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
Dear Editors of the Annals of the Rheumatic Diseases,
I am writing to bring to your attention a discrepancy I have identified in Table 1 of the article titled "Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis" published in your esteemed journal. The error pertains to the numbers of patients and controls listed in the table, which do not align with the description provided in the "Patient and public involvement" section of the article's MATERIALS AND METHODS.
This inconsistency has the potential to mislead readers and may impact their understanding and interpretation of the study's findings. After careful consideration and verification, it is evident that the data provided in Table 1 should accurately reflect the numbers described in the "Patient and public involvement" section. I respectfully recommend rectifying the table to ensure alignment with the stated patient and public involvement.
I appreciate the opportunity provided by the Annals of the Rheumatic Diseases for open discourse, which serves to uphold the integrity and accuracy of scientific research. My intention is to contribute to the improvement of the published work, ensuring its accuracy and reliability. Addressing this discrepancy will further enhance the quality of the published work and provide readers with the precise and reliable information they seek.
Dear Editors of the Annals of the Rheumatic Diseases,
I am writing to bring to your attention a discrepancy I have identified in Table 1 of the article titled "Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis" published in your esteemed journal. The error pertains to the numbers of patients and controls listed in the table, which do not align with the description provided in the "Patient and public involvement" section of the article's MATERIALS AND METHODS.
This inconsistency has the potential to mislead readers and may impact their understanding and interpretation of the study's findings. After careful consideration and verification, it is evident that the data provided in Table 1 should accurately reflect the numbers described in the "Patient and public involvement" section. I respectfully recommend rectifying the table to ensure alignment with the stated patient and public involvement.
I appreciate the opportunity provided by the Annals of the Rheumatic Diseases for open discourse, which serves to uphold the integrity and accuracy of scientific research. My intention is to contribute to the improvement of the published work, ensuring its accuracy and reliability. Addressing this discrepancy will further enhance the quality of the published work and provide readers with the precise and reliable information they seek.
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.
The EULAR 2023 recommendations for the management of systemic lupus erythematosus (SLE) outline a number of principles and approaches, most of which are based on high-level evidence [1]. Indeed, numerous studies, meta-analyses and double-blind randomized controlled trials have been conducted in recent years, leading to the approval or consolidation of the use of new molecules in SLE. The expansion of the therapeutic armamentarium represents an important development for patients, with the constant aim of limiting the morbidity and mortality of SLE. This is particularly true for lupus nephritis, for which clinical trials and therapeutic innovations over the last 20 years have led to a marked improvement in prognosis.
However, this progress needs to be tempered in certain populations where the risk of developing more severe kidney disease with poorer prognosis has long been known but still persists, and it is time to focus on these high-risk profiles. The most vulnerable population are individuals of African descent, who have the highest risk profile and the poorest long-term prognosis [2]. While socioeconomic factors and access to treatment are key determinants, other elements need to be explored to explain this risk profile. In a cohort of African-Europeans with similar access to care, long-term renal survival was significantly lower than in Caucasian patients [3]. One of the factors associated with this poor renal prognosis was the higher frequency of relapses in th...
The EULAR 2023 recommendations for the management of systemic lupus erythematosus (SLE) outline a number of principles and approaches, most of which are based on high-level evidence [1]. Indeed, numerous studies, meta-analyses and double-blind randomized controlled trials have been conducted in recent years, leading to the approval or consolidation of the use of new molecules in SLE. The expansion of the therapeutic armamentarium represents an important development for patients, with the constant aim of limiting the morbidity and mortality of SLE. This is particularly true for lupus nephritis, for which clinical trials and therapeutic innovations over the last 20 years have led to a marked improvement in prognosis.
However, this progress needs to be tempered in certain populations where the risk of developing more severe kidney disease with poorer prognosis has long been known but still persists, and it is time to focus on these high-risk profiles. The most vulnerable population are individuals of African descent, who have the highest risk profile and the poorest long-term prognosis [2]. While socioeconomic factors and access to treatment are key determinants, other elements need to be explored to explain this risk profile. In a cohort of African-Europeans with similar access to care, long-term renal survival was significantly lower than in Caucasian patients [3]. One of the factors associated with this poor renal prognosis was the higher frequency of relapses in this population, raising the question of their sustained response to immunosuppressive therapy [3].
In fact, there is no data in the literature to support superiority between drugs in individuals of African descent. The EUROLUPUS study included a very small number of patients of African descent, and the ALMS study, although including the largest number of patients of this ethnicity (46/370; 12.4%), does not allow to draw any conclusions about the superiority of mycophenolate over cyclophosphamide [4]. Although numerically superior, the difference in response rates was not statistically significant in the post hoc analysis (OR 1.8 95%CI [0.5 to 5.7], p=0.39) [5]. Here, one could argue that lack of power explains the lack of statistical significance, but is actually consistent with the need of special focus and increased inclusion in randomized clinical trials (RCTs) of these high-risk profile patients.
Furthermore, lessons can be learned from RCTs with the recent example of belimumab, which failed to reach statistical significance on its primary endpoint in a trial specifically designed to assess its efficacy in African-Americans patients with SLE [6]. Some preliminary data have suggested ethnic differences in B Lymphocyte Stimulator levels, which may require adaptation of the treatment regimen in people of African descent [7]. Similarly, other preclinical data suggest ethnic differences in SLE pathways that may explain differences in treatment response and potentially highlight future therapeutic targets [7–9]. The prevalence and impact of high-risk apolipoprotein 1 (ApoL1) gene variants in this population, while important, should not be seen as a dead end [10], as renal inflammation can respond to immunosuppressive therapies, even among patients with these specific genetic background.
Taken together, it is unlikely that increased enrollment of individuals of African descent in RCTs will be sufficient on its own until the potential molecular mechanisms behind the differences and excess risk in these populations are thoroughly investigated and elucidated. Given the worst outcomes of SLE and lupus nephritis among African descents, it's a safe bet that efforts to elucidate the pathophysiology of high-risk profiles will not be in vain and that the resulting therapeutic innovations will benefit to all patients, regardless of their ancestry.
References
1 Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2023;ard-2023-224762.
2 Farinha F, Pepper RJ, Oliveira DG, et al. Outcomes of membranous and proliferative lupus nephritis – analysis of a single-centre cohort with more than 30 years of follow-up. Rheumatology. 2020;59:3314–23.
3 Enfrein A, Pirson V, Le Guern V, et al. Worse long-term renal outcome of lupus nephritis patients of African descent living in Europe. RMD Open. 2022;8:e002386.
4 Appel GB, Contreras G, Dooley MA, et al. Mycophenolate versus Cyclophosphamide for Induction Treatment of Lupus Nephritis. J Am Soc Nephrol. 2009;20:1103–12.
5 Isenberg D, Appel GB, Contreras G, et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology. 2010;49:128–40.
6 Ginzler E, Guedes Barbosa LS, D’Cruz D, et al. Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022;74:112–23.
7 Ritterhouse LL, Crowe SR, Niewold TB, et al. B lymphocyte stimulator levels in systemic lupus erythematosus: Higher circulating levels in African American patients and increased production after influenza vaccination in patients with low baseline levels. Arthritis Rheum. 2011;63:3931–41.
8 Allen PC, Roberts K, Rubio JE, et al. Genome-wide DNA methylation analysis implicates enrichment of interferon pathway in African American patients with Systemic Lupus Erythematosus and European Americans with lupus nephritis. J Autoimmun. 2023;139:103089.
9 Slight-Webb S, Thomas K, Smith M, et al. Ancestry-based differences in the immune phenotype are associated with lupus activity. JCI Insight. 2023;8:e169584.
10 Freedman BI, Langefeld CD, Andringa KK, et al. End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1: APOL1 in Lupus Nephritis ESRD. Arthritis Rheumatol. 2014;66:390–6.
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
We read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals wi...
We read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals with CSA have a tendency to higher ACPA and rheumatoid factor (RF) titres compared to lower risk arthralgia patients [6]. Higher titres imply recognition of more citrullinated epitopes recognised by several immunoglobulin subtypes including IgG, IgM, IgA and IgE. The increase in ACPA subtypes have been shown to correlate with an increase in cytokine levels such as TNF-, IL-6, IL-12 and interferon- [7,8]. It appears that maturation of this response occurs prior to the conversion of CSA to RA. Several studies have observed that higher ACPA titres in CSA are associated with development of RA [4,9]. Our group has shown that seropositive arthralgia patients at risk for developing RA had greater than 50% macroscopic synovitis or vascularity scores at knee arthroscopy and that an ACPA titre of >340IU (the upper limit of sensitivity at our laboratory), was associated with progression to RA [10].
Another clinical area where ACPA and RF titres are relevant in RA is when selecting a therapeutic agent. Seropositive patients are more likely to respond to abatacept and rituximab [7,11–14]. Those with higher ACPA titres had a better clinical response to abatacept compared to adalimumab in the AMPLE trial [7]. Significant reductions in both ACPA and RF titres have been observed in RA patients after 3 months on abatacept and the reduction in ACPA has been shown to be an independent predictor of abatacept persistence at 12 months, possibly attributable to sustained therapeutic response [11]. B-cell depletion with rituximab has also been shown to reduce ACPA levels and improve disease activity in RA [15]. However, not all seropositive patients respond to these agents, constituting a significant unmet need
Despite the work to date, it is clear that further large prospective studies are needed to improve risk prediction models in the pre-clinical RA phase to allow for better identification of these individuals “at risk” and to develop new preventative strategies, as well as more and improved treatment options.
References
1 Pisetsky DS. Annals of the Rheumatic Diseases collection on autoantibodies in the rheumatic diseases: new insights into pathogenesis and the development of novel biomarkers. Ann Rheum Dis. 2023;82:1243–7.
2 Van Der Woude D, Syversen SW, Van Der Voort EIH, et al. The ACPA isotype profile reflects long-term radiographic progression in rheumatoid arthritis. Ann Rheum Dis. 2010;69:1110–6.
3 Majka DS, Deane KD, Parrish LA, et al. Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. Annals of the Rheumatic Diseases. 2008;67:801–7.
4 Bos WH, Wolbink GJ, Boers M, et al. Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheum Dis. 2010;69:490–4.
5 Nielen MMJ, Van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis & Rheumatism. 2004;50:380–6.
6 Westra J, Brouwer E, Raveling-Eelsing E, et al. Arthritis autoantibodies in individuals without rheumatoid arthritis: follow-up data from a Dutch population-based cohort (Lifelines). Rheumatology. 2021;60:658–66.
7 Sokolove J, Schiff M, Fleischmann R, et al. Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial. Ann Rheum Dis. 2016;75:709–14.
8 Suwannalai P, Van De Stadt LA, Radner H, et al. Avidity maturation of anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis & Rheumatism. 2012;64:1323–8.
9 Van De Stadt LA, Van Der Horst AR, De Koning MHMT, et al. The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia. Annals of the Rheumatic Diseases. 2011;70:128–33.
10 Gorman A, Flynn K, Turk M, et al. Predicting Progression to RA in Patients with Seropositive Arthralgia. Arthritis Rheumatol. 2021;73.
11 Endo Y, Koga T, Kawashiri S-Y, et al. Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan. Scandinavian Journal of Rheumatology. 2020;49:13–7.
12 Sellam J, Hendel-Chavez H, Rouanet S, et al. B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six-month, national, multicenter, open-label study. Arthritis & Rheumatism. 2011;63:933–8.
13 Chatzidionysiou K, Lie E, Nasonov E, et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Annals of the Rheumatic Diseases. 2011;70:1575–80.
14 Isaacs JD, Cohen SB, Emery P, et al. Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis. Ann Rheum Dis. 2013;72:329–36.
15 Teng YO, Wheater G, Hogan VE, et al. Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity. Arthritis Res Ther. 2012;14:R57.
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.
We have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Firstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this st...
We have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Firstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this study is notable. We suggest that further subgroup analysis could
strengthen the study's conclusions.
This article highlights the use of methotrexate, TNFi, and JAK inhibitors in
treating rheumatoid arthritis (RA) and discusses the evolving role of JAK inhibitors in
RA treatment[4]. Recent studies, including this one, suggest an increased tumor risk
associated with JAK inhibitors, warranting caution among rheumatologists[5].
In summary, while this meta-analysis underscores a potential increased tumor
risk with JAK inhibitors, the limited number and scope of studies due to the relatively
recent introduction of these drugs suggest that these findings are preliminary. We
appreciate the authors' efforts in highlighting these risks, which serve as an important
caution for clinicians.
References:
[1] Russell MD, Stovin C, Alveyn E, et al. JAK inhibitors and the risk of malignancy: a
meta-analysis across disease indications. Ann Rheum Dis. 2023;82(8):1059-1067. [2] Mishra P, Ali Ahmad MF, Al-Keridis LA, et al. Methotrexate-conjugated zinc oxide
nanoparticles exert a substantially improved cytotoxic effect on lung cancer cells by inducing
apoptosis. Front Pharmacol. 2023;14:1194578. [3] Crepeau PK, Sutton W, Sahli Z, et al. Prevalence and risk factors for dysphagia in older adults
after thyroid and parathyroid surgery. Surgery. 2023. [4] Harrington R, Al Nokhatha SA, Conway R. JAK inhibitors in rheumatoid arthritis: an
evidence-based review on the emerging clinical data. J Inflamm Res. 2020;14(13):519-531. [5] Yoshida S, Miyata M, Suzuki E, et al. Safety of JAK and IL-6 inhibitors in patients with
rheumatoid arthritis: a multicenter cohort study. Front Immunol. 2023;14:1267749.
With great interest, we have read the recent article by Konzett et al1 on determination of the most powerful American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) between active treatment and placebo in RA trials. In this well-designed study, the authors systematically analyzed the time courses of ACR20, 50 and 70 responses from randomized, double-blind, placebo-controlled, phase II and phase III RA drug approval trials. The conclusion was ACR20 remains the most sensitive discriminator at early time points in the novel therapeutics (bDMARDs and tsDMARDs) placebo-controlled RA trials.
However, the placebo response seems ignored in the comparison of response trajectories of ACR20, 50 and 70. First, we noticed that the authors showed longitudinal dynamics of different ACR response rates and concluded ACR20 response provided highly sensitive to early treatment effect (Figure 2)1. The “treatment effect” in this case should be the relative effect of treatment compared with placebo ( treatment response - placebo response)2, however, it appears that the mean normalized ACR response rates in Figure 2 relies solely on data from the treatment group, without factoring in the placebo group. The placebo response rate in RA clinical trials has significantly increased in the era of bDMARDs/tsDMARDs3, which has also been confirmed in the supplementary material section 8.21. A substantial placebo response can hinder the ability to discern treatment effects4. Th...
With great interest, we have read the recent article by Konzett et al1 on determination of the most powerful American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) between active treatment and placebo in RA trials. In this well-designed study, the authors systematically analyzed the time courses of ACR20, 50 and 70 responses from randomized, double-blind, placebo-controlled, phase II and phase III RA drug approval trials. The conclusion was ACR20 remains the most sensitive discriminator at early time points in the novel therapeutics (bDMARDs and tsDMARDs) placebo-controlled RA trials.
However, the placebo response seems ignored in the comparison of response trajectories of ACR20, 50 and 70. First, we noticed that the authors showed longitudinal dynamics of different ACR response rates and concluded ACR20 response provided highly sensitive to early treatment effect (Figure 2)1. The “treatment effect” in this case should be the relative effect of treatment compared with placebo ( treatment response - placebo response)2, however, it appears that the mean normalized ACR response rates in Figure 2 relies solely on data from the treatment group, without factoring in the placebo group. The placebo response rate in RA clinical trials has significantly increased in the era of bDMARDs/tsDMARDs3, which has also been confirmed in the supplementary material section 8.21. A substantial placebo response can hinder the ability to discern treatment effects4. Therefore, considering the placebo response may be more appropriate. Second, the control arms in the study not only included placebo only arms, but also placebo plus csDMARDs arms1. Evidence showed that patients receiving placebo in combination with csDMARDs had a higher placebo response compared to those receiving placebo only5. Hence, firstly, the placebo response should be taken into account. Secondly, the three ACR criteria should be discussed in terms of how well they can discriminate between active treatment and placebo in different control groups.
Additionally, the authors collected the ACR20, 50 and 70 scores at multiple time points over the course of phase II and phase III RCTs. There is a disconnect between phase II and phase III trials, where phase II trials could overestimate treatment effects6. Combining both for evaluation may introduce bias to the results. Therefore, it would be better if readers were able to view the results by separating the discussion of Phase II and Phase III studies.
Taken together, these aspects indicate the need to further consider the aforementioned methodological issues. We respect the significant contributions of the authors and look forward to more communications.
References
1. Konzett, V., Kerschbaumer, A., Smolen, J. S. & Aletaha, D. Determination of the most appropriate ACR response definition for contemporary drug approval trials in rheumatoid arthritis. Ann. Rheum. Dis. ard-2023-224477 (2023) doi:10.1136/ard-2023-224477.
2. Nikolakopoulou, A. et al. When does the placebo effect have an impact on network meta-analysis results? BMJ Evid.-Based Med. bmjebm-2022-112197 (2023) doi:10.1136/bmjebm-2022-112197.
3. Bechman, K., Yates, M., Norton, S., Cope, A. P. & Galloway, J. B. Placebo Response in Rheumatoid Arthritis Clinical Trials. J. Rheumatol. 47, 28–34 (2020).
4. Neogi, T. & Colloca, L. Placebo effects in osteoarthritis: implications for treatment and drug development. Nat. Rev. Rheumatol. 19, 613–626 (2023).
5. Kerschbaumer, A., Rivai, Z. I., Smolen, J. S. & Aletaha, D. Impact of pre-existing background therapy on placebo responses in randomised controlled clinical trials of rheumatoid arthritis. Ann. Rheum. Dis. 81, 1374–1378 (2022).
6. Kerschbaumer, A. et al. Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology. Nat. Med. 26, 974–980 (2020).
We are thrilled and grateful to see an update of the systemic lupus erythematosus (SLE) treatment recommendations after 4 years’ time since 2019. Because of the efforts of a Task Force of world-leading SLE experts, we are now able to follow these useful recommendations in daily clinical practice. In this version, several new ideas to treat SLE come into view. We are now entering the era of biologics, with more on the way, which might significantly change the way we treat SLE. Apart from rituximab, belimumab, and anifrolumab, there is another B cell related biologic, telitacicept, a BLyS/APRIL dual inhibitor, with a successful phase II trial1; larger confirmatory trials are currently underway. As recommended in the version, early diagnosis and treatment are emphasized. The biologics are used earlier than before, not requiring conventional immunosuppresants first; this change is a bit step forward, indicating that early intervention is important.
The treatment of SLE is like walking on a blade. Balancing the benefits and harms is an art, for which the use of glucocorticoids (GC) is a typical example. I totally agree that the use of GC is only for ‘bridging therapy’ in SLE. But we can expect that, different from the treatment of rheumatoid arthritis (RA), the taper of GC in SLE is not as easy as in RA and the duration will be longer. In this recommendation, it is clearly stated that GC should be taped gradually. However, in terms of the cessation of GC, it is not clear...
We are thrilled and grateful to see an update of the systemic lupus erythematosus (SLE) treatment recommendations after 4 years’ time since 2019. Because of the efforts of a Task Force of world-leading SLE experts, we are now able to follow these useful recommendations in daily clinical practice. In this version, several new ideas to treat SLE come into view. We are now entering the era of biologics, with more on the way, which might significantly change the way we treat SLE. Apart from rituximab, belimumab, and anifrolumab, there is another B cell related biologic, telitacicept, a BLyS/APRIL dual inhibitor, with a successful phase II trial1; larger confirmatory trials are currently underway. As recommended in the version, early diagnosis and treatment are emphasized. The biologics are used earlier than before, not requiring conventional immunosuppresants first; this change is a bit step forward, indicating that early intervention is important.
The treatment of SLE is like walking on a blade. Balancing the benefits and harms is an art, for which the use of glucocorticoids (GC) is a typical example. I totally agree that the use of GC is only for ‘bridging therapy’ in SLE. But we can expect that, different from the treatment of rheumatoid arthritis (RA), the taper of GC in SLE is not as easy as in RA and the duration will be longer. In this recommendation, it is clearly stated that GC should be taped gradually. However, in terms of the cessation of GC, it is not clear when, during clinical remission, GC can be stopped completely. Moreover, the GC dose is recommended to be lower than 5mg, but evidence is still scarce. In the 2019 recommendation, GC dose is recommended as lower than 7.5mg. In the future, is it possible that the dose of GC will fall to even less? As new drugs continue to appear, complete remission without GC might not be a dream.
In the treatment of thrombocytopenia, tacrolimus (TAC) and sirolimus were also reported 2,3. Moreover, recombinant human thrombopoietin can also be used as adjunct treatment4. Regarding the treatment of lupus nephritis (LN), the initial dose of GC in China, 1mg/kg/day of GC, is widely used and 250-1000mg/day as a pulse dose is not commonly used. Is 1mg/kg/day also an acceptable dose in new-onset LN? In figure 1, it is a question whether a calcineurin inhibitor such as TAC can be used as a second line treatment of mild disease, similar to mycophenolate mofetil, azathioprine, methotrexate. In clinical practice, it is also a commonly used regime, not only used in LN.
In this version, fatigue, non-inflammatory pain, mood disturbance and cognitive dysfunction, which are widely reported by the patients, were considered. More studies are needed to help patients obtain relief from these symptoms.
References:
1.Sohita Dhillon.Telitacicept: First Approval.Drugs.2021 Sep;81(14):1671-1675.
2.Y Li, X Feng.Efficacy and safety of tacrolimus in systemic lupus erythematosus patients with refractory thrombocytopenia: a retrospective study.Lupus. 2018 Jan;27(1):60-65.
3.Chanyuan Wu, Qian Wang, Dong Xu,et al. Sirolimus for patients with connective tissue disease-related refractory thrombocytopenia: a single-arm, open-label clinical trial.Rheumatology (Oxford). 2021 Jun 18;60(6):2629-2634.
4.Yafei Yu, Yu Hou, Yajing Zhao,et al.Platelet autoantibody specificity and response to rhTPO treatment in patients with primary immune thrombocytopenia.Br J Haematol. 2021 Jul;194(1):191-194.
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 MoreDear Editors of the Annals of the Rheumatic Diseases,
I am writing to bring to your attention a discrepancy I have identified in Table 1 of the article titled "Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis" published in your esteemed journal. The error pertains to the numbers of patients and controls listed in the table, which do not align with the description provided in the "Patient and public involvement" section of the article's MATERIALS AND METHODS.
This inconsistency has the potential to mislead readers and may impact their understanding and interpretation of the study's findings. After careful consideration and verification, it is evident that the data provided in Table 1 should accurately reflect the numbers described in the "Patient and public involvement" section. I respectfully recommend rectifying the table to ensure alignment with the stated patient and public involvement.
I appreciate the opportunity provided by the Annals of the Rheumatic Diseases for open discourse, which serves to uphold the integrity and accuracy of scientific research. My intention is to contribute to the improvement of the published work, ensuring its accuracy and reliability. Addressing this discrepancy will further enhance the quality of the published work and provide readers with the precise and reliable information they seek.
Thank you for your attention to this matter...
Show MoreDear 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...
The EULAR 2023 recommendations for the management of systemic lupus erythematosus (SLE) outline a number of principles and approaches, most of which are based on high-level evidence [1]. Indeed, numerous studies, meta-analyses and double-blind randomized controlled trials have been conducted in recent years, leading to the approval or consolidation of the use of new molecules in SLE. The expansion of the therapeutic armamentarium represents an important development for patients, with the constant aim of limiting the morbidity and mortality of SLE. This is particularly true for lupus nephritis, for which clinical trials and therapeutic innovations over the last 20 years have led to a marked improvement in prognosis.
However, this progress needs to be tempered in certain populations where the risk of developing more severe kidney disease with poorer prognosis has long been known but still persists, and it is time to focus on these high-risk profiles. The most vulnerable population are individuals of African descent, who have the highest risk profile and the poorest long-term prognosis [2]. While socioeconomic factors and access to treatment are key determinants, other elements need to be explored to explain this risk profile. In a cohort of African-Europeans with similar access to care, long-term renal survival was significantly lower than in Caucasian patients [3]. One of the factors associated with this poor renal prognosis was the higher frequency of relapses in th...
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...
Show MoreWe read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals wi...
Show MoreWe 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 MoreWe have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Show MoreFirstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this st...
With great interest, we have read the recent article by Konzett et al1 on determination of the most powerful American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) between active treatment and placebo in RA trials. In this well-designed study, the authors systematically analyzed the time courses of ACR20, 50 and 70 responses from randomized, double-blind, placebo-controlled, phase II and phase III RA drug approval trials. The conclusion was ACR20 remains the most sensitive discriminator at early time points in the novel therapeutics (bDMARDs and tsDMARDs) placebo-controlled RA trials.
However, the placebo response seems ignored in the comparison of response trajectories of ACR20, 50 and 70. First, we noticed that the authors showed longitudinal dynamics of different ACR response rates and concluded ACR20 response provided highly sensitive to early treatment effect (Figure 2)1. The “treatment effect” in this case should be the relative effect of treatment compared with placebo ( treatment response - placebo response)2, however, it appears that the mean normalized ACR response rates in Figure 2 relies solely on data from the treatment group, without factoring in the placebo group. The placebo response rate in RA clinical trials has significantly increased in the era of bDMARDs/tsDMARDs3, which has also been confirmed in the supplementary material section 8.21. A substantial placebo response can hinder the ability to discern treatment effects4. Th...
Show MoreWe are thrilled and grateful to see an update of the systemic lupus erythematosus (SLE) treatment recommendations after 4 years’ time since 2019. Because of the efforts of a Task Force of world-leading SLE experts, we are now able to follow these useful recommendations in daily clinical practice. In this version, several new ideas to treat SLE come into view. We are now entering the era of biologics, with more on the way, which might significantly change the way we treat SLE. Apart from rituximab, belimumab, and anifrolumab, there is another B cell related biologic, telitacicept, a BLyS/APRIL dual inhibitor, with a successful phase II trial1; larger confirmatory trials are currently underway. As recommended in the version, early diagnosis and treatment are emphasized. The biologics are used earlier than before, not requiring conventional immunosuppresants first; this change is a bit step forward, indicating that early intervention is important.
The treatment of SLE is like walking on a blade. Balancing the benefits and harms is an art, for which the use of glucocorticoids (GC) is a typical example. I totally agree that the use of GC is only for ‘bridging therapy’ in SLE. But we can expect that, different from the treatment of rheumatoid arthritis (RA), the taper of GC in SLE is not as easy as in RA and the duration will be longer. In this recommendation, it is clearly stated that GC should be taped gradually. However, in terms of the cessation of GC, it is not clear...
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