We read with great interest the recent article written by Araujo CSR et al entitled “Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomized clinical trial” published in the Annals of Rheumatic Diseases on February 22, 2022 [1]. The major impact of this trial was the reinforcement of the immunogenic effect of a 2-week methotrexate discontinuation after each dose of the Sinovac-CoronaVac vaccine against SARS-CoV-2 compared to methotrexate continuation in patients with rheumatoid arthritis (seroconversion rates: 78.4% vs 54.5%, p-0.019 and geometric mean antibody titers: 34.2 (25.2–46.4) vs 16.8 (11.9–23.6), p=0.003, respectively).
Previous experience with other non-COVID-19 vaccines, like the influenza or pneumococcal vaccines, has indicated that discontinuation of immunosuppresants improves the immunogenicity of a given vaccine [2,3]. Based on this knowledge, we had proposed that it would be beneficial for patients with autoimmune rheumatic diseases to get vaccinated against SARS-CoV-2 preferably when the underlying rheumatic disease is in remission and after temporal withdrawal of anti-metabolites within 10 days before and after each vaccine dose along with similar modifications in anti-cytokine drugs and corticosteroid dosages >10mg/ day (prednisone equivalent) [4]. In fact, applying that in a comparative study it was shown that the magnitude of antibody responses to mRNA-based S...
We read with great interest the recent article written by Araujo CSR et al entitled “Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomized clinical trial” published in the Annals of Rheumatic Diseases on February 22, 2022 [1]. The major impact of this trial was the reinforcement of the immunogenic effect of a 2-week methotrexate discontinuation after each dose of the Sinovac-CoronaVac vaccine against SARS-CoV-2 compared to methotrexate continuation in patients with rheumatoid arthritis (seroconversion rates: 78.4% vs 54.5%, p-0.019 and geometric mean antibody titers: 34.2 (25.2–46.4) vs 16.8 (11.9–23.6), p=0.003, respectively).
Previous experience with other non-COVID-19 vaccines, like the influenza or pneumococcal vaccines, has indicated that discontinuation of immunosuppresants improves the immunogenicity of a given vaccine [2,3]. Based on this knowledge, we had proposed that it would be beneficial for patients with autoimmune rheumatic diseases to get vaccinated against SARS-CoV-2 preferably when the underlying rheumatic disease is in remission and after temporal withdrawal of anti-metabolites within 10 days before and after each vaccine dose along with similar modifications in anti-cytokine drugs and corticosteroid dosages >10mg/ day (prednisone equivalent) [4]. In fact, applying that in a comparative study it was shown that the magnitude of antibody responses to mRNA-based SARS-CoV-2 vaccines improved when methotrexate was withheld for a 10-day period before and after each dose compared to when all treatment regimens were maintained [median antibody titers: 7.88 (6.51-8.47) vs 5.20 (2.85-7.30), p<0.001, respectively] [5]. We are glad to see that Araujo CSR and colleagues came to the same conclusion by discontinuing methotrexate for 2 weeks after each vaccine dose. All these highly indicate that methotrexate withdrawal following vaccination improves immunogenicity of COVID-19 vaccines. However, in contrast to our observations that treatment modifications were not accompanied by more disease flares [10/73 (13.7%) vs 7/48 (14.6%), p=0.8910], in the trial by Araujo CSR et al the occurrence of disease flares was higher among those who temporarily interrupted methotrexate compared to those who continued their treatment [23/60 (38.3%) vs 14/69 (20.3%), p=0.024].
In conclusion, this randomized study by Araujo CSR et al confirms our early observations and reinforces current recommendations of methotrexate withdrawal during COVID-19 vaccination along with active disease activity surveillance according to patient’s characteristics and withdrawal periods.
REFERENCES
1. Araujo CSR, Medeiros-Ribeiro AC, Saad CGS, et al Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomised clinical trial Ann Rheum Dis Published Online First: 22 February 2022. doi: 10.1136/annrheumdis-2021-221916.
2. Park JK, Lee YJ, Shin K, et al. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis 2018;77:annrheumdis-2018-213222–904.
3. Winthrop KL, Silverfield J, Racewicz A, et al. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis. Ann Rheum Dis 2016;75:687–95.
4. Moutsopoulos HM. A recommended paradigm for vaccination of rheumatic disease patients with the SARS-CoV-2 vaccine. J Autoimmun. 2021 Jul;121:102649. doi: 10.1016/j.jaut.2021.102649. Epub 2021 May 1. PMID: 33984571; PMCID: PMC8088234.
5. Tzioufas AG et al. A prospective multicenter study assessing humoral immunogenicity and safety of the mRNA SARS-CoV-2 vaccines in Greek patients with systemic autoimmune and autoinflammatory rheumatic diseases. J Autoimmun. 2021 Dec;125:102743. doi: 10.1016/j.jaut.2021.102743. Epub 2021 Oct 28. PMID: 34757289; PMCID: PMC8552665.
Ugarte-Gil, et al (1) recently published a study reporting several characteristics associated with severe COVID-19 outcomes in people with systemic lupus erythematosus(SLE). Demographic factors, comorbidities, active or untreated SLE, and patients treated with glucocorticoids were the most noticeable features. Even though several covariates had been taken into consideration to minimize the impacts of these confounders, we presume vaccination could play a crucial role in the COVID-19 outcomes.
Previous studies had pointed out the protective effect that vaccination could provide against poor outcomes in the general population (2). In spite of a lack of evidence on the efficacy of COVID-19 vaccines in patients with SLE, achieving adequate sero-protection after receiving COVID-19 vaccine could be expected according to the expert opinion based on the knowledge on the use of other vaccines in this specific group of patients (3). A review article published by Wei Tang, et al (4) showed that commonly used immunosuppressants inclusive of glucocorticoids, methotrexate, mycophenolate mofetil/mycophenolic acid and rituximab might impede vaccine responses, causing less sufficient immune responses after getting COVID-19 vaccines in SLE patients. Hence, we suggest a subgroup analysis according to whether being vaccinated or not to have better data interpretation and to clarify the possible factors that may lead to critical consequences in SLE patients infected with COVID-19. ...
Ugarte-Gil, et al (1) recently published a study reporting several characteristics associated with severe COVID-19 outcomes in people with systemic lupus erythematosus(SLE). Demographic factors, comorbidities, active or untreated SLE, and patients treated with glucocorticoids were the most noticeable features. Even though several covariates had been taken into consideration to minimize the impacts of these confounders, we presume vaccination could play a crucial role in the COVID-19 outcomes.
Previous studies had pointed out the protective effect that vaccination could provide against poor outcomes in the general population (2). In spite of a lack of evidence on the efficacy of COVID-19 vaccines in patients with SLE, achieving adequate sero-protection after receiving COVID-19 vaccine could be expected according to the expert opinion based on the knowledge on the use of other vaccines in this specific group of patients (3). A review article published by Wei Tang, et al (4) showed that commonly used immunosuppressants inclusive of glucocorticoids, methotrexate, mycophenolate mofetil/mycophenolic acid and rituximab might impede vaccine responses, causing less sufficient immune responses after getting COVID-19 vaccines in SLE patients. Hence, we suggest a subgroup analysis according to whether being vaccinated or not to have better data interpretation and to clarify the possible factors that may lead to critical consequences in SLE patients infected with COVID-19.
Interestingly, the ordinal regression models examining the association between medication usage and disease severity of COVID-19 in this study revealed more favorable outcomes when SLE was treated with belimumab (1). A meta-analysis conducted by Singh et al (5) concluded six randomized controlled trials that belimumab showed clinically significant efficacy in comparison with placebo in participants with SLE at 52 weeks. Taken together with the better COVID-19 outcomes in patients using belimumab in the present study and evidence regarding the promising results of belimumab provided by former studies, we regard belimumab may be a potential direction for future research in SLE patients infected with COVID-19.
(1) Ugarte-Gil, M.F., Alarcón, G.S., Izadi, Z., et al. 2022. Characteristics associated with poor COVID-19 outcomes in individuals with systemic lupus erythematosus: data from the COVID-19 Global Rheumatology Alliance. Annals of the Rheumatic Diseases annrheumdis–202. doi:10.1136/annrheumdis-2021-221636
(2) Tartof, S.Y., Slezak, J.M., Fischer, et al. 2021. Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study. The Lancet 398, 1407–1416. doi:10.1016/s0140-6736(21)02183-8
(3) Mason, A., Anver, H., Lwin, et al. 2021. Lupus, vaccinations and COVID-19: What we know now. Lupus 30, 1541–1552.doi:10.1177/09612033211024355
(4) Tang, W., Gartshteyn, Y., Ricker, E., et al. 2021. The Use of COVID-19 Vaccines in Patients with SLE. Current Rheumatology Reports 23. doi:10.1007/s11926-021-01046-2
(5) Singh JA, Shah NP, Mudano AS.2021. Belimumab for systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Feb 25;2(2):CD010668. doi: 10.1002/14651858.CD010668
We read with great interest the recent publication by Balsa et al.,[1] which reported that patient–physician agreement on the treatment, the type of treatment prescribed (favoring second-line conventional disease-modifying rheumatic drugs and biological disease-modifying rheumatic drugs/targeted synthetic disease-modifying rheumatic drugs), and the patient feeling privileged by the medication received are effective predictors of medication adherence in patients with rheumatoid arthritis (RA). In contrast, sociodemographic or clinical factors were not associated with medication adherence. This study focuses on medication adherence as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
First, epidemiologists agree that studies assessing a relation at one moment in time are called cross-sectional studies.[2] If the follow-up time is considered, the study is longitudinal, and it is either a cohort or a case-control study. A cohort or a case-control study must be applied to variables that can be reasonably assumed stable over time. However, this study was a six-month multicentre observational longitudinal prospective study, and medication adherence is related to psychological, communicational, and logistic factors measured at the same time. Therefore, this study is better labeled a cross-sectional study, since psychological, communicational, and logistic factors cannot be assumed to be...
We read with great interest the recent publication by Balsa et al.,[1] which reported that patient–physician agreement on the treatment, the type of treatment prescribed (favoring second-line conventional disease-modifying rheumatic drugs and biological disease-modifying rheumatic drugs/targeted synthetic disease-modifying rheumatic drugs), and the patient feeling privileged by the medication received are effective predictors of medication adherence in patients with rheumatoid arthritis (RA). In contrast, sociodemographic or clinical factors were not associated with medication adherence. This study focuses on medication adherence as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
First, epidemiologists agree that studies assessing a relation at one moment in time are called cross-sectional studies.[2] If the follow-up time is considered, the study is longitudinal, and it is either a cohort or a case-control study. A cohort or a case-control study must be applied to variables that can be reasonably assumed stable over time. However, this study was a six-month multicentre observational longitudinal prospective study, and medication adherence is related to psychological, communicational, and logistic factors measured at the same time. Therefore, this study is better labeled a cross-sectional study, since psychological, communicational, and logistic factors cannot be assumed to be stable over time.
Second, the sociodemographic factors are not predictive factors for medication adherence among patients with RA in this study. However, other socioeconomic variables such as race, employment status, and cultural differences[3] were not fully captured in this dataset, which may have impacted medication adherence in patients with RA. The differences in characteristics between all three groups further emphasize the need to better incorporate these types of socioeconomic variables into the methods for identifying predictive factors and managing high-risk patients in both routine clinical care and clinical research studies, particularly in relation to medication adherence.
Third, it is interesting that at six months, 86.0% and 80.6% of the patients adhered to the medications based on a Compliance Questionnaire Rheumatology (CQR) score and Reported Adherence to Medication (RAM) score (self-report adherence), respectively. Previous studies have clearly demonstrated that self-reports tend to overestimate adherence behavior compared with other assessment methods.[4, 5] However, the percentage of adherence in self-report RAM scores is less than in CQR scores in this study. Hence, there might be a self-serving bias in self-report RAM that authors should consider. Although the authors did an exceptional job of outlining the importance of acknowledging and counteracting the types of biases, other circumstances should be considered in self-report assessments.
In conclusion, although we have some concerns about the study by Balsa et al.,1 we applaud the authors for their commendable work and hope that this study will benefit readers. We look forward to further work on the important topic of medication adherence management and hope that integrating multifaceted interventions for the improvement of medication adherence will benefit patients with RA.
Contributors All authors reviewed the draft and approved the submission of the manuscript.
Competing interests None declared.
References:
1. Balsa A, García de Yébenes MJ, Carmona L, et al. Multilevel factors predict medication adherence in rheumatoid arthritis: a 6-month cohort study. Ann Rheum Dis 2022;81:327-34.
2. Dekkers OM, Groenwold RHH. Study design: what's in a name? Eur J Endocrinol 2020;183:E11-3.
3. Salt E, Frazier SK. Predictors of medication adherence in patients with rheumatoid arthritis. Drug Dev Res 2011;72:756-63.
4. Bright EE, Stanton AL. Correspondence between objective and self-reported endocrine therapy adherence among women with breast cancer. Ann Behav Med 2019;53:849-57.
5. van Breukelen-van der Stoep DF, Zijlmans J, van Zeben D, et al. Adherence to cardiovascular prevention strategies in patients with rheumatoid arthritis. Scand J Rheumatol 2015;44:443-8.
Dear editor,
I read with interest the recently published new EULAR recommendations for managing the cardiovascular risk in patients with inflammatory rheumatic diseases [1]. They were long-awaited, and opportunely the targeted diseases are now broader, as previous ones focused primarily on chronic inflammatory arthritis [2].
With rising numbers worldwide, gout is a major cardiovascular risk factor directly linked to all forms of atherosclerotic diseases. By having gout, there is a 40% increased chance of dying from the coronary disease [3]. So, focused management to reduce these serious complications is necessary, and establishing an individual patient's risk is essential. Surprisingly, the experts rely on risk prediction using standard risk assessment tools, claiming the absence of validation studies. I should partially disagree at this point. Certainly, no longitudinal studies have evaluated the predicted rates of cardiovascular events in gout to date. However, our group studied the discriminative value of SCORE and Framingham tools in detecting patients with carotid plaques, a high-risk indicator [4]. A moderate discriminative capacity was unveiled, with areas under the curve of 0.711 for SCORE and 0.683 for Framingham [5]. Specificity was quite good, but the tools lacked enough sensitivity. Moreover, Gamala and colleagues incorporated gout into the modified Dutch SCORE as an inflammatory risk factor [6]. It led to a 28.3% upgrade to the high-risk stag...
Dear editor,
I read with interest the recently published new EULAR recommendations for managing the cardiovascular risk in patients with inflammatory rheumatic diseases [1]. They were long-awaited, and opportunely the targeted diseases are now broader, as previous ones focused primarily on chronic inflammatory arthritis [2].
With rising numbers worldwide, gout is a major cardiovascular risk factor directly linked to all forms of atherosclerotic diseases. By having gout, there is a 40% increased chance of dying from the coronary disease [3]. So, focused management to reduce these serious complications is necessary, and establishing an individual patient's risk is essential. Surprisingly, the experts rely on risk prediction using standard risk assessment tools, claiming the absence of validation studies. I should partially disagree at this point. Certainly, no longitudinal studies have evaluated the predicted rates of cardiovascular events in gout to date. However, our group studied the discriminative value of SCORE and Framingham tools in detecting patients with carotid plaques, a high-risk indicator [4]. A moderate discriminative capacity was unveiled, with areas under the curve of 0.711 for SCORE and 0.683 for Framingham [5]. Specificity was quite good, but the tools lacked enough sensitivity. Moreover, Gamala and colleagues incorporated gout into the modified Dutch SCORE as an inflammatory risk factor [6]. It led to a 28.3% upgrade to the high-risk stage. Until the existence of validation cohorts, these results should be considered. Using risk scales developed for the general population without including inflammatory items carries a significant probability of false-negative categorization, especially at the intermediate-risk level [5,6]. Conversely, a high-risk categorization is quite confident.
Furthermore, the 2022 Recommendations might have encouraged the routine use of carotid ultrasound to detect subclinical atherosclerosis - several papers sustain this approach in our diseases [7,8]. The process is quick and reliable, and the widespread presence of ultrasound in our clinics, not requiring specific probes or software, facilitates its implementation.
Cardiovascular comorbidity is an outstanding problem and remains the first cause of death in our rheumatic patients [9]. Therefore, a major step forward is needed to ameliorate it.
References.
1 Drosos GC, Vedder D, Houben E, et al. EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome. Annals of the Rheumatic Diseases Published Online First: 1 February 2022. doi:10.1136/annrheumdis-2021-221733
2 Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017;76:17–28. doi:10.1136/annrheumdis-2016-209775
3 Clarson LE, Chandratre P, Hider SL, et al. Increased cardiovascular mortality associated with gout: a systematic review and meta-analysis. Eur J Prev Cardiol 2015;22:335–43. doi:10.1177/2047487313514895
4 Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227–337. doi:10.1093/eurheartj/ehab484
5 Andrés M, Bernal JA, Sivera F, et al. Cardiovascular risk of patients with gout seen at rheumatology clinics following a structured assessment. Ann Rheum Dis 2017;76:1263–8. doi:10.1136/annrheumdis-2016-210357
6 Gamala M, Jacobs JWG, Linn-Rasker SP, et al. Cardiovascular risk in patients with new gout: should we reclassify the risk? Clin Exp Rheumatol 2020;38:533–5.
7 Roman MJ, Shanker B-A, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2399–406. doi:10.1056/NEJMoa035471
8 Corrales A, González-Juanatey C, Peiró ME, et al. Carotid ultrasound is useful for the cardiovascular risk stratification of patients with rheumatoid arthritis: results of a population-based study. Ann Rheum Dis 2014;73:722–7. doi:10.1136/annrheumdis-2012-203101
9 England BR, Sayles H, Michaud K, et al. Cause-Specific Mortality in Male US Veterans With Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2016;68:36–45. doi:10.1002/acr.22642
We thank the author for this comment and his interest in our report. We agree that obinutuzumab has shown efficacy in a phase 2 trial in rituximab-naïve SLE patients. In our report, three of four patients did not respond to rituximab prior to receiving obinutuzumab. In our CREST syndrome patient (case 4), the combined obinutuzumab/chemotherapy led to a remission of her chronic lymphatic leukemia; leukocyte counts dropped from >200/nl to normal values. During this therapy, cutaneous calcinosis located on the distal upper extremities gradually regressed until its disappearance in clinical examination. We thank the author for pointing out that due to multiple comedications the disappearance of calcinosis cannot be solely traced back to obinutuzumab. However, we are not aware of cases in which calcinosis resolved due to chemotherapy so that we think obinutuzumab might have been at least partially responsible for this improvement. Further studies are needed to corroborate the effect of obinutuzumab on cutaneous manifestations in systemic sclerosis.
We read with great interest the article by Corbera-Bellalta et al. entitled “Blocking GM-CSF Receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers, and neoangiogenesis in ex-vivo cultured arteries from patients with giant cell arteritis” (1). We believe that the study is of great importance because it demonstrates that blocking the GM-CSF pathway alleviates crucial pathological hallmarks of giant cell arteritis (GCA). These hallmarks include leukocyte infiltration, production of pro-inflammatory cytokines, tissue destructive matrix metalloproteinases (MMP’s), and neoangiogenesis. Additionally, the recently reported preliminary data of the first phase II clinical trial of mavrilimumab in combination with a 26-week glucocorticoid (GC) taper in GCA patients is very promising (2). The primary end point, being the difference in the time to first relapse between mavrilimumab treatment and placebo was achieved (p=0.0263). Moreover, the sustained remission rate at 26 weeks was higher in the mavrilimumab vs placebo group (83.2% vs 49.9%, respectively, p =0.0038).
Recently, we reported on a distinct CD206+ macrophage subset that produces YKL-40 and MMP-9 in GCA affected vessels (3, 4). We proposed a pathogenic model in which these CD206+ macrophages play major roles in fueling leukocyte infiltration, vascular destruction, and neoangiogenesis. Furthermore, we showed that these CD206+/MMP-9+/YKL-40+ tissue destructive and proinflammatory macrophage...
We read with great interest the article by Corbera-Bellalta et al. entitled “Blocking GM-CSF Receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers, and neoangiogenesis in ex-vivo cultured arteries from patients with giant cell arteritis” (1). We believe that the study is of great importance because it demonstrates that blocking the GM-CSF pathway alleviates crucial pathological hallmarks of giant cell arteritis (GCA). These hallmarks include leukocyte infiltration, production of pro-inflammatory cytokines, tissue destructive matrix metalloproteinases (MMP’s), and neoangiogenesis. Additionally, the recently reported preliminary data of the first phase II clinical trial of mavrilimumab in combination with a 26-week glucocorticoid (GC) taper in GCA patients is very promising (2). The primary end point, being the difference in the time to first relapse between mavrilimumab treatment and placebo was achieved (p=0.0263). Moreover, the sustained remission rate at 26 weeks was higher in the mavrilimumab vs placebo group (83.2% vs 49.9%, respectively, p =0.0038).
Recently, we reported on a distinct CD206+ macrophage subset that produces YKL-40 and MMP-9 in GCA affected vessels (3, 4). We proposed a pathogenic model in which these CD206+ macrophages play major roles in fueling leukocyte infiltration, vascular destruction, and neoangiogenesis. Furthermore, we showed that these CD206+/MMP-9+/YKL-40+ tissue destructive and proinflammatory macrophages are induced upon GM-CSF signaling. In agreement with our findings, Corbera-Bellata et al. show that blockade of the GM-CSF Receptor α with mavrilimumab resulted in marked reduction in expression of CD206 (transcript) and MMP-9 (transcript & protein levels), leukocyte infiltration and neoangiogenesis.
We would like to put forward that YKL-40, also known as human cartilage-glycoprotein 39 or Chitinase 3-like 1/CHI3L1), could be a relevant biomarker to aid GCA patient stratification for treatment with mavrilimumab. YKL-40 is highly expressed by macrophages in inflammatory conditions and its overexpression is highly driven by GM-CSF (4, 5). Additionally, YKL-40 has been reported to be one of the upstream signals for MMP-9 expression by macrophages involved in tissue destruction and in the promotion of neovessel formation, two crucial processes in the pathogenesis of GCA (6, 7). Our group has previously reported that serum levels of YKL-40 are elevated at diagnosis and remain elevated during GC treatment in GCA patients (4, 8). Furthermore, higher levels of YKL-40 at diagnosis predicted a longer duration of GC treatment (8). In line with elevated YKL-40 levels, myeloid cells are also elevated in the circulation of GCA patients at diagnosis and during GC treatment (9). In tissue, macrophages remain present in the vessel wall after GC treatment (10). Thus, it appears that macrophages producing YKL-40, likely skewed by GM-CSF, are insufficiently targeted by GC treatment. As mavrilimumab treatment blocks the GM-CSF pathway and thereby affects the myeloid compartment, patients with high YKL-40 levels at baseline may especially benefit from mavrilimumab treatment. Future studies should evaluate whether serum levels of YKL-40 predict the response to mavrilimumab. Furthermore, it would be interesting to determine to what extent mavrilimumab is able to suppress the persistent YKL-40 response in patients with GCA. Taken together, we propose that serum YKL-40 measurements could be of interest for precision medicine and monitoring treatment efficacy of patients with GCA in the context of mavrilimumab treatment.
References:
1. M. Corbera-Bellalta, et al., Blocking GM-CSF receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers and neoangiogenesis in ex vivo cultured arteries from patients with giant cell arteritis. Ann. Rheum. Dis., annrheumdis-2021-220873 (2022).
2. M. C. Cid, et al., Mavrilimumab (anti GM-CSF Receptor α Monoclonal Antibody) Reduces Time to Flare and Increases Sustained Remission in a Phase 2 Trial of Patients with Giant Cell Arteritis [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10).
3. W. F. Jiemy, et al., Distinct macrophage phenotypes skewed by local granulocyte macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐CSF) are associated with tissue destruction and intimal hyperplasia in giant cell arteritis. Clin. Transl. Immunol. 9 (2020).
4. Y. van Sleen, et al., A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL-40 - IL-13 Receptor α2 Axis. Arthritis Rheumatol. (2021) https:/doi.org/10.1002/ART.41887 (July 28, 2021).
5. J. S. Johansen, K. S. Krabbe, K. Moller, B. K. Pedersen, Circulating YKL-40 levels during human endotoxaemia. Clin. Exp. Immunol. 140, 343–348 (2005).
6. S. Libreros, R. Garcia-Areas, P. Keating, R. Carrio, V. L. Iragavarapu-Charyulu, Exploring the role of CHI3L1 in “pre-metastatic” lungs of mammary tumor-bearing mice. Front. Physiol. 4, 392 (2013).
7. R. Watanabe, et al., MMP (matrix metalloprotease)-9-producing monocytes enable T cells to invade the vessel wall and cause vasculitis. Circ. Res. 123, 700–715 (2018).
8. Y. van Sleen, et al., Markers of angiogenesis and macrophage products for predicting disease course and monitoring vascular inflammation in giant cell arteritis. Rheumatology (Oxford). 58, 1383–1392 (2019).
9. Y. van Sleen, et al., Leukocyte Dynamics Reveal a Persistent Myeloid Dominance in Giant Cell Arteritis and Polymyalgia Rheumatica. Front. Immunol. 10 (2019).
10. J. J. Maleszewski, et al., Clinical and pathological evolution of giant cell arteritis: A prospective study of follow-up temporal artery biopsies in 40 treated patients. Mod. Pathol. 30, 788–796 (2017).
We thank Cheng et al1 for their interest in our paper ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’.2 Below we provide point-by-point replies to the comments.
First, we would like to clarify the roles of digoxin and ouabain in this study. We performed three rounds of drug screening and found that only ouabain could robustly induce the expressions of anabolic marker genes, including COL2A1, aggrecan (ACAN) and cartilage oligomeric matrix protein (COMP).3,4 The fact that ouabain belongs to a family of cardenolides prompted us to determine whether other cardenolides also possess the similar anabolic effects in chondrocytes, which led to the isolation of digoxin as another cardenolide that could also induce the expressions of anabolic marker genes in chondrocytes. We appreciate the author’s statement that ouabain demonstrated better protection against OA in some assays mentioned in their correspondence. However, digoxin also showed significant protective effects against OA in multiple analyses performed, quite similar to ouabain. For instance, there is no difference in the osteophyte number between digoxin and ouabain treatment groups (Figure 2F and 2G). More importantly, digoxin is known to be the only safe inotropic drug for oral use that improves hemodynamics.5 This led us to hypothesize that records related to digoxin might be accessible in general practitioner based medical records databases. Indeed, we foun...
We thank Cheng et al1 for their interest in our paper ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’.2 Below we provide point-by-point replies to the comments.
First, we would like to clarify the roles of digoxin and ouabain in this study. We performed three rounds of drug screening and found that only ouabain could robustly induce the expressions of anabolic marker genes, including COL2A1, aggrecan (ACAN) and cartilage oligomeric matrix protein (COMP).3,4 The fact that ouabain belongs to a family of cardenolides prompted us to determine whether other cardenolides also possess the similar anabolic effects in chondrocytes, which led to the isolation of digoxin as another cardenolide that could also induce the expressions of anabolic marker genes in chondrocytes. We appreciate the author’s statement that ouabain demonstrated better protection against OA in some assays mentioned in their correspondence. However, digoxin also showed significant protective effects against OA in multiple analyses performed, quite similar to ouabain. For instance, there is no difference in the osteophyte number between digoxin and ouabain treatment groups (Figure 2F and 2G). More importantly, digoxin is known to be the only safe inotropic drug for oral use that improves hemodynamics.5 This led us to hypothesize that records related to digoxin might be accessible in general practitioner based medical records databases. Indeed, we found that digoxin was the only cardenolides drug included in the data from The Health Improvement Network (THIN). Results indicated that digoxin use was associated with reduced risk of knee or hip OA-associated joint replacement among patients with atrial fibrillation. Therefore, we chose both ouabain and digoxin as the representatives of cardenolides in this study and emphasized the potential importance of digoxin in treating patients with OA in clinics.
Second, it would be ideal and probably more valuable to focus on digoxin use in OA patients without other diseases, including atrail fibrillation. Unfortunately, such information is unavailable in the available database, including The Health Improvement Network (THIN), this is because of the fact that digoxin is only used in patients with atrial fibrillation with or without OA.
Both ouabain and digoxin are FDA-approved drugs and their side effects have been well established. In addition, both ouabain and digoxin did not show detectable toxicity in our in vitro and in vivo assays (online supplemental figure 11). Having said that, we do appreciate the comments that combined use of digoxin and ouabain with lower dosages of drugs may exert synergistic protective effects against OA and may reduce their side effects, which worthwhile further investigations in future.
REFERENCES
1 Cheng YZ, Zhou LJ and Hai Y. Correspondence on ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’ by Kai-di Wang. Ann Rheum Dis 2022.
2 Wang KD, Ding X, Jiang N, et al. Digoxin targets low density lipoprotein
receptor-related protein 4 and protects against osteoarthritis. Ann Rheum Dis 2021
De1: annrheumdis-2021-221380.
3 Fu WY, Hettinghouse A, Chen Y., et al., 14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis. Ann Rheum Dis 2021;80(12): p. 1615-1627.
4 Liu, RH, Chen YH, Fu WY, et al., Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis. Ann Rheum Dis 2019;78(11): p. 1524-1535.
5 Kjeldsen K, Nørgaard A, Gheorghiade M. Myocardial Na,K-ATPase: the molecular
basis for the hemodynamic effect of digoxin therapy in congestive heart failure.
Cardiovasc Res 2002;55:710–3.
We read with great interest the article by Eunji et al.1, who reported changes in target expression in patients with rheumatoid arthritis (RA), possibly via meQTL-mediated DMR, thereby affecting CD4+ T cell differentiation. The mechanism merits further attention, as it may provide insight into the cause of autoimmune disease.
As the authors stated, CD4+ T cells play an important role in the pathogenesis of RA. From February 2016 to October 2021, 2518 patients with RA in our hospital provided peripheral blood samples to test CD4+ T cell subsets by flow cytometry. Compared with 100 healthy controls (HCs), we observed altered CD4+ T cell numbers in RA patients. RA patients had a lower absolute number of regulatory T cells (Tregs) (P < 0.001) but a higher proportion of effector T cells, such as Th17 (P < 0.05) (Figure 1).
Recent major advances have been made in our understanding of genomic and epigenetic changes in arthritis, particularly regarding aberrant DNA methylation, microRNA and noncoding RNA deregulation, and altered histone modifications, which alter the transcriptional activity of genes involved in autoimmune responses2. In addition to the findings of Eunji et al. that mutation-driven methylation altered CD4+ T cell expression to increase RA risk, lncRNAs also played a key role in regulating CD4+ T cell gene signatures. In our study, high-throughput sequencing data from CD4+ T cell subpopulations of 27 RA patients and 24 HCs were obtained from GSE1...
We read with great interest the article by Eunji et al.1, who reported changes in target expression in patients with rheumatoid arthritis (RA), possibly via meQTL-mediated DMR, thereby affecting CD4+ T cell differentiation. The mechanism merits further attention, as it may provide insight into the cause of autoimmune disease.
As the authors stated, CD4+ T cells play an important role in the pathogenesis of RA. From February 2016 to October 2021, 2518 patients with RA in our hospital provided peripheral blood samples to test CD4+ T cell subsets by flow cytometry. Compared with 100 healthy controls (HCs), we observed altered CD4+ T cell numbers in RA patients. RA patients had a lower absolute number of regulatory T cells (Tregs) (P < 0.001) but a higher proportion of effector T cells, such as Th17 (P < 0.05) (Figure 1).
Recent major advances have been made in our understanding of genomic and epigenetic changes in arthritis, particularly regarding aberrant DNA methylation, microRNA and noncoding RNA deregulation, and altered histone modifications, which alter the transcriptional activity of genes involved in autoimmune responses2. In addition to the findings of Eunji et al. that mutation-driven methylation altered CD4+ T cell expression to increase RA risk, lncRNAs also played a key role in regulating CD4+ T cell gene signatures. In our study, high-throughput sequencing data from CD4+ T cell subpopulations of 27 RA patients and 24 HCs were obtained from GSE118829, which contains naive CD4+ T, central memory CD4+ T, and effector memory CD4+ T cell gene signatures. Using the RobustRankAggreg algorithm, we found that 75 integrated differentially expressed (DE) lncRNAs and 2730 DE mRNAs were co-expressed in naive, central memory, and effector memory CD4+ T cells (Figure 2A–C). In the mRNA expression profile, 489 common DE genes were used in the subsequent studies described below (Figure 2D).
We obtained 748 paired DE mRNAs and lncRNAs with a Pearson correlation coefficient > 0.7 and P < 0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the upregulated lncRNA-related mRNAs (lrmRNAs) were enriched in the Th17 cell differentiation pathway. In addition, several genes were enriched in the Jak/STAT signaling pathway, which is involved in the pathogenesis of RA (Figure 2E)3. Downregulated lrmRNAs were associated mainly with Th1 and Th2 cell differentiation. In addition, these genes were enriched in histone demethylation, which suggested that lrmRNAs affect methylation (Figure 2F)3.
These findings revealed the different CD4+ T cell subsets in patients with RA and revealed the role of lncRNAs in regulating CD4+ T transcriptomic features, which might be an important aspect of the methylation regulatory mechanism.
Reference:
1. Ha E, Bang SY, Lim J, et al. Genetic variants shape rheumatoid arthritis-specific transcriptomic features in CD4(+) T cells through differential DNA methylation, explaining a substantial proportion of heritability. Annals of the rheumatic diseases 2021;80(7):876-83. doi: 10.1136/annrheumdis-2020-219152 [published Online First: 2021/01/14]
2. Wang Z, Chang C, Lu Q. Epigenetics of CD4+ T cells in autoimmune diseases. Current opinion in rheumatology 2017;29(4):361-68. doi: 10.1097/bor.0000000000000393 [published Online First: 2017/04/01]
3. Deviatkin AA, Vakulenko YA, Akhmadishina LV, et al. Emerging Concepts and Challenges in Rheumatoid Arthritis Gene Therapy. Biomedicines 2020;8(1) doi: 10.3390/biomedicines8010009 [published Online First: 2020/01/16]
Contributors
Study design and manuscript writing: RZ, SS and JQ. Data extraction, quality assessment, analysis and interpretation of data: RZ, SS and JQ. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. P-FH and X-FL had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding
This work was supported by the National Natural Science Foundation of China (No. 82001740).
Conflict of interest statement
The authors declare that there is no conflict of nterest.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the Second Hospital of Shanxi Medical University (2016 KY-007).
Patient consent
The data was anonymous and the requirement for informed consent was waived.
Figure 1. Comparison of peripheral CD4+ T subsets between healthy controls (n = 100) and RA patients (n = 2518). The absolute counts (Figure A–D) and proportions (Figure E–H) of Th1 (CD4+IFN-γ+), Th2 (CD4+IL-4+), Th17 (CD4+IL-17+), and Tregs (CD4+CD25+FOXP3+) were determined by flow cytometry combined with standard absolute counting beads. Data are presented as the mean ± SD and were compared using unpaired two-tailed t-tests.
Figure 2. Common specific genes and enrichment analysis of CD4+ T cells. (A–C) The volcano plot shows that DE lncRNAs and DE mRNAs in central memory CD4+ T cell (CH), effector memory CD4+ T cell (EH), and naïve CD4+ T cell (NH) . Blue and red represent downregulated and upregulated lncRNAs and mRNAs, respectively. DE lncRNAs and DE mRNAs were selected based on P < 0.05. (D) Heatmap of the 75 DE lncRNAs determined using the RobustRankAggreg method with an adjusted P < 0.05. (E and F) Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology enrichment analyses of biological processes associated with the commonly expressed lncRNA-related mRNAs, which included 250 upregulated and 121 downregulated genes.
Dear Editor, we read the article entitle “Attenuated response to fourth dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series [1]” with a great interest. The efficacy of COVID-19 vaccine among specific groups of vaccine recipients with underlying disease is a current important clinical issue. For many groups of patients, including to those with autoimmune diseases, the low immune response to standard vaccination is observed. Extra-dose vaccination is proposed. For the fourth dose of COVID-19 vaccine, it is currently a new idea. Few reports are published. The clinical evidence is required for supporting whether the fourth dose of vaccine will be useful or not and whether there will be any risk of too much vaccination [2]. This report is one of an early publication on this issue. A previous publication is on kidney transplant case. As expected, the high immune response after the fourth dose of vaccine is observed [3]. However, as also seen in the present report, there are various types of first, second and third dose vaccines that each subject in the series received and it might affect the final immune response after the fourth dose vaccine administration. Also, there is usually no confirmation to rule out a possible incidence of asymptomatic COVID-19 infection which might occur in the period between doses of COVID-19 vaccines. These important concerns should be addressed and control of those confounding factors is important if further clinical res...
Dear Editor, we read the article entitle “Attenuated response to fourth dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series [1]” with a great interest. The efficacy of COVID-19 vaccine among specific groups of vaccine recipients with underlying disease is a current important clinical issue. For many groups of patients, including to those with autoimmune diseases, the low immune response to standard vaccination is observed. Extra-dose vaccination is proposed. For the fourth dose of COVID-19 vaccine, it is currently a new idea. Few reports are published. The clinical evidence is required for supporting whether the fourth dose of vaccine will be useful or not and whether there will be any risk of too much vaccination [2]. This report is one of an early publication on this issue. A previous publication is on kidney transplant case. As expected, the high immune response after the fourth dose of vaccine is observed [3]. However, as also seen in the present report, there are various types of first, second and third dose vaccines that each subject in the series received and it might affect the final immune response after the fourth dose vaccine administration. Also, there is usually no confirmation to rule out a possible incidence of asymptomatic COVID-19 infection which might occur in the period between doses of COVID-19 vaccines. These important concerns should be addressed and control of those confounding factors is important if further clinical researches on the fourth dose of COVID-19 vaccine is planned.
Conflict of interest
Authors ask for waiving for any charge for this correspondence.
References
1. Teles M, Connolly CM, Frey S, Chiang TP, Alejo JJ, Boyarsky BJ, Shah AA, Albayda J, Christopher-Stine L, Werbel WA, Segev DL, Paik JJ. Attenuated response to fourth dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series. Ann Rheum Dis. 2022 Jan 17:annrheumdis-2021-221641. doi: 10.1136/annrheumdis-2021-221641. Online ahead of print.
2. Burki TK. Fourth dose of COVID-19 vaccines in Israel. Lancet Respir Med. 2022 Jan 11:S2213-2600(22)00010-8.
3. . Caillard S, Thaunat O, Benotmane I, Masset C, Blancho G. Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case SeriesAnn Intern Med. 2022 Jan 11:L21-0598. doi: 10.7326/L21-0598. Online ahead of print.Kamar N, Abravanel F, Marion O, Romieu-Mourez R, Couat C, Del Bello A, Izopet J. Assessment of 4 Doses of SARS-CoV-2 Messenger RNA-Based Vaccine in Recipients of a Solid Organ Transplant. JAMA Netw Open. 2021 Nov 1;4(11):e2136030.
Dear Editor,
I want to congratulate Kvacskay et al. on an ingenious case series. While we have had evidence of the efficacy of obninutuzumab in lupus nephritis (2) in phase 2 trials and the RIM trial did show the efficacy of rituximab in anti-Jo1 positive myositis hence the expected responses with obinutuzumab, owing to its greater and more effective B cell depletion. The most interesting of the cases was case 4, where, according to the authors, obinutuzumab led to clearance of calcinosis in the patient. In a case series by Narváez et al.(4) only 50% of the patients with calcinosis in systemic sclerosis responded to rituximab (none of them had a complete response) in the systematic review, only one patient had a complete response to the treatment; overall among 19 patients, only 1 had complete response, so complete response with obinutuzumab is quite exciting as nothing sort of works for calcinosis.
When the authors mean complete response, do they mean complete radiological response and clinical response?
Also, the patient was given chlorambucil and bendamustine for her CLL, so the authors' attributing the response was solely due to obinutuzumab is doubtful.
1. Kvacskay P, Merkt W, Günther J, et al. Obinutuzumab in connective tissue diseases after former rituximab-non-response: a case series. Annals of the Rheumatic Diseases. Published Online First: 13 January 2022. doi: 10.1136/annrheumdis-2021-221756
2.Furie RA, Aroca G, Cascino MD, e...
Dear Editor,
I want to congratulate Kvacskay et al. on an ingenious case series. While we have had evidence of the efficacy of obninutuzumab in lupus nephritis (2) in phase 2 trials and the RIM trial did show the efficacy of rituximab in anti-Jo1 positive myositis hence the expected responses with obinutuzumab, owing to its greater and more effective B cell depletion. The most interesting of the cases was case 4, where, according to the authors, obinutuzumab led to clearance of calcinosis in the patient. In a case series by Narváez et al.(4) only 50% of the patients with calcinosis in systemic sclerosis responded to rituximab (none of them had a complete response) in the systematic review, only one patient had a complete response to the treatment; overall among 19 patients, only 1 had complete response, so complete response with obinutuzumab is quite exciting as nothing sort of works for calcinosis.
When the authors mean complete response, do they mean complete radiological response and clinical response?
Also, the patient was given chlorambucil and bendamustine for her CLL, so the authors' attributing the response was solely due to obinutuzumab is doubtful.
1. Kvacskay P, Merkt W, Günther J, et al. Obinutuzumab in connective tissue diseases after former rituximab-non-response: a case series. Annals of the Rheumatic Diseases. Published Online First: 13 January 2022. doi: 10.1136/annrheumdis-2021-221756
2.Furie RA, Aroca G, Cascino MD, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Annals of the Rheumatic Diseases 2022;81:100-107.
3. Oddis CV, Reed AM, Aggarwal R, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013;65(2):314-324. doi:10.1002/art.37754
4. Narváez, Javier et al. “Effectiveness and safety of rituximab for the treatment of refractory systemic sclerosis associated calcinosis: A case series and systematic review of the literature.” Autoimmunity reviews vol. 18,3 (2019): 262-269. doi:10.1016/j.autrev.2018.10.006
We read with great interest the recent article written by Araujo CSR et al entitled “Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomized clinical trial” published in the Annals of Rheumatic Diseases on February 22, 2022 [1]. The major impact of this trial was the reinforcement of the immunogenic effect of a 2-week methotrexate discontinuation after each dose of the Sinovac-CoronaVac vaccine against SARS-CoV-2 compared to methotrexate continuation in patients with rheumatoid arthritis (seroconversion rates: 78.4% vs 54.5%, p-0.019 and geometric mean antibody titers: 34.2 (25.2–46.4) vs 16.8 (11.9–23.6), p=0.003, respectively).
Previous experience with other non-COVID-19 vaccines, like the influenza or pneumococcal vaccines, has indicated that discontinuation of immunosuppresants improves the immunogenicity of a given vaccine [2,3]. Based on this knowledge, we had proposed that it would be beneficial for patients with autoimmune rheumatic diseases to get vaccinated against SARS-CoV-2 preferably when the underlying rheumatic disease is in remission and after temporal withdrawal of anti-metabolites within 10 days before and after each vaccine dose along with similar modifications in anti-cytokine drugs and corticosteroid dosages >10mg/ day (prednisone equivalent) [4]. In fact, applying that in a comparative study it was shown that the magnitude of antibody responses to mRNA-based S...
Show MoreUgarte-Gil, et al (1) recently published a study reporting several characteristics associated with severe COVID-19 outcomes in people with systemic lupus erythematosus(SLE). Demographic factors, comorbidities, active or untreated SLE, and patients treated with glucocorticoids were the most noticeable features. Even though several covariates had been taken into consideration to minimize the impacts of these confounders, we presume vaccination could play a crucial role in the COVID-19 outcomes.
Show MorePrevious studies had pointed out the protective effect that vaccination could provide against poor outcomes in the general population (2). In spite of a lack of evidence on the efficacy of COVID-19 vaccines in patients with SLE, achieving adequate sero-protection after receiving COVID-19 vaccine could be expected according to the expert opinion based on the knowledge on the use of other vaccines in this specific group of patients (3). A review article published by Wei Tang, et al (4) showed that commonly used immunosuppressants inclusive of glucocorticoids, methotrexate, mycophenolate mofetil/mycophenolic acid and rituximab might impede vaccine responses, causing less sufficient immune responses after getting COVID-19 vaccines in SLE patients. Hence, we suggest a subgroup analysis according to whether being vaccinated or not to have better data interpretation and to clarify the possible factors that may lead to critical consequences in SLE patients infected with COVID-19.
...
We read with great interest the recent publication by Balsa et al.,[1] which reported that patient–physician agreement on the treatment, the type of treatment prescribed (favoring second-line conventional disease-modifying rheumatic drugs and biological disease-modifying rheumatic drugs/targeted synthetic disease-modifying rheumatic drugs), and the patient feeling privileged by the medication received are effective predictors of medication adherence in patients with rheumatoid arthritis (RA). In contrast, sociodemographic or clinical factors were not associated with medication adherence. This study focuses on medication adherence as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
Show MoreFirst, epidemiologists agree that studies assessing a relation at one moment in time are called cross-sectional studies.[2] If the follow-up time is considered, the study is longitudinal, and it is either a cohort or a case-control study. A cohort or a case-control study must be applied to variables that can be reasonably assumed stable over time. However, this study was a six-month multicentre observational longitudinal prospective study, and medication adherence is related to psychological, communicational, and logistic factors measured at the same time. Therefore, this study is better labeled a cross-sectional study, since psychological, communicational, and logistic factors cannot be assumed to be...
Dear editor,
I read with interest the recently published new EULAR recommendations for managing the cardiovascular risk in patients with inflammatory rheumatic diseases [1]. They were long-awaited, and opportunely the targeted diseases are now broader, as previous ones focused primarily on chronic inflammatory arthritis [2].
With rising numbers worldwide, gout is a major cardiovascular risk factor directly linked to all forms of atherosclerotic diseases. By having gout, there is a 40% increased chance of dying from the coronary disease [3]. So, focused management to reduce these serious complications is necessary, and establishing an individual patient's risk is essential. Surprisingly, the experts rely on risk prediction using standard risk assessment tools, claiming the absence of validation studies. I should partially disagree at this point. Certainly, no longitudinal studies have evaluated the predicted rates of cardiovascular events in gout to date. However, our group studied the discriminative value of SCORE and Framingham tools in detecting patients with carotid plaques, a high-risk indicator [4]. A moderate discriminative capacity was unveiled, with areas under the curve of 0.711 for SCORE and 0.683 for Framingham [5]. Specificity was quite good, but the tools lacked enough sensitivity. Moreover, Gamala and colleagues incorporated gout into the modified Dutch SCORE as an inflammatory risk factor [6]. It led to a 28.3% upgrade to the high-risk stag...
Show MoreWe thank the author for this comment and his interest in our report. We agree that obinutuzumab has shown efficacy in a phase 2 trial in rituximab-naïve SLE patients. In our report, three of four patients did not respond to rituximab prior to receiving obinutuzumab. In our CREST syndrome patient (case 4), the combined obinutuzumab/chemotherapy led to a remission of her chronic lymphatic leukemia; leukocyte counts dropped from >200/nl to normal values. During this therapy, cutaneous calcinosis located on the distal upper extremities gradually regressed until its disappearance in clinical examination. We thank the author for pointing out that due to multiple comedications the disappearance of calcinosis cannot be solely traced back to obinutuzumab. However, we are not aware of cases in which calcinosis resolved due to chemotherapy so that we think obinutuzumab might have been at least partially responsible for this improvement. Further studies are needed to corroborate the effect of obinutuzumab on cutaneous manifestations in systemic sclerosis.
We read with great interest the article by Corbera-Bellalta et al. entitled “Blocking GM-CSF Receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers, and neoangiogenesis in ex-vivo cultured arteries from patients with giant cell arteritis” (1). We believe that the study is of great importance because it demonstrates that blocking the GM-CSF pathway alleviates crucial pathological hallmarks of giant cell arteritis (GCA). These hallmarks include leukocyte infiltration, production of pro-inflammatory cytokines, tissue destructive matrix metalloproteinases (MMP’s), and neoangiogenesis. Additionally, the recently reported preliminary data of the first phase II clinical trial of mavrilimumab in combination with a 26-week glucocorticoid (GC) taper in GCA patients is very promising (2). The primary end point, being the difference in the time to first relapse between mavrilimumab treatment and placebo was achieved (p=0.0263). Moreover, the sustained remission rate at 26 weeks was higher in the mavrilimumab vs placebo group (83.2% vs 49.9%, respectively, p =0.0038).
Recently, we reported on a distinct CD206+ macrophage subset that produces YKL-40 and MMP-9 in GCA affected vessels (3, 4). We proposed a pathogenic model in which these CD206+ macrophages play major roles in fueling leukocyte infiltration, vascular destruction, and neoangiogenesis. Furthermore, we showed that these CD206+/MMP-9+/YKL-40+ tissue destructive and proinflammatory macrophage...
Show MoreWe thank Cheng et al1 for their interest in our paper ‘Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis’.2 Below we provide point-by-point replies to the comments.
Show MoreFirst, we would like to clarify the roles of digoxin and ouabain in this study. We performed three rounds of drug screening and found that only ouabain could robustly induce the expressions of anabolic marker genes, including COL2A1, aggrecan (ACAN) and cartilage oligomeric matrix protein (COMP).3,4 The fact that ouabain belongs to a family of cardenolides prompted us to determine whether other cardenolides also possess the similar anabolic effects in chondrocytes, which led to the isolation of digoxin as another cardenolide that could also induce the expressions of anabolic marker genes in chondrocytes. We appreciate the author’s statement that ouabain demonstrated better protection against OA in some assays mentioned in their correspondence. However, digoxin also showed significant protective effects against OA in multiple analyses performed, quite similar to ouabain. For instance, there is no difference in the osteophyte number between digoxin and ouabain treatment groups (Figure 2F and 2G). More importantly, digoxin is known to be the only safe inotropic drug for oral use that improves hemodynamics.5 This led us to hypothesize that records related to digoxin might be accessible in general practitioner based medical records databases. Indeed, we foun...
We read with great interest the article by Eunji et al.1, who reported changes in target expression in patients with rheumatoid arthritis (RA), possibly via meQTL-mediated DMR, thereby affecting CD4+ T cell differentiation. The mechanism merits further attention, as it may provide insight into the cause of autoimmune disease.
Show MoreAs the authors stated, CD4+ T cells play an important role in the pathogenesis of RA. From February 2016 to October 2021, 2518 patients with RA in our hospital provided peripheral blood samples to test CD4+ T cell subsets by flow cytometry. Compared with 100 healthy controls (HCs), we observed altered CD4+ T cell numbers in RA patients. RA patients had a lower absolute number of regulatory T cells (Tregs) (P < 0.001) but a higher proportion of effector T cells, such as Th17 (P < 0.05) (Figure 1).
Recent major advances have been made in our understanding of genomic and epigenetic changes in arthritis, particularly regarding aberrant DNA methylation, microRNA and noncoding RNA deregulation, and altered histone modifications, which alter the transcriptional activity of genes involved in autoimmune responses2. In addition to the findings of Eunji et al. that mutation-driven methylation altered CD4+ T cell expression to increase RA risk, lncRNAs also played a key role in regulating CD4+ T cell gene signatures. In our study, high-throughput sequencing data from CD4+ T cell subpopulations of 27 RA patients and 24 HCs were obtained from GSE1...
Dear Editor, we read the article entitle “Attenuated response to fourth dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case series [1]” with a great interest. The efficacy of COVID-19 vaccine among specific groups of vaccine recipients with underlying disease is a current important clinical issue. For many groups of patients, including to those with autoimmune diseases, the low immune response to standard vaccination is observed. Extra-dose vaccination is proposed. For the fourth dose of COVID-19 vaccine, it is currently a new idea. Few reports are published. The clinical evidence is required for supporting whether the fourth dose of vaccine will be useful or not and whether there will be any risk of too much vaccination [2]. This report is one of an early publication on this issue. A previous publication is on kidney transplant case. As expected, the high immune response after the fourth dose of vaccine is observed [3]. However, as also seen in the present report, there are various types of first, second and third dose vaccines that each subject in the series received and it might affect the final immune response after the fourth dose vaccine administration. Also, there is usually no confirmation to rule out a possible incidence of asymptomatic COVID-19 infection which might occur in the period between doses of COVID-19 vaccines. These important concerns should be addressed and control of those confounding factors is important if further clinical res...
Show MoreDear Editor,
I want to congratulate Kvacskay et al. on an ingenious case series. While we have had evidence of the efficacy of obninutuzumab in lupus nephritis (2) in phase 2 trials and the RIM trial did show the efficacy of rituximab in anti-Jo1 positive myositis hence the expected responses with obinutuzumab, owing to its greater and more effective B cell depletion. The most interesting of the cases was case 4, where, according to the authors, obinutuzumab led to clearance of calcinosis in the patient. In a case series by Narváez et al.(4) only 50% of the patients with calcinosis in systemic sclerosis responded to rituximab (none of them had a complete response) in the systematic review, only one patient had a complete response to the treatment; overall among 19 patients, only 1 had complete response, so complete response with obinutuzumab is quite exciting as nothing sort of works for calcinosis.
When the authors mean complete response, do they mean complete radiological response and clinical response?
Also, the patient was given chlorambucil and bendamustine for her CLL, so the authors' attributing the response was solely due to obinutuzumab is doubtful.
1. Kvacskay P, Merkt W, Günther J, et al. Obinutuzumab in connective tissue diseases after former rituximab-non-response: a case series. Annals of the Rheumatic Diseases. Published Online First: 13 January 2022. doi: 10.1136/annrheumdis-2021-221756
Show More2.Furie RA, Aroca G, Cascino MD, e...
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