with great interest.[1] This article defined the “flare” as the number of disease activity score changes calculated from two large cohort datasets. The definition presented a clear division of disease activity, functional capacities, patient-oriented outcomes, and joint deformity progression after the flare.
We have made another flare definition and evaluated the validity of the definition using our small cohort dataset. Patients with rheumatoid arthritis (RA) who met the 2010 EULAR/ACR classification criteria [2] and followed up for more than three consecutive years were recruited. The flare was defined as a change of disease activity score represented by simplified disease activity index (SDAI) and clinical disease activity index (CDAI) corresponding to the shift in functional capacities represented with Health Assessment Questionnaire Disability Index (HAQ) no less than 0.125 compared to three months ago was calculated using a receiver operating characteristic analysis (ROC). Changes of components of the SDAI and CDAI score, HAQ score, patient’s pain score and fatigue score using a visual analog scale (PS-VAS and Fatigue-VAS), quality of life score calculated with EuroQol-5th dimensions -5L (QOLS) from 3 months before, and change of annual joint deformity progress represented with modified Sharp/van der Heijde score (dTSS) from before to afte...
I read the report by Zonozoi et al. with great interest (1). It is of particular importance to note that while the intent of this trial was to compare biomarker-driven strategies for maintenance of remission in ANCA-associated vasculitis, the design of the trial resulted in a much different outcome. Given the result that more than seven times as much rituximab was given to patients in the B-cell biomarker arm relative to the autoantibody biomarker arm, the practical and main result of this trial is a comparison of continuing or discontinuing rituximab after ~2 years of remission on rituximab. Since the MAINRITSAN3 trial has shown that discontinuing rituximab after ~2 years of remission has a large impact on relapse rates, a trial that effectively compares biomarkers would need to have similar amounts of rituximab in each arm in order to prevent the result from being dominated by excess or lack of rituximab (2). In concordance, the results of the current trial are nearly identical to those of MAINRITSAN3, with a 4% relapse rate in the heavily treated arms of both trials, and 21% and 26% relapse rate with little or no treatment, respectively. As it turns out, since doses of rituximab were 1000 mg in the current trial and 500 mg in MAINRITSAN3, the total dose of rituximab during the maintenance phase of the heavily treated arms were almost identical for both trials as well.
In this study, only a minority of clinical relapses (no more than 6 of 20 patients with potent...
Show MoreWith regard to the article on ‘2023 ACR/EULAR antiphospholipid syndrome classification criteria’ by ‘Medha et al’, we believe that it contains substantial inadequacies in the obstetric domain, which weakens the application of this guideline in the antiphospholipid syndrome classification.
Show MoreFirstly, on the clinical criteria obstetric domain, the classification arbitrarily divides fetal death into two categories------pregnancy loss between 10 weeks 0 days and 15 weeks 6 days gestation (early fetal death), or between 16 weeks 0 days and 34 weeks 0 days gestation, which has no support from previous consensus to set 16 weeks as a cutoff point1,2. In addition, since the author bestow the same weigh on these two categories, makes the dividing line even more unnecessary. And on top of that, in terms of fetal death, the classification slights to take pregnancy loss beyond 34 weeks of gestation into account. In our dataset of the past 7 years, the incidence of pregnancy loss beyond 34 gestational weeks in all diagnosed obstetric antiphospholipid syndrome associated fetal loss cases is 4.3% (3/70). Also, it is in accordance with other datasets in which include fetal loss beyond 34 gestational weeks as bona fide OAPS patients3. Hence, this particular classification serves no purpose in increasing its specificity, while jeopardizing its sensitivity.
Secondly, the preeclampsia with severe features column fails to include placental abruption4, heart failure5 and He...
Dear Editors:
We read with interest the article by Moulin et al. entitled ‘Counteracting tryptophan metabolism alterations as a new therapeutic strategy for rheumatoid arthritis’.1 Alterations in tryptophan (Trp) metabolism have been documented in the context of rheumatoid arthritis (RA). The aim of this study was to ascertain whether these alterations contribute to the development of RA and can be regarded as potential therapeutic targets. Based on the authors' findings, both preclinical and clinical data suggest that modifications in Trp metabolism actively contribute to the pathogenesis of RA and may represent a novel therapeutic approach.
Following a comprehensive analysis of the article, we have identified an error that requires further investigation and rectification. According to the data presented in Table 1, it is apparent that within the ESPOIR cohort, 45 individuals (77.5%) out of the 574 patients are identified as female. However, it is imperative to acknowledge that the accurate representation should indicate that a total of 445 individuals (77.5%) out of the 574 patients are indeed female.
Nevertheless, we would like to express our gratitude to the authors for shedding light on the involvement of Trp metabolism alterations in the pathogenesis of RA and proposing it as a potential novel therapeutic avenue.
Reference
Show More1. Moulin D, Millard M, Taïeb M, et al. Counteracting tryptophan metabolism alterations as a new therapeutic s...
Dear Editor,
We read with great interest the study by Zonozi and colleagues, which presented the outcomes of a randomized trial comparing rituximab dosing strategies for maintaining remission in ANCA vasculitis [1]. The study proposed that rituximab dosed for B-cell repopulation results in fewer clinical relapses than when dosed for a rise in ANCA level. While acknowledging the valuable contribution of this study, we would like to express a few concerns related to methodology.
First, the authors chose to evaluate B-cell repopulation by assessing CD20-positive B-cell levels in peripheral blood. This deviation from the conventional approach of assessing CD19-positive B-cell levels, as seen in prior studies [2,3], prompts inquiries about the reasoning behind selecting CD20 as a marker for repopulation. This is particularly important considering its role in the rituximab dosing strategy within the B-cell arm.
Second, the study design suggests a dosage of 1gm in the B-cell arm for B-cell repopulation and 2gm, typically a remission induction dose in the ANCA arm, for serological flare. This differs from the usual practise of 500mg observed in MAINRITSAN2 and MAINRITSAN3 trials for maintenance of remission, and it would be beneficial to understand the reasoning behind this choice within the context of this study [2,3].
Third, a study by Thiel and colleagues demonstrated a significantly prolonged duration of B-cell depletion following rituximab treatmen...
Show MoreWe read the article “Maintenance of remission of ANCA vasculitis by rituximab based on B cell repopulation versus serological flare: a randomised trial” with interest as we believe that this may cause a paradigm shift in the way that these patients are managed. However, as Immunologists, we have some reservations with regards to the impact that these changes may have.
The authors report administering much higher doses of rituximab to patients enrolled in the B cell arm of the study, compared to the ANCA arm (mean 3.6g vs 0.5g per person), and the decision to re-introduce rituximab was based on a very low cutoff of ≥10 cells/mm3 (=0.01 x109/L; local reference range >0.1 x109/L). As such, we would expect a much more pronounced immunosuppressive effect in those patients and, not surprisingly, a higher rate of serious infectious adverse events were reported in the B cell arm. More importantly, 2 patient deaths due to COVID-19 were noted in this group, while none in the ANCA arm.
Several similar cases of persistent or fatal COVID-19 infection in patients treated with rituximab have been reported in the literature[1,2]. Severe infectious sequalae due to multiple other viruses have also been reported, including hepatitis B, VZV, CMV, enterovirus, adenovirus, JC virus, BK virus, HPV, HSV and others[3]. A similar pattern emerges in patients with absent B cells due to any other cause, which suggests a key role for peripheral B cells in their development[4].
...Show MoreThe authors report that AS is associated with an increased mortality, more so among the females (1). Their observations further strengthen the recent understanding that women are not so lucky (2) after all, when they acquire AS. However, we would like to point out to a neglected point in the current report, an issue related to the proposed sex differences in the risk of death.
The mean age of entry of AS patients into this work was 44 years. On the other hand, we know that AS usually starts well before age 30 and according to one study, at a median age of 25 for males and 28 for females (3). Thus, most of the patients in the current report had AS years before entering this study. Therefore, the current report really concerns the fate of AS patients after quite a number of years of disease duration. A previous study about mortality in AS had shown that males and females had a similar survival after disease onset for about a decade after which the decrease in male survival became apparent. On the other hand, it took 35 years from disease onset when the female survival began to decrease (4). It follows that the design of the current work does not allow us to assess the survival of AS from the time of disease onset.
Finally, we surely agree with the authors that more work is needed to assess the proposed increased mortality among women with AS.
Dear Editor,
Show MoreI am writing to draw your attention to the profound implications of the article by Baraliakos et al. (1). This study is a beacon of hope for individuals living with axial spondyloarthritis (axSpA) and underscores the potential of Bimekizumab (BKZ) as a transformative treatment.
The study's findings reveal that BKZ, a monoclonal antibody inhibiting interleukin (IL)-17A and IL-17F, has exhibited unparalleled efficacy in patients with both non-radiographic (nr-) and radiographic (r-) axSpA. These results are not just promising; they are monumental. The study demonstrates that improvements achieved with BKZ at Week 16 persist to Week 52. Key metrics, including Assessment of SpondyloArthritis International Society ≥40% response, Ankylosing Spondylitis Disease Activity Score, high-sensitivity C-reactive protein levels, and MRI inflammation of the sacroiliac joints/spine, continued to improve in patients who received BKZ.
Of equal significance is the fact that patients who transitioned from a placebo to BKZ at Week 16 experienced comparable results to those who received BKZ from the outset. This underlines the sustained efficacy of BKZ and its potential to improve the quality of life for axSpA patients. Furthermore, BKZ demonstrated the ability to reduce objective measures of inflammation, such as MRI scores and hs-CRP levels, consistently across treatment groups. These reductions correlate with improvements in patient-reported outcomes, includ...
We read with great interest the pooled analysis of the MAINRITSAN trials and believe that certain study conclusions and inferences warrant further discussion and clarification (1).
Since the MAINRITSAN trials represent the largest body of Class I evidence regarding rituximab maintenance in AAV, any inference drawn from them needs to be carefully worded since it is likely to be translated into clinical practice as standard-of-care with immediate effect. In this light, we believe that the authors’ conclusion that “extending RTX to 36 months does not appear to reduce the long- term relapse rate compared with 18 months of fixed- dose RTX and should probably only be considered in patients at high risk of relapse” should be a bit guarded for the following reasons.
As pointed out previously by us after the publication of MAINRITSAN-3, ANCA-associated vasculitides warrant long-term maintenance therapy with rituximab (at least for 4 years as opined by the MAINRITSAN-3 authors in response) (2,3). However, the conclusions of the current pooled analysis seem rather contradictory and in fact, counterintuitive. A closer look at the Kaplan-Meier survival curve for overall relapses (Figure 2B of the pooled analysis) shows that the plot of the 36-month fixed/fixed RTX seems to clearly diverge from the other groups including the 18-month fixed RTX after month 30 (when the effect of the last dose of RTX is expected to have worn off), a fact which is reinforced by the obtained...
Show MoreDear Editor,
I am writing to express our particular interest in the article "Rheuma-VOR study: optimising healthcare of rheumatic diseases by multiprofessional coordinating centres" by Dreher et al (1), where a prospective multicenter study was conducted with the implementation of an early referral strategy that succeeded in reducing the rheumatological medical care waiting time to 6.6 months, compared to the usual reference time of 27.7 months.
It is undeniable that the delay in referring patients with suspected rheumatoid arthritis remains a challenge. In a report conducted at a second-level hospital in Mexico, we evaluated 206 referrals to the rheumatology service from the primary level of care. We found an average of 28.2 (SD 46.9) months elapsed from the onset of symptoms to rheumatological evaluation (2).
In contrast, the study by van Nies et al conducted in the Netherlands established an early referral clinic, which managed to reduce the referral time from the general practitioner to 2 weeks and the total time elapsed from the onset of symptoms to rheumatological care to 10.6 weeks. 59% (n=162) received attention within the first 12 weeks after the onset of symptoms (3).
Within the referral system at the Mexican Social Security Institute in Monterrey, Mexico, we implemented an early referral program with the aim of reducing referral times. The program was applied to patients evaluated at the primary level who presented hand arth...
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