With great interest, we read the article by Wang Y et al., which suggested that Megakaryocytes (MKs) expansion might contribute to the pathogenesis of Rheumatoid Arthritis (RA)1. MKs are large, polyploid cells that originate from hematopoietic stem cells (HSC) and give rise to platelets. However, the authors fall short in recognizing the role of MK-derived platelets in RA.
Wang Y et al. identified increased MKs in peripheral blood of RA using single-cell RNA sequencing and flow cytometry approaches. They provide clues that MKs act as specific endogenous antigen-presenting cells (APCs), triggering the initial autoimmune T cell for RA pathogenesis1. Of note, novel evidence suggests that MKs derived from bone marrow (BM), lung2 and liver3, instead serve as immunomodulatory or secretory cells4. The generation of platelets is the primary function of MKs.
Indeed, many characteristics and roles of platelets inherit from MKs. For example, once activated, platelets present antigens via MHC class I molecules (MHC-I) derived from parent MKs5; in this way, the immunogenic information can be conveyed to platelets. Similarly, platelets can also act as an essential immune effector in RA6. An array of platelet surface receptors is responsible for activation, adhesion, and thrombus formation via initiating a complex network of signaling pathways in the presence of ligands. In addition, it is well known that ligands for platelet receptors such as collagen, fibrinogen, serotonin,...
With great interest, we read the article by Wang Y et al., which suggested that Megakaryocytes (MKs) expansion might contribute to the pathogenesis of Rheumatoid Arthritis (RA)1. MKs are large, polyploid cells that originate from hematopoietic stem cells (HSC) and give rise to platelets. However, the authors fall short in recognizing the role of MK-derived platelets in RA.
Wang Y et al. identified increased MKs in peripheral blood of RA using single-cell RNA sequencing and flow cytometry approaches. They provide clues that MKs act as specific endogenous antigen-presenting cells (APCs), triggering the initial autoimmune T cell for RA pathogenesis1. Of note, novel evidence suggests that MKs derived from bone marrow (BM), lung2 and liver3, instead serve as immunomodulatory or secretory cells4. The generation of platelets is the primary function of MKs.
Indeed, many characteristics and roles of platelets inherit from MKs. For example, once activated, platelets present antigens via MHC class I molecules (MHC-I) derived from parent MKs5; in this way, the immunogenic information can be conveyed to platelets. Similarly, platelets can also act as an essential immune effector in RA6. An array of platelet surface receptors is responsible for activation, adhesion, and thrombus formation via initiating a complex network of signaling pathways in the presence of ligands. In addition, it is well known that ligands for platelet receptors such as collagen, fibrinogen, serotonin, ADP, and pro-inflammatory molecules are dysregulated in RA6, leading to an increased interaction with platelet receptors. This elevated cascade reaction allows platelets and their microparticles to become pro-inflammatory entities themselves, modulate immune cells, and then influence disease activity. Hence, we presumed that MK could promote RA in a platelet-dependent or/and independent manner.
In conclusion, we appreciate the work of Wang, Y. et al. for providing new insight into the potential pathogenesis of patients with RA. We suggest that considering the platelet as a potential concern for MK expansion may give clinicians one more light on treatment in the future.
Reference
1. Wang Y, Xie X, Zhang C, et al. Rheumatoid arthritis, systemic lupus erythematosus and primary Sjogren's syndrome shared megakaryocyte expansion in peripheral blood. Annals of the rheumatic diseases 2021 doi: 10.1136/annrheumdis-2021-220066 [published Online First: 2021/09/01]
2. Pariser DN, Hilt ZT, Ture SK, et al. Lung megakaryocytes are immune modulatory cells. The Journal of clinical investigation 2021;131(1) doi: 10.1172/JCI137377 [published Online First: 2020/10/21]
3. Wang H, He J, Xu C, et al. Decoding Human Megakaryocyte Development. Cell Stem Cell 2021;28(3):535-49 e8. doi: 10.1016/j.stem.2020.11.006 [published Online First: 2020/12/20]
4. Tilburg J, Becker IC, Italiano JE. Don't you forget about me(gakaryocytes). Blood 2021 doi: 10.1182/blood.2020009302 [published Online First: 2021/09/29]
5. Marcoux G, Laroche A, Hasse S, et al. Platelet EVs contain an active proteasome involved in protein processing for antigen presentation via MHC-I molecules. Blood 2021 doi: 10.1182/blood.2020009957 [published Online First: 2021/07/23]
6. Olumuyiwa-Akeredolu OO, Page MJ, Soma P, et al. Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis. Nat Rev Rheumatol 2019;15(4):237-48. doi: 10.1038/s41584-019-0187-9 [published Online First: 2019/03/03]
We read with interest the Viewpoint article by Braun and Landewé regarding post-hoc analysis of back pain in trials of IL-23 inhibitor therapy in patients with peripheral psoriatic arthritis (PsA) [1]. Indeed, we share their concerns regarding study design, the use of outcome measures developed for axial spondyloarthritis (axSpA) and, most importantly, the attribution of the diagnostic label “physician-reported spondylitis” in these patients. In addition to the issues eloquently outlined in the article, it is important to be aware that the pre-test probability of inflammatory disease being directly responsible for back pain is likely much lower in patients with PsA who are older, and therefore more likely to have mechanical or non-specific back pain, than people presenting with axSpA. In other words, even before doing any test, a middle-aged person with PsA, as represented in most phase III PsA clinical trials, is more likely to have non-inflammatory than inflammatory back pain. These “causes” of back pain do of course co-exist and are not easily distinguished by clinical or imaging assessments. For example, disc and degenerative spinal disease can lead to apparent inflammatory features, such as bone marrow oedema on magnetic resonance imaging [2, 3] that are likely a secondary response to altered biomechanical stresses rather than primary inflammatory disease and therefore unlikely to be responsive to biologic therapies. Furthermore, imaging data on the prevalence and na...
We read with interest the Viewpoint article by Braun and Landewé regarding post-hoc analysis of back pain in trials of IL-23 inhibitor therapy in patients with peripheral psoriatic arthritis (PsA) [1]. Indeed, we share their concerns regarding study design, the use of outcome measures developed for axial spondyloarthritis (axSpA) and, most importantly, the attribution of the diagnostic label “physician-reported spondylitis” in these patients. In addition to the issues eloquently outlined in the article, it is important to be aware that the pre-test probability of inflammatory disease being directly responsible for back pain is likely much lower in patients with PsA who are older, and therefore more likely to have mechanical or non-specific back pain, than people presenting with axSpA. In other words, even before doing any test, a middle-aged person with PsA, as represented in most phase III PsA clinical trials, is more likely to have non-inflammatory than inflammatory back pain. These “causes” of back pain do of course co-exist and are not easily distinguished by clinical or imaging assessments. For example, disc and degenerative spinal disease can lead to apparent inflammatory features, such as bone marrow oedema on magnetic resonance imaging [2, 3] that are likely a secondary response to altered biomechanical stresses rather than primary inflammatory disease and therefore unlikely to be responsive to biologic therapies. Furthermore, imaging data on the prevalence and natural history of spinal involvement in PsA are limited. We therefore agree that more research is required to both define inflammatory axial involvement in PsA (for which global initiatives are ongoing, as outlined by Braun and Landewé) and to evaluate the effect of specific therapies on this component of psoriatic disease. The latter will need to be tested in appropriately recruited PsA populations and will likely require comparison between active therapies with similar efficacy in both peripheral joint and skin disease to mitigate for the bystander effect resulting from improvements in these non-axial domains.
However, until this is resolved, clinicians are faced with a dilemma when choosing a biologic therapy for PsA patients with significant spinal symptoms. Indeed, where spinal symptoms are the sole or dominant musculoskeletal complaint in a person with psoriasis, there is clearly a requirement to determine, as far as possible, whether or not there is likely to be active inflammatory axial disease to warrant biologic therapy. This should be done using a combination of clinical, imaging and laboratory assessment, while also taking into account context and likelihood. However, in PsA patients with spinal symptoms who also have significant active peripheral joint disease that warrants biologic therapy in its own right, should IL-23 inhibitors be avoided on the basis of the negative data from for these agents in axSpA trials [4, 5]? For now, we believe that in light of the difficulty in determining the nature of the axial involvement in PsA, treatment decisions should be based on considerations relating to peripheral musculoskeletal disease, extent of cutaneous psoriasis, previous therapies, extra-articular manifestations, comorbidities and safety to select the most appropriate therapy for these patients. While we agree with Braun and Landewé that the current post-hoc analyses do not prove that IL-23 inhibitors are efficacious for inflammatory axial disease in PsA, we suggest that, until further robust evidence is available, the presence of axial symptoms, whether inflammatory or non-inflammatory, should not be considered a reason to avoid IL-23 inhibitor therapy, if that is perceived to be otherwise the most appropriate and safest choice for that individual’s peripheral musculoskeletal and cutaneous disease.
REFERENCES
1. Braun J, Landewé R. No efficacy of anti-IL-23 therapy for axial spondyloarthritis in randomised controlled trials but in post-hoc analyses of psoriatic arthritis-related ‘physician-reported spondylitis’? Ann Rheum Dis Published Online First: 16 October 2021. doi: 10.1136/annrheumdis-2021-221422
2. Tsoi C, Griffith JF, Lee RKL, et al Imaging of sacroiliitis: Current status, limitations and pitfalls. Quant Imaging Med Surg 2019;9:318-35
3. Berthelot JM, le Goff B, Maugars Y, et al. Sacroiliac joint edema by MRI: Far more often mechanical than inflammatory? Joint Bone Spine 2016;83:3-5
4. Deodhar A, Gensler LS, Sieper J, et al. Three multicenter, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of ustekinumab in axial spondyloarthritis. Arthritis Rheumatol 2019;71:258–70.
5. Baeten D, Østergaard M, Wei JC-C, et al. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann Rheum Dis 2018;77:1295–302.
ACKNOWLEDGEMENTS
HM-O is supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Thank you for pointing out that the conclusion was not clear. The authors would like to modify it to 'The interim analysis revealed that up to 66% of patients receiving APR reached REM/LDA, as measured by cDAPSA at 8 months.'
I read with great interest the article by Trahtemberg et al.[1] on the clinical relevance of antiphospholipid antibodies (aPLs), in particular anticardiolipin antibodies (aCLs), in critically-ill COVID-19 positive and negative patients. Severe COVID-19 is associated with a hypercoagulable state. Early studies identified the presence of aPLs in critically-ill COVID-19 patients[2], which has attracted considerable attention as the presence of aPLs is one of the mechanisms leading to coagulopathy. Substantial efforts then tried to associate the thrombotic events seen in COVID-19 to aPLs status. The results seem negative, but a number of different types of autoantibodies were identified [3]. Chang et al. recently reported that autoantibodies were present in approximately half of the hospitalized COVID-19 patients, but in less than 15% of healthy controls [4]. In addition to aCLs and anti-beta 2 glycoprotein 1 antibodies (aβ2-GP1), they also identified autoantibodies targeting autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes as well as targeting interferons/interleukins and other cytokines[4]. These findings suggest that COVID-19, in particular patients with severe/critical conditions, displayed certain autoimmune features.
In the well-designed study by Trahtemberg et al., the authors expanded the cohort by including COVID-19 negative patients who were admitted to intensive care unit (ICU) with ac...
I read with great interest the article by Trahtemberg et al.[1] on the clinical relevance of antiphospholipid antibodies (aPLs), in particular anticardiolipin antibodies (aCLs), in critically-ill COVID-19 positive and negative patients. Severe COVID-19 is associated with a hypercoagulable state. Early studies identified the presence of aPLs in critically-ill COVID-19 patients[2], which has attracted considerable attention as the presence of aPLs is one of the mechanisms leading to coagulopathy. Substantial efforts then tried to associate the thrombotic events seen in COVID-19 to aPLs status. The results seem negative, but a number of different types of autoantibodies were identified [3]. Chang et al. recently reported that autoantibodies were present in approximately half of the hospitalized COVID-19 patients, but in less than 15% of healthy controls [4]. In addition to aCLs and anti-beta 2 glycoprotein 1 antibodies (aβ2-GP1), they also identified autoantibodies targeting autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes as well as targeting interferons/interleukins and other cytokines[4]. These findings suggest that COVID-19, in particular patients with severe/critical conditions, displayed certain autoimmune features.
In the well-designed study by Trahtemberg et al., the authors expanded the cohort by including COVID-19 negative patients who were admitted to intensive care unit (ICU) with acute respiratory failure. They found that aCLs were present in 59% severe COVID-19 patients, but were also detected in 35% contemporaneous non-COVID-19 patients. They also identified the presence of a broad range of non-antiphospholipid syndrome (APS) autoantibodies as well as anti-cytokine autoantibodies. Specifically, over 50% patients were positive for anti-nuclear antibodies (ANA), and 38% patients were positive for anti-cytokine autoantibodies [1]. These findings thus confirmed and extended previous observations that the autoimmune feature may be not restricted to severe COVID-19, but may be a common feature of severe respiratory diseases.
aPLs can be induced in a number of virus infections, but ANA and other autoantibodies are normally absent [5]. However, a broad range of autoantibodies, in particular ANA, are present in severe COVID-19, rendering the severe COVID-19 more resemble of a systemic autoimmune disease. In fact, by detailed characterization of B cell responses through high-dimensional flow cytometry, Woodruff et al. have found that the immunological landscape associated with effector B cell mobilization in COVID-19 is highly similar to the one observed in patients with active autoimmune processes, and in particular with active systemic lupus erythematosus (SLE)[6]. Instead of predicting thrombotic events, the autoimmune features may be associated with disease severity. Trahtemberg et al.[1] found that the presence of aCLs was associated with more severe disease independent of COVID-19 status, which is consistent with the findings by Woodruff et al., who have found that disease severity and poor clinical outcomes of COVID-19 are closely correlated with intense activation of the extrafollicular B cell pathway that leads to the generation of autoreactive antibody-secreting cell (ASCs) responses [6]. Multiple tissues/organs damage due to widespread and overwhelming inflammation (i.e. cytokine storm) during severe COVID-19 may result in excessive generation and accumulation of autoantigens [7], which could boost production of autoantibodies that had previously existed at very low levels in the body.
Although Trahtemberg et al.’s work provide critical insights that transient breakage of immune tolerance and the generation of autoantibodies may be a common phenomenon in severe viral infections, a number of questions need to be answered in furture studies. For example, the presence of autoantibodies in COVID-19 displayed substantial heterogeneity in terms of types and titers. For example, Trahtemberg et al. [1] failed to detect aβ2-GP1 in patients with COVID-19, but other studies reported the existence of these aPLs [2, 4, 8, 9]. Xiao et al. showed that the levels of aPLs rapidly decreased after hitting the peak [9]. It seems that the emergence of autoantibodies is due to a sporadic loss of self-tolerance. It thus remains unknown when aPLs first emerged and the chronological order of the emergence of different aPLs. It also remains unclear whether ANAs and other autoantibodies (i.e. anti-cytokine antibodies) follow the similar pattern. The timing of sample collection seems an important factor. Second, COVID-19 and some autoimmune disorders (i.e. SLE or APS) share some clinical and laboratory similarities. It has been reported that some patients develop autoimmune diseases, such as Guillain-Barre syndrome or SLE, after COVID-19 infection [10]. It is thus unclear whether or not COVID-19 infection accelerates the pathological process in these predisposed subjects, or just a coincidence. Third, it remains to be determined whether or not vaccinated subjects develop autoantibodies after being infected by SARS-CoV-2, especially in those who have severe COVID-19.
References
1. Trahtemberg U, Rottapel R, Dos Santos CC, Slutsky AS, Baker A, Fritzler MJ. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Ann Rheum Dis. 2021 Sep; 80(9):1236-1240.
2. Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 23; 382(17):e38.
3. Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol. 2020 Aug; 217:108480.
4. Chang SE, Feng A, Meng W, Apostolidis SA, Mack E, Artandi M, et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun. 2021 Sep 14; 12(1):5417.
5. Mendoza-Pinto C, Garcia-Carrasco M, Cervera R. Role of Infectious Diseases in the Antiphospholipid Syndrome (Including Its Catastrophic Variant). Curr Rheumatol Rep. 2018 Aug 20; 20(10):62.
6. Woodruff MC, Ramonell RP, Nguyen DC, Cashman KS, Saini AS, Haddad NS, et al. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat Immunol. 2020 Dec; 21(12):1506-1516.
7. Wilson JG, Simpson LJ, Ferreira AM, Rustagi A, Roque J, Asuni A, et al. Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI Insight. 2020 Sep 3; 5(17).
8. Borghi MO, Beltagy A, Garrafa E, Curreli D, Cecchini G, Bodio C, et al. Anti-Phospholipid Antibodies in COVID-19 Are Different From Those Detectable in the Anti-Phospholipid Syndrome. Front Immunol. 2020; 11:584241.
9. Xiao M, Zhang Y, Zhang S, Qin X, Xia P, Cao W, et al. Antiphospholipid Antibodies in Critically Ill Patients With COVID-19. Arthritis Rheumatol. 2020 Dec; 72(12):1998-2004.
10. Liu Y, Sawalha AH, Lu Q. COVID-19 and autoimmune diseases. Curr Opin Rheumatol. 2021 Mar 1; 33(2):155-162.
We read with great interest the recently published article by Adriawan et al 1 in which the authors confirmed that the regulatory T response is deficient in GCA, which is related, at least in part, to a defect in the glycolytic pathway that yields to, a decrease in the expression of GARP and CD25 and a decrease in calcium influx after T-cell receptor engagement.
Apart the fact that this study did not find a decrease in the percentage of circulating Treg, probably due to the small number of patients included compared to the other studies,2,3 these results confirm previous work in the field, including our own,3 and add new elements which provide a better understanding in the mechanistic pathways involved in this Treg dysfunction in GCA. The data from these 3 studies 1-3 suggest that interleukin-6, which is a major therapeutic target in GCA, plays a central role in the increase of FoxP3-exon 2 deficient (FoxP3∆2) Tregs, whose suppressive capacities are reduced, but which also induce an increase in IL-17 production because these cells produce more IL-17 than healthy Tregs and favour the Th17 polarization of effector CD4+ T cells.3
In their work, the authors also showed that tocilizumab, by blocking IL-6 signaling, restores the calcium influx of Tregs and thus their suppressive function.1 This result is in agreement with our recently reported data showing that tocilizumab restored the ability of Tregs to inhibit effector T cell proliferation and Th17 polarization...
We read with great interest the recently published article by Adriawan et al 1 in which the authors confirmed that the regulatory T response is deficient in GCA, which is related, at least in part, to a defect in the glycolytic pathway that yields to, a decrease in the expression of GARP and CD25 and a decrease in calcium influx after T-cell receptor engagement.
Apart the fact that this study did not find a decrease in the percentage of circulating Treg, probably due to the small number of patients included compared to the other studies,2,3 these results confirm previous work in the field, including our own,3 and add new elements which provide a better understanding in the mechanistic pathways involved in this Treg dysfunction in GCA. The data from these 3 studies 1-3 suggest that interleukin-6, which is a major therapeutic target in GCA, plays a central role in the increase of FoxP3-exon 2 deficient (FoxP3∆2) Tregs, whose suppressive capacities are reduced, but which also induce an increase in IL-17 production because these cells produce more IL-17 than healthy Tregs and favour the Th17 polarization of effector CD4+ T cells.3
In their work, the authors also showed that tocilizumab, by blocking IL-6 signaling, restores the calcium influx of Tregs and thus their suppressive function.1 This result is in agreement with our recently reported data showing that tocilizumab restored the ability of Tregs to inhibit effector T cell proliferation and Th17 polarization in vitro. However, our in vivo results temper these data. First, we found that this effect was less clear-cut in patients treated with tocilizumab and prednisone, since only the improvement in the ability of Treg to inhibit Th17 polarization was statistically significant after 3 months of treatment when the disease was in remission.3 Moreover, in the study we conducted,3,4 the percentage of Treg or FoxP3∆2 Tregs did not evolve differently between relapsers and non-relapsers after 6 months of follow-up (figure 1). Thus, we hypothesize that the blockade of the IL-6 effect is less complete in in vivo than in vitro experiments and/or that other signaling pathways are involved in the regulation of Treg biology.
As CD25 expression, which has suppressive functions, is decreased in FoxP3∆2 Tregs and induced by the effect of IL-2, it may be useful to investigate the value of combination therapies coupling IL-6 pathway blockade with tocilizumab and low-dose IL-2 administration in order to potentiate the Treg immune response, as it has been tried in other vasculitides.5
REFERENCES
1. Adriawan IR, Atschekzei F, Dittrich-Breiholz O, et al. Novel aspects of regulatory T cell dysfunction as a therapeutic target in giant cell arteritis. Annals of the rheumatic diseases 2021.
2. Miyabe C, Miyabe Y, Strle K, et al. An expanded population of pathogenic regulatory T cells in giant cell arteritis is abrogated by IL-6 blockade therapy. Annals of the rheumatic diseases 2017;76:898-905.
3. Samson M, Greigert H, Ciudad M, et al. Improvement of Treg immune response after treatment with tocilizumab in giant cell arteritis. Clinical & translational immunology 2021;10:e1332.
4. Samson M, Devilliers H, Ly KH, et al. Tocilizumab as an add-on therapy to glucocorticoids during the first 3months of treatment of Giant cell arteritis: A prospective study. European journal of internal medicine 2018;57:96-104.
5. Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. The New England journal of medicine 2011;365:2067-77.
Figure 1: variation of the percentages of Treg (CD4+CD25highFoxP3+) and Treg deficient in exon 2 of FoxP3 (FoxP3∆2 Treg) in patients treated with glucocorticoids (GC) and tocilizumab (8 mg/Kg/4 weeks IV for 4 infusions [week 0 to week 12]) for a new onset GCA depending on the occurrence of relapse from week 12 to week 26 of follow-up. NS: non-significant (comparison of the variation between both groups; Student t-tests).
Monti et. al. reported a decrease in Fast Track Clinic (FTC) assessments for Giant Cell Arteritis (GCA) during the COVID-19 pandemic and an increase in irreversible visual loss; other groups have found increased incidence of GCA during the COVID-19 pandemic.1,2,3 We created an FTC in 2017 to rapidly evaluate and treat patients with possible GCA using vascular ultrasound and also noticed an increase in permanent vision loss. We conducted a medical records review study during two time periods of patients referred to the FTC with concern for GCA to evaluate how many had permanent visual loss.4 The “COVID-19 period” was defined as 3/1/2020-8/31/2020 the “pre-COVID-19 period was 3/1/2019-8/31/2019. Patients received an ultrasound for GCA performed by a specially trained vascular sonographer. A positive ultrasound for GCA had either halo sign with compression in the temporal arteries and branches or increased intima-media thickness (IMT) in the large vessels. Patients were referred for temporal artery biopsy (TAB) at the discretion of the rheumatologist.
25 patients were referred to the FTC during both the COVID-19 period and pre-COVID-19 period and nine diagnosed with GCA in each group. 52% of patients experienced symptoms for less than two weeks prior to presenting to medical care during the COVID-19 period, 48% pre-COVID-19. The median number of days from the time first seen in the medical system until referral to the FTC was 7 days during COVID-19 compared to 8.5 day...
Monti et. al. reported a decrease in Fast Track Clinic (FTC) assessments for Giant Cell Arteritis (GCA) during the COVID-19 pandemic and an increase in irreversible visual loss; other groups have found increased incidence of GCA during the COVID-19 pandemic.1,2,3 We created an FTC in 2017 to rapidly evaluate and treat patients with possible GCA using vascular ultrasound and also noticed an increase in permanent vision loss. We conducted a medical records review study during two time periods of patients referred to the FTC with concern for GCA to evaluate how many had permanent visual loss.4 The “COVID-19 period” was defined as 3/1/2020-8/31/2020 the “pre-COVID-19 period was 3/1/2019-8/31/2019. Patients received an ultrasound for GCA performed by a specially trained vascular sonographer. A positive ultrasound for GCA had either halo sign with compression in the temporal arteries and branches or increased intima-media thickness (IMT) in the large vessels. Patients were referred for temporal artery biopsy (TAB) at the discretion of the rheumatologist.
25 patients were referred to the FTC during both the COVID-19 period and pre-COVID-19 period and nine diagnosed with GCA in each group. 52% of patients experienced symptoms for less than two weeks prior to presenting to medical care during the COVID-19 period, 48% pre-COVID-19. The median number of days from the time first seen in the medical system until referral to the FTC was 7 days during COVID-19 compared to 8.5 days pre-COVID-19. The median number of days from referral until ultrasound was completed was 1 day during COVID-19 and 2 days pre-COVID-19, and the median number of days on prednisone prior to ultrasound for GCA was 1 during COVID-19 and 2 pre-COVID-19. During the COVID-19 period, 7 patients received TAB compared to 13 patients pre-COVID-19. Median days to temporal artery biopsy was increased in during COVID-19 group at 21 days compared to 7 in the pre-COVID-19 group. All TABs were negative.
During the COVID-19 period, seven patients had a positive ultrasound for GCA, and two patients were diagnosed based on clinical history. During the pre-COVID-19 period five patients had positive ultrasound findings for GCA, and four patients were diagnosed based on clinical history.
Permanent vision loss due to GCA during the COVID-19 period occurred in four patients, and none in the pre-COVID-19 period. Vision loss improved somewhat but did not resolve entirely with treatment in 3 patients (one with bilateral anterior ischemic optic neuropathy (AION), one with unilateral AION and one with bilateral optic nerve edema), and 1 patient experienced permanent vision loss without any improvement due to unilateral retinal ischemia.
We found no change in referral rates during the COVID-19 pandemic but found alarming rates of permanent vision loss compared to historical controls. One notable difference between the two groups was the time from FTC activation to TAB, which was prolonged during the COVID-19 period; it seems unlikely to have contributed to negative outcomes as all TABs were negative and vision impairment occurred prior to FTC activation. This may indicate that complications arose as a result of either delayed presentation or delayed FTC activation, but this is not supported by our analysis. Patients in both groups were referred to the FTC quickly, and underwent workup within 1-2 days. Despite similarities, outcomes were worse during the COVID-19 period. Further research is necessary to elucidate the etiology of the increase in permanent vision loss in patients with GCA during the COVID-19 pandemic.
References
1. Monti, S. et al. Impact of delayed diagnoses at the time of COVID-19: increased rate of preventable bilateral blindness in giant cell arteritis. Ann. Rheum. Dis. 79, 1658–1659 (2020).
2. Lecler, A., Villeneuve, D., Vignal, C. & Sené, T. Increased rather than decreased incidence of giant-cell arteritis during the COVID-19 pandemic. Ann. Rheum. Dis. 80, e89–e89 (2021).
3. Luther, R. et al. Increased number of cases of giant cell arteritis and higher rates of ophthalmic involvement during the era of COVID-19. Rheumatol. Adv. Pract. 4, rkaa067 (2020).
4. Harris, P. A. et al. Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 42, 377–381 (2009).
We thank Professors Lee and Song for their interest in our genome-wide association study (GWAS) of chronic widespread musculoskeletal pain (CWP)[1]. Their correspondence has raised several methodological concerns. First, CWP is a prominent feature of fibromyalgia. Clinically, it’s impossible to diagnose fibromyalgia without having CWP[2]. Therefore, the relevance of our findings to fibromyalgia cannot be ignored although we were careful not to conflate the two traits and did not claim genetic association with fibromyalgia. Second, the authors raise the relationship of the traits with age and sex; we adjusted for these covariates in the discovery GWAS and replication study. The important issue of body mass index (BMI) was much debated in our experimental design meetings. We elected not to adjust for BMI in the study for the following reasons:- (i) adjustment for heritable covariates (such as BMI) are not recommended in GWAS as this can lead to collider bias[3, 4] (ii) we wanted to explore the shared heritability of BMI and CWP using genetic correlation, (iii) adjustment for BMI would have affected genetic correlation and partial genetic correlation estimates reported in the paper and (vi) while so few variants have been described to date using GWAS for CWP, we were keen not to reduce the variance in the phenotype even if that led us to identify variants pleiotropic for BMI and CWP. Third, we have selected our controls for GWAS carefully by excluding important diagnostic con...
We thank Professors Lee and Song for their interest in our genome-wide association study (GWAS) of chronic widespread musculoskeletal pain (CWP)[1]. Their correspondence has raised several methodological concerns. First, CWP is a prominent feature of fibromyalgia. Clinically, it’s impossible to diagnose fibromyalgia without having CWP[2]. Therefore, the relevance of our findings to fibromyalgia cannot be ignored although we were careful not to conflate the two traits and did not claim genetic association with fibromyalgia. Second, the authors raise the relationship of the traits with age and sex; we adjusted for these covariates in the discovery GWAS and replication study. The important issue of body mass index (BMI) was much debated in our experimental design meetings. We elected not to adjust for BMI in the study for the following reasons:- (i) adjustment for heritable covariates (such as BMI) are not recommended in GWAS as this can lead to collider bias[3, 4] (ii) we wanted to explore the shared heritability of BMI and CWP using genetic correlation, (iii) adjustment for BMI would have affected genetic correlation and partial genetic correlation estimates reported in the paper and (vi) while so few variants have been described to date using GWAS for CWP, we were keen not to reduce the variance in the phenotype even if that led us to identify variants pleiotropic for BMI and CWP. Third, we have selected our controls for GWAS carefully by excluding important diagnostic confounders[5] and performed sensitivity GWAS analyses excluding non-musculoskeletal pain participants from the control group. It was not possible to exclude such diagnostic confounders from the replication cohorts. Finally, we observed no heterogeneity when we performed both sample size- and inverse variance weighted- meta-analyses. Thus, the meta-analysis findings may be considered valid for the full spectrum of CWP.
References
1. Rahman MS, Winsvold BS, Chavez Chavez SO, Borte S, Tsepilov YA, Sharapov SZ, et al. Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain. Annals of the Rheumatic Diseases. 2021:annrheumdis-2020-219624.
2. Häuser W, Sarzi-Puttini P, Fitzcharles MA. Fibromyalgia syndrome: under-, over- and misdiagnosis. Clin Exp Rheumatol. 2019 Jan-Feb; 37 Suppl 116(1):90-97.
3. Aschard H, Vilhjálmsson BJ, Joshi AD, Price AL, Kraft P. Adjusting for heritable covariates can bias effect estimates in genome-wide association studies. Am J Hum Genet. 2015 Feb 5; 96(2):329-339.
4. Vansteelandt S, Goetgeluk S, Lutz S, Waldman I, Lyon H, Schadt EE, et al. On the adjustment for covariates in genetic association analysis: a novel, simple principle to infer direct causal effects. Genetic epidemiology. 2009; 33(5):394-405.
5. Häuser W, Perrot S, Sommer C, Shir Y, Fitzcharles MA. Diagnostic confounders of chronic widespread pain: not always fibromyalgia. Pain Rep. 2017; 2(3).
With great interest, we read the paper by Perez-Garcia et al for reporting the impaired fertility of 628 male patients with inflammatory arthritis (IA) from multiple hospitals in the Netherlands.1 Based on the result, the authors suggested that treatment strategies should be appropriately re-concerned for male IA patients who want to have children. Although the author has stated the limitations of the research, some details need to be addressed clearly.
Firstly, Disease duration may be an interfering factor of fertility.2 In this research, men diagnosed ≤40 years had a longer disease duration than men diagnosed ≥41 years, with a higher rate of low sperm quality and a lower number of children. Besides, smoking and drinking history were not included in the demographic characteristics of patients, since those factors may have great effects on male fertility.3 Then, the age of the partners of the participants were not taken into calculation which may have a great effect on the number of children of the male IA patients, and the willingness of the partners to have children as well. 4 5 The effects of disease and drugs on the results were not distinguished in the study, and both of them may have effects on the fertility.6
Secondly, all data were collected from a questionnaire survey, including the patient’s partner time to pregnancy, female fertility evaluation, and the patient’s sperm quality, which may cause subjective bias. We noticed that out of 628 patients, onl...
With great interest, we read the paper by Perez-Garcia et al for reporting the impaired fertility of 628 male patients with inflammatory arthritis (IA) from multiple hospitals in the Netherlands.1 Based on the result, the authors suggested that treatment strategies should be appropriately re-concerned for male IA patients who want to have children. Although the author has stated the limitations of the research, some details need to be addressed clearly.
Firstly, Disease duration may be an interfering factor of fertility.2 In this research, men diagnosed ≤40 years had a longer disease duration than men diagnosed ≥41 years, with a higher rate of low sperm quality and a lower number of children. Besides, smoking and drinking history were not included in the demographic characteristics of patients, since those factors may have great effects on male fertility.3 Then, the age of the partners of the participants were not taken into calculation which may have a great effect on the number of children of the male IA patients, and the willingness of the partners to have children as well. 4 5 The effects of disease and drugs on the results were not distinguished in the study, and both of them may have effects on the fertility.6
Secondly, all data were collected from a questionnaire survey, including the patient’s partner time to pregnancy, female fertility evaluation, and the patient’s sperm quality, which may cause subjective bias. We noticed that out of 628 patients, only 87 men reported the fertility evaluation outcome, which reduced the representation of the data to the overall sample of the study.
Thirdly, no negative control group was set in the study. There was no direct comparison between participants and the general population of the same age group, but only with men who were older than 40 years in the similar literature. In the results part, the mean total number of children per man for all participants was very close to the number of the men who were older than 40 years in the Netherlands, and whether it was significantly different was not mentioned. It seems to be uncertain that whether IA contributed to the impaired fertility of male patients.
We do believe that the male fertility situation of IA patients needs for great attention. But we suggest that the author should clearly addressed the confounders we talked about above. We also suggest that some objective examinations could be tested such as the patient's reproductive function, including semen analysis, hormonal investigation, microbiologic assessment, and scrotal ultrasound, rather than obtaining the information through questionnaire surveys.7 Moreover, we hope to read more comprehensive studies in which negative control groups were set into analysis in the coming future by the authors.
REFERENCES
1 Perez-Garcia LF, Röder E, Goekoop RJ, et al. Impaired fertility in men diagnosed with inflammatory arthritis: results of a large multicentre study (iFAME-Fertility). Ann Rheum Dis. 2021 Aug 9: annrheumdis-2021-220709. doi: 10.1136/annrheumdis-2021-220709.
2 Ursin K, Lydersen S, Skomsvoll JF, et al. Factors Associated With Time to Pregnancy in Women With Axial Spondyloarthritis: A Registry-Based Multicenter Study. Arthritis Care Res (Hoboken). 2021 Aug;73(8):1201-1209. doi: 10.1002/acr.24233.
3 Sansone A, Di Dato C, de Angelis C, Menafra D, Pozza C, Pivonello R, Isidori A, Gianfrilli D. Smoke, alcohol and drug addiction and male fertility. Reprod Biol Endocrinol. 2018 Jan 15;16(1):3. doi: 10.1186/s12958-018-0320-7.
4 Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril. 2001 Feb;75(2):237-48. doi: 10.1016/s0015-0282(00)01679-4.
5 Dolhain RJ. Rheumatoid arthritis and pregnancy; not only for rheumatologists interested in female health issues. Ann Rheum Dis. 2010 Feb;69(2):317-8. doi: 10.1136/ard.2009.120741.
6 Brouwer J, Hazes JM, Laven JS, et al. Fertility in women with rheumatoid arthritis: influence of disease activity and medication. Ann Rheum Dis. 2015 Oct;74(10):1836-41. doi: 10.1136/annrheumdis-2014-205383.
7 Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, Krausz C; European Association of Urology Working Group on Male Infertility. European Association of Urology guidelines on Male Infertility: the 2012 update. Eur Urol. 2012 Aug;62(2):324-32. doi: 10.1016/j.eururo.2012.04.048.
Dear editor:
We read with great interest in the article by Maria Prendecki, which reported repeated SARS-CoV-2 vaccinations could induce humoral and T-cell responses in those patients who are immunosuppressed. The authors collected data from a total 161 patients with immune-mediated glomerulonephritis and vasculitis from 17 January 2021 and 9 March 2021, and conducted a cohort study. However, some conclusions and findings in this study need to be further clarified.
Firstly, in the sample collection and baseline data of the RESULTS section, we can see that a total of 114 patients have previously received rituximab treatment, 69 of which received Rituximab treatment in the past six months. However, in the statistical table 1, we see that there were only 99 patients who had previously treated with rituximab, and only 56 patients received rituximab treatment within six months. Is the difference in sample data between the two likely to affect the statistical results?
Secondly, the article focused on patients in the IS group only for matching age and vaccine type. Does the article ignore the past medical history or past medication history for matching?
Last but not least, there is a big difference in the interval between the first dose of vaccine and the second dose of the patient in the healthy group and the IS group, and the second dose of the healthy group can only choose the BNT vaccine. Will the above two likely to have interference factors in this...
Dear editor:
We read with great interest in the article by Maria Prendecki, which reported repeated SARS-CoV-2 vaccinations could induce humoral and T-cell responses in those patients who are immunosuppressed. The authors collected data from a total 161 patients with immune-mediated glomerulonephritis and vasculitis from 17 January 2021 and 9 March 2021, and conducted a cohort study. However, some conclusions and findings in this study need to be further clarified.
Firstly, in the sample collection and baseline data of the RESULTS section, we can see that a total of 114 patients have previously received rituximab treatment, 69 of which received Rituximab treatment in the past six months. However, in the statistical table 1, we see that there were only 99 patients who had previously treated with rituximab, and only 56 patients received rituximab treatment within six months. Is the difference in sample data between the two likely to affect the statistical results?
Secondly, the article focused on patients in the IS group only for matching age and vaccine type. Does the article ignore the past medical history or past medication history for matching?
Last but not least, there is a big difference in the interval between the first dose of vaccine and the second dose of the patient in the healthy group and the IS group, and the second dose of the healthy group can only choose the BNT vaccine. Will the above two likely to have interference factors in this research?
Finally, the definition of how the healthy participants were selected into this study does not seem to be very clear.
For the above reasons, we recommend that sample collection should be considered in this study. This will allow us to realize the immune response to the SARS-CoV-2 vaccination between the IS group and healthy volunteer group more thoroughly.
Which method was used for the estimation of creatinine clearance? If Cockcroft-Gault equation was used, was the Ideal Body Weight used for patients with normal BMI and the Adjusted Body Weight for obese patients?
With great interest, we read the article by Wang Y et al., which suggested that Megakaryocytes (MKs) expansion might contribute to the pathogenesis of Rheumatoid Arthritis (RA)1. MKs are large, polyploid cells that originate from hematopoietic stem cells (HSC) and give rise to platelets. However, the authors fall short in recognizing the role of MK-derived platelets in RA.
Show MoreWang Y et al. identified increased MKs in peripheral blood of RA using single-cell RNA sequencing and flow cytometry approaches. They provide clues that MKs act as specific endogenous antigen-presenting cells (APCs), triggering the initial autoimmune T cell for RA pathogenesis1. Of note, novel evidence suggests that MKs derived from bone marrow (BM), lung2 and liver3, instead serve as immunomodulatory or secretory cells4. The generation of platelets is the primary function of MKs.
Indeed, many characteristics and roles of platelets inherit from MKs. For example, once activated, platelets present antigens via MHC class I molecules (MHC-I) derived from parent MKs5; in this way, the immunogenic information can be conveyed to platelets. Similarly, platelets can also act as an essential immune effector in RA6. An array of platelet surface receptors is responsible for activation, adhesion, and thrombus formation via initiating a complex network of signaling pathways in the presence of ligands. In addition, it is well known that ligands for platelet receptors such as collagen, fibrinogen, serotonin,...
We read with interest the Viewpoint article by Braun and Landewé regarding post-hoc analysis of back pain in trials of IL-23 inhibitor therapy in patients with peripheral psoriatic arthritis (PsA) [1]. Indeed, we share their concerns regarding study design, the use of outcome measures developed for axial spondyloarthritis (axSpA) and, most importantly, the attribution of the diagnostic label “physician-reported spondylitis” in these patients. In addition to the issues eloquently outlined in the article, it is important to be aware that the pre-test probability of inflammatory disease being directly responsible for back pain is likely much lower in patients with PsA who are older, and therefore more likely to have mechanical or non-specific back pain, than people presenting with axSpA. In other words, even before doing any test, a middle-aged person with PsA, as represented in most phase III PsA clinical trials, is more likely to have non-inflammatory than inflammatory back pain. These “causes” of back pain do of course co-exist and are not easily distinguished by clinical or imaging assessments. For example, disc and degenerative spinal disease can lead to apparent inflammatory features, such as bone marrow oedema on magnetic resonance imaging [2, 3] that are likely a secondary response to altered biomechanical stresses rather than primary inflammatory disease and therefore unlikely to be responsive to biologic therapies. Furthermore, imaging data on the prevalence and na...
Show MoreThank you for pointing out that the conclusion was not clear. The authors would like to modify it to 'The interim analysis revealed that up to 66% of patients receiving APR reached REM/LDA, as measured by cDAPSA at 8 months.'
Dear Editor,
I read with great interest the article by Trahtemberg et al.[1] on the clinical relevance of antiphospholipid antibodies (aPLs), in particular anticardiolipin antibodies (aCLs), in critically-ill COVID-19 positive and negative patients. Severe COVID-19 is associated with a hypercoagulable state. Early studies identified the presence of aPLs in critically-ill COVID-19 patients[2], which has attracted considerable attention as the presence of aPLs is one of the mechanisms leading to coagulopathy. Substantial efforts then tried to associate the thrombotic events seen in COVID-19 to aPLs status. The results seem negative, but a number of different types of autoantibodies were identified [3]. Chang et al. recently reported that autoantibodies were present in approximately half of the hospitalized COVID-19 patients, but in less than 15% of healthy controls [4]. In addition to aCLs and anti-beta 2 glycoprotein 1 antibodies (aβ2-GP1), they also identified autoantibodies targeting autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes as well as targeting interferons/interleukins and other cytokines[4]. These findings suggest that COVID-19, in particular patients with severe/critical conditions, displayed certain autoimmune features.
In the well-designed study by Trahtemberg et al., the authors expanded the cohort by including COVID-19 negative patients who were admitted to intensive care unit (ICU) with ac...
Show MoreWe read with great interest the recently published article by Adriawan et al 1 in which the authors confirmed that the regulatory T response is deficient in GCA, which is related, at least in part, to a defect in the glycolytic pathway that yields to, a decrease in the expression of GARP and CD25 and a decrease in calcium influx after T-cell receptor engagement.
Show MoreApart the fact that this study did not find a decrease in the percentage of circulating Treg, probably due to the small number of patients included compared to the other studies,2,3 these results confirm previous work in the field, including our own,3 and add new elements which provide a better understanding in the mechanistic pathways involved in this Treg dysfunction in GCA. The data from these 3 studies 1-3 suggest that interleukin-6, which is a major therapeutic target in GCA, plays a central role in the increase of FoxP3-exon 2 deficient (FoxP3∆2) Tregs, whose suppressive capacities are reduced, but which also induce an increase in IL-17 production because these cells produce more IL-17 than healthy Tregs and favour the Th17 polarization of effector CD4+ T cells.3
In their work, the authors also showed that tocilizumab, by blocking IL-6 signaling, restores the calcium influx of Tregs and thus their suppressive function.1 This result is in agreement with our recently reported data showing that tocilizumab restored the ability of Tregs to inhibit effector T cell proliferation and Th17 polarization...
Monti et. al. reported a decrease in Fast Track Clinic (FTC) assessments for Giant Cell Arteritis (GCA) during the COVID-19 pandemic and an increase in irreversible visual loss; other groups have found increased incidence of GCA during the COVID-19 pandemic.1,2,3 We created an FTC in 2017 to rapidly evaluate and treat patients with possible GCA using vascular ultrasound and also noticed an increase in permanent vision loss. We conducted a medical records review study during two time periods of patients referred to the FTC with concern for GCA to evaluate how many had permanent visual loss.4 The “COVID-19 period” was defined as 3/1/2020-8/31/2020 the “pre-COVID-19 period was 3/1/2019-8/31/2019. Patients received an ultrasound for GCA performed by a specially trained vascular sonographer. A positive ultrasound for GCA had either halo sign with compression in the temporal arteries and branches or increased intima-media thickness (IMT) in the large vessels. Patients were referred for temporal artery biopsy (TAB) at the discretion of the rheumatologist.
25 patients were referred to the FTC during both the COVID-19 period and pre-COVID-19 period and nine diagnosed with GCA in each group. 52% of patients experienced symptoms for less than two weeks prior to presenting to medical care during the COVID-19 period, 48% pre-COVID-19. The median number of days from the time first seen in the medical system until referral to the FTC was 7 days during COVID-19 compared to 8.5 day...
Show MoreWe thank Professors Lee and Song for their interest in our genome-wide association study (GWAS) of chronic widespread musculoskeletal pain (CWP)[1]. Their correspondence has raised several methodological concerns. First, CWP is a prominent feature of fibromyalgia. Clinically, it’s impossible to diagnose fibromyalgia without having CWP[2]. Therefore, the relevance of our findings to fibromyalgia cannot be ignored although we were careful not to conflate the two traits and did not claim genetic association with fibromyalgia. Second, the authors raise the relationship of the traits with age and sex; we adjusted for these covariates in the discovery GWAS and replication study. The important issue of body mass index (BMI) was much debated in our experimental design meetings. We elected not to adjust for BMI in the study for the following reasons:- (i) adjustment for heritable covariates (such as BMI) are not recommended in GWAS as this can lead to collider bias[3, 4] (ii) we wanted to explore the shared heritability of BMI and CWP using genetic correlation, (iii) adjustment for BMI would have affected genetic correlation and partial genetic correlation estimates reported in the paper and (vi) while so few variants have been described to date using GWAS for CWP, we were keen not to reduce the variance in the phenotype even if that led us to identify variants pleiotropic for BMI and CWP. Third, we have selected our controls for GWAS carefully by excluding important diagnostic con...
Show MoreWith great interest, we read the paper by Perez-Garcia et al for reporting the impaired fertility of 628 male patients with inflammatory arthritis (IA) from multiple hospitals in the Netherlands.1 Based on the result, the authors suggested that treatment strategies should be appropriately re-concerned for male IA patients who want to have children. Although the author has stated the limitations of the research, some details need to be addressed clearly.
Show MoreFirstly, Disease duration may be an interfering factor of fertility.2 In this research, men diagnosed ≤40 years had a longer disease duration than men diagnosed ≥41 years, with a higher rate of low sperm quality and a lower number of children. Besides, smoking and drinking history were not included in the demographic characteristics of patients, since those factors may have great effects on male fertility.3 Then, the age of the partners of the participants were not taken into calculation which may have a great effect on the number of children of the male IA patients, and the willingness of the partners to have children as well. 4 5 The effects of disease and drugs on the results were not distinguished in the study, and both of them may have effects on the fertility.6
Secondly, all data were collected from a questionnaire survey, including the patient’s partner time to pregnancy, female fertility evaluation, and the patient’s sperm quality, which may cause subjective bias. We noticed that out of 628 patients, onl...
Dear editor:
We read with great interest in the article by Maria Prendecki, which reported repeated SARS-CoV-2 vaccinations could induce humoral and T-cell responses in those patients who are immunosuppressed. The authors collected data from a total 161 patients with immune-mediated glomerulonephritis and vasculitis from 17 January 2021 and 9 March 2021, and conducted a cohort study. However, some conclusions and findings in this study need to be further clarified.
Firstly, in the sample collection and baseline data of the RESULTS section, we can see that a total of 114 patients have previously received rituximab treatment, 69 of which received Rituximab treatment in the past six months. However, in the statistical table 1, we see that there were only 99 patients who had previously treated with rituximab, and only 56 patients received rituximab treatment within six months. Is the difference in sample data between the two likely to affect the statistical results?
Show MoreSecondly, the article focused on patients in the IS group only for matching age and vaccine type. Does the article ignore the past medical history or past medication history for matching?
Last but not least, there is a big difference in the interval between the first dose of vaccine and the second dose of the patient in the healthy group and the IS group, and the second dose of the healthy group can only choose the BNT vaccine. Will the above two likely to have interference factors in this...
Which method was used for the estimation of creatinine clearance? If Cockcroft-Gault equation was used, was the Ideal Body Weight used for patients with normal BMI and the Adjusted Body Weight for obese patients?
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