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.
With great interest, we read the recently published article by Heckert et al regarding the tendency of recurrence of joint inflammation in patients with rheumatoid arthritis (RA) based on the sub-analysis of the BeSt study 1. In this study, the authors found that joint swelling in RA patients tended to recur in the same joints over time (OR 2.37, 95% CI 2.30 to 2.43, p<0.001). We congratulate the teams for their great work. Meanwhile, the important and interesting findings prompt us to think about the possible underlying mechanisms, which was just simply explained in the discussion. The authors pointed out that previous exposure to inflammatory triggers might mount a local alert state in the joint, promoting site-specific recurrence of inflammation. 2 We agree to their hypothesis, and would like to comment on the possible mechanisms in more depth from the aspect of Resident memory T cells (TRM) to the clinical findings.
TRM cells have been recognized as a group of sentinels maintained in diverse anatomic compartments which resident in the tissue niche for a long-term in both human and mouse models. TRM requires distinct signals for the maintenance and survival in specific tissues. 3 4 It has been found that TRM is associated with the onset, progression and relapse of autoimmune diseases, such as psoriasis, spondylarthritis and lupus. 5-7 Recently, TRM which residents in the synovium was proved to be essential for the flare of arthritis in the animal model of recur...
With great interest, we read the recently published article by Heckert et al regarding the tendency of recurrence of joint inflammation in patients with rheumatoid arthritis (RA) based on the sub-analysis of the BeSt study 1. In this study, the authors found that joint swelling in RA patients tended to recur in the same joints over time (OR 2.37, 95% CI 2.30 to 2.43, p<0.001). We congratulate the teams for their great work. Meanwhile, the important and interesting findings prompt us to think about the possible underlying mechanisms, which was just simply explained in the discussion. The authors pointed out that previous exposure to inflammatory triggers might mount a local alert state in the joint, promoting site-specific recurrence of inflammation. 2 We agree to their hypothesis, and would like to comment on the possible mechanisms in more depth from the aspect of Resident memory T cells (TRM) to the clinical findings.
TRM cells have been recognized as a group of sentinels maintained in diverse anatomic compartments which resident in the tissue niche for a long-term in both human and mouse models. TRM requires distinct signals for the maintenance and survival in specific tissues. 3 4 It has been found that TRM is associated with the onset, progression and relapse of autoimmune diseases, such as psoriasis, spondylarthritis and lupus. 5-7 Recently, TRM which residents in the synovium was proved to be essential for the flare of arthritis in the animal model of recurrent synovitis by adapting a T-cell-driven, joint specific model of antigen-induced arthritis. 8 In a subsequent study on human RA synovium, a subset of T cell was also found to display TRM markers, especially in the late-stage leukocyte-poor tissues. These synovial TRM cells exhibited a restricted T cell receptor repertoire. Moreover, it has been shown that CD8+ rather than CD4+ TRM plays a predominant role in recurrent joint-specific inflammation.
We therefore propose that the synovial TRM cells may be involved in or even play an essential role in the arthritis recurrence in the same joint in RA patients. The mechanism also suggests a new potential therapeutic approach for achieving sustained RA remission by targeting synovial TRM. This is worthy of further investigation.
Reference
1. Heckert SL, Bergstra SA, Matthijssen XME, et al. Joint inflammation tends to recur in the same joints during the rheumatoid arthritis disease course. Annals of the rheumatic diseases 2021 doi: 10.1136/annrheumdis-2021-220882 [published Online First: 2021/09/01]
2. Friščić J, Böttcher M, Reinwald C, et al. The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity 2021;54(5):1002-21.e10. doi: 10.1016/j.immuni.2021.03.003 [published Online First: 2021/03/25]
3. Clark RA. Resident memory T cells in human health and disease. Science translational medicine 2015;7(269):269rv1. doi: 10.1126/scitranslmed.3010641 [published Online First: 2015/01/09]
4. Szabo PA, Miron M, Farber DL. Location, location, location: Tissue resident memory T cells in mice and humans. Science immunology 2019;4(34) doi: 10.1126/sciimmunol.aas9673 [published Online First: 2019/04/07]
5. Boyman O, Hefti HP, Conrad C, et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. The Journal of experimental medicine 2004;199(5):731-6. doi: 10.1084/jem.20031482 [published Online First: 2004/02/26]
6. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nature medicine 2012;18(7):1069-76. doi: 10.1038/nm.2817 [published Online First: 2012/07/10]
7. Winchester R, Wiesendanger M, Zhang HZ, et al. Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell β-chain clonotypes in progressive lupus nephritis. Arthritis and rheumatism 2012;64(5):1589-600. doi: 10.1002/art.33488 [published Online First: 2011/12/02]
8. Chang MH, Levescot A, Nelson-Maney N, et al. Arthritis flares mediated by tissue-resident memory T cells in the joint. Cell reports 2021;37(4):109902. doi: 10.1016/j.celrep.2021.109902 [published Online First: 2021/10/28]
The surveys were conducted in 1970s. At that time the majority of
Finns drank traditional boiled coffee. The use of decaffeinated coffee was
exceptional. In the Mini-Finland Health Survey, there was a negative
correlation between daily cups of tea and coffee (age and sex adjusted
partial r= -0.30, p...
The surveys were conducted in 1970s. At that time the majority of
Finns drank traditional boiled coffee. The use of decaffeinated coffee was
exceptional. In the Mini-Finland Health Survey, there was a negative
correlation between daily cups of tea and coffee (age and sex adjusted
partial r= -0.30, p<_0.001. however="however" tea="0.91," consumption="consumption" showed="showed" no="no" association="association" with="with" the="the" presence="presence" of="of" rheumatoid="rheumatoid" factor="factor" age="age" and="and" sex="sex" adjusted="adjusted" odds="odds" ratio="ratio" per="per" one="one" cup="cup" _95="_95" confidence="confidence" interval="0.73-1.13)" did="did" not="not" confound="confound" results="results" we="we" reported.p="reported.p"/>Unfortunately we had no
information on the consumption of colas, but according to indirect
information on sales of cola beverages the contribution of caffeine from
this source was minimal in Finns at that time.
Markku Heliövaara
Kimmo Aho
Paul Knekt
Antti Reunanen
Arpo Aromaa
National Public Health Institute, Helsinki, Finland
Olli Impivaara
Social Insurance Institution, Research and Development Centre, Turku, Finland
Correspondence to: Dr Markku Heliövaara, National Public Health
Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland
This potentially valuable information about a relationship between
coffee consumption and the presence of the rhematoid factor is difficult
to evaluate because of a lack of clarity in definitions. What is meant by
"coffee"? Is coffee, caffeinated or decaffeinated? This is an obvious
distinction that readers need to consider these findings.
Also, it would
have been interesting to have information ab...
This potentially valuable information about a relationship between
coffee consumption and the presence of the rhematoid factor is difficult
to evaluate because of a lack of clarity in definitions. What is meant by
"coffee"? Is coffee, caffeinated or decaffeinated? This is an obvious
distinction that readers need to consider these findings.
Also, it would
have been interesting to have information about other beverage
consumption, such as colas and/or teas which may or may not have affected
or clarified the results which, currently, have no theoretical
underpinnings. However, the information is an exciting start to
understanding factors that contribute to this disabling and prevalent
illness.
I was intrigued when I heard the report of this paper in view of the
widely held belief that copper jewellery is also beneficial in the
treatment of arthritis.
In the case of the gold rings it has to be remembered that gold rings
are seldom pure gold. Even 22 carat gold rings are 22/24 parts gold, the
rest being copper.
In view of this what evidence is there that the gold and not the...
I was intrigued when I heard the report of this paper in view of the
widely held belief that copper jewellery is also beneficial in the
treatment of arthritis.
In the case of the gold rings it has to be remembered that gold rings
are seldom pure gold. Even 22 carat gold rings are 22/24 parts gold, the
rest being copper.
In view of this what evidence is there that the gold and not the
copper was responsible for the observed effect? Where the team able to
observe anyone with a platinum, copper or silver ring; and what effects if
any, where noted on the arthritis in such cases? Taking it further was
there anyone who had a pure (24ct) gold ring and what had been the effect
on their case?
I am wondering why, in this day and age, researchers into the long
term effects/links of infections and the possible connection with
potentially devastating conditions do not use PCR testing for the
identification of these infecting or trigger organisms?
My understanding is that PCR testing is far more sensitive than indirect
methods of detecting the body's response to the bug concerned.
I am wondering why, in this day and age, researchers into the long
term effects/links of infections and the possible connection with
potentially devastating conditions do not use PCR testing for the
identification of these infecting or trigger organisms?
My understanding is that PCR testing is far more sensitive than indirect
methods of detecting the body's response to the bug concerned.
I read with intrest this work and indeed I ask authors why do we
search for indirect signs when the direct one is well seen by this
ultrasonographic modality? Many new imaging machians introduced in this
field and I notice that we try to find what the old machians dose. The
plain X ray show bone errosion late and when the authors use the US
modality the try to see what the plain X ray shows and in my...
I read with intrest this work and indeed I ask authors why do we
search for indirect signs when the direct one is well seen by this
ultrasonographic modality? Many new imaging machians introduced in this
field and I notice that we try to find what the old machians dose. The
plain X ray show bone errosion late and when the authors use the US
modality the try to see what the plain X ray shows and in my opinion the
synovial thicknning is the halmark sign in this case even many and many
papares show that the subclinical casses may show no errosion on plain
Xray where the US dose - another example is the use of EMG do detect the
nerve affaction inCTS or cubital tunnel syndrome or other nerve
entrapments while the US can show the nerve pathology early and the cause
can be detected where the EMG study show that there is some problem -what
it is? It dose not say. Finally in our lab, we try to see the disease by
the modality of intrest we try to see the mean pathology directly that
will decrease the time and cost and deal with direct signs.
Davis et al [1] emphasize the necessity of a uniform definition of the
term "disease duration" for the case of ankylosing spondylitis (AS)
because different definitions have been used in the past. Besides the
duration since disease onset (time of first symptoms), the duration since
the time of diagnosis of AS has also sometimes been named "disease
duration" [2]. We very much support the initiative fo...
Davis et al [1] emphasize the necessity of a uniform definition of the
term "disease duration" for the case of ankylosing spondylitis (AS)
because different definitions have been used in the past. Besides the
duration since disease onset (time of first symptoms), the duration since
the time of diagnosis of AS has also sometimes been named "disease
duration" [2]. We very much support the initiative for a uniform
definition which would indeed ensure comparability across studies and thus
facilitate future research.
The conclusion in [1] that "important components of the
recommendations to better define duration of disease were found to be :
(1) time since onset of axial AS-specific symptoms (inflammatory back
pain),
(2) onset of signs of spondyloarthritis, peripheral or extra-articular
symptoms,
(3) onset of associated SpAs, and
(4) time since diagnosis of AS by a health-care provider"
does, however, not contribute to a uniform definition.
In two recent surveys [3–5] we found that up to 48 years may lie
between first symptoms of AS and the diagnosis of AS, with an average
delay in diagnosis of 8.9 years and 8.8 years, respectively, in these
surveys.
As an AS researcher and a rheumatologist, both with AS ourselves, we
want to emphasize that using the time since diagnosis as "disease
duration" does not only disregard many years of the patients' suffering
from an undiagnosed but nevertheless very interfering disease. More
important: This definition may lead to severe scientific errors in
epidemiologic studies. If, for instance, the dependence of the extent of
ankylosis on the disease duration is investigated (as in [4, 6]) and the
duration between first complaints and diagnosis were neglected, an
extended ankylosis found already at "disease duration" = 0 would not at
all be surprising. The growth of syndesmophytes does not wait until the
disease is diagnosed. If, as another example, the annual incidence of
vertebral fractures and its dependence on the disease duration is
investigated as in [7], a "disease duration" neglecting the disease
duration before the diagnosis of AS, may likewise lead to wrong
conclusions, and vertebral fractures which are in fact a result of many
years with the disease may be found at negative "disease durations". These
examples may illustrate why we regard a “disease duration” of AS
neglecting the years before its diagnosis as being unscientific, in
contrast to the authors of [1] who mention that ”the time since diagnosis
of AS will aid in issues related to regulation, research, and education”.
The authors of [1] also argue that assessing disease duration by
studying patient histories from medical records may lack accuracy because
of missed or inappropriate diagnosis, and that this might be true for
patient's recall of symptoms as well. However, replacing a possibly
inaccurate value by a value which is definitely wrong by many years, makes
it even worse.
We agree that the time of diagnosis should be collected in addition –
besides the time of first symptoms – when data for research is collected.
We regret that this is not done, for instance, in the national database of
the German collaborative arthritis centres [8] where an evaluation of the
delay in diagnosis of AS is therefore impossible. It is also not possible
by use of this database to verify the interesting dependence of the female
percentage among AS patients on the decade in which the diagnosis was made
[4].
A quantity like the disease duration cannot be defined by four
alternative and contradictive definitions. We would expect a clear-cut
definition like, for instance:
(1) In general, "disease duration" of AS is defined as the duration since
onset of AS-specific symptoms (inflammatory back pain).
(2) If onset of peripheral signs of spondyloarthritis precede axial
symptoms, this may be used as beginning of the "disease duration". This
should however be documented.
(3) The onset of signs for an associated SpA without AS-specific symptoms
should not be used as beginning of the “disease duration” of AS.
(4) The duration since diagnosis of AS by a healthcare provider may be of
interest in some connections of research but should never be called
"disease duration".
Ernst Feldtkeller, PhD
Vice president of the Ankylosing Spondylitis International Federation
Michaeliburgstr. 15, D-81671 München, Germany
Tel: 0049-89-493376
Fax: 0049-89-49003836
feldtkeller@t-online.de
Jon Erlendsson, MD, rheumatologist
President of the Ankylosing Spondylitis International Federation
Grønningen 10, DK-8700 Horsens, Denmark
jon.erlendsson@stofanet.dk
References
1. Davis JC, Dougados M, Braun J, Sieper J, van der Heijde D, and van
der Linden S for the ASAS (ASsessment of Ankylosing Spondylitis)
International Working Group. The Definition of Disease Duration in
Ankylosing Spondylitis: Reassessing the Concept. Ann Rheum Dis 2006 Feb 7;
[Epub ahead of print]
2. Spoorenberg, A. et al., A comparative study of the usefulness of
the Bath Ankylosing Spondylitis Functional Index and the Dougados
Functional Index in the assessment of ankylosing spondylitis. J Rheumatol
1999;26:961–965
3. Feldtkeller E. Erkrankungsalter und Diagnoseverzögerung bei
Spondylarthropathien. Z Rheumatol 1999;58:21–30
5. Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun
J. Age at disease onset and diagnosis delay in HLA-B27 negative vs.
positive patients with ankylosing spondylitis. Rheumatol Int 2003;23:61–66
6. Brophy S, Mackay K, Al-Saidi A, Taylor G, Calin A. The natural
history of ankylosing spondylitis as defined by radiological progression.
J Rheumatol. 2002;29:1236–1243
7. Feldtkeller E, Vosse D, Geusens P, van der Linden S. Prevalence
and annual incidence of vertebral fractures in patients with ankylosing
spondylitis. Rheumatol Int. 2006 Jan;26(3):234-239
8. Zink A, Listing J, Klindworth C, Zeidler H for the German
Collaborative Arthritis Centers. The national database of the German
collaborative arthritis centres: I. Structure, aims, and patients. Ann
Rheum Dis 2001;60:199-206.
The article by Björnådal et al.[1] addresses an issue which has become
increasingly recognized in the past decade.[2-4] They took a somewhat
unique approach, examining cause of parental death. The authors[1] are to
be congratulated for excluding individuals with alternative (to rheumatoid
arthritis) discharge diagnoses, recognizing the 'lumping' character of the
current ACR criteria[5] and partially ob...
The article by Björnådal et al.[1] addresses an issue which has become
increasingly recognized in the past decade.[2-4] They took a somewhat
unique approach, examining cause of parental death. The authors[1] are to
be congratulated for excluding individuals with alternative (to rheumatoid
arthritis) discharge diagnoses, recognizing the 'lumping' character of the
current ACR criteria[5] and partially obviating the lumping problem.[6]
As I personally record familial evidence of cardiac disease rather
than mortality, this article by Björnådal et al.[1] would stimulate a
modification of my approach - should their work be extrapolatable to
clinical outpatient practice. However, it is not clear that the group
studied by Björnådal et al.[1] is representative of general rheumatologic
practice. Perhaps it is representative of those individuals who required
hospitalization for their disease or for a concurrent, incidental
disorder.
Several additional caveats must also be considered. We do not know
what biases were created by excluding individuals with absence of full
parental information, which accounted for 25% of discharged rheumatoid
patients in their study. This is similar to the 25% missing observations
that Björnådal et al.[1] cited as problematic for interpretation of the work
of Maradit-Kremers et al.[7] It would be intriguing to learn if missing
data would reveal differential characteristics of rheumatoid patients
incurring cardiovascular deaths. It also would be of interest to learn of
the criteria for adjucation of deaths as cardiovascular, given the
notoriety of death certificates.
Cardiovascular mortality is of concern in rheumatoid arthritis and
perhaps even paradoxical, given the anti-thrombotic / cardioprotective
effects attributed to some COX-1 agents,[8,9] although steroid use may be
the pertinent factor? It would have been of great interest to examine
differential NSAID, steroid, and of course aspirin use between the groups.
Does aspirin make a difference, and do steroids modify/compromise any
related benefit?
Most good research elicits more questions than it answers. The study
by Björnådal et al.[1] raises a number of intriguing questions, which I hope
will be answered by further analysis of their data base.
References
1 Björnådal L, Brandt L, Klareskog L, Askling J. Impact of parental
history on patients’ cardiovascular mortality in rheumatoid arthritis.
Ann Rheum Dis 2006;65:741-5.
2 Callahan LF, Pincus T. Mortality in the rheumatic diseases.
Arthritis Care Res 1995;8:229-41.
3 Björnådal L, Baecklund E, Yin L, Granath F, Klareskog L, Ekbom A.
Decreasing mortality in patients with rheumatoid arthritis: Results from a
large population based cohort in Sweden, 1964-95. J Rheumatol 2002;29:906
-12.
4 Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE
et al. Cardiovascular morbidity and mortality in women diagnosed with
rheumatoid arthrritis. Circulation 2003;107:1303-7.
5 Arnett FC, Edworth SM, Bloch DA. The American Rheumatism
Association revised criteria for the calssification of rheumatoid
arthr4itis. Arthritis Rheum 1988;31:315-24.
6 Rothschild BM. Two faces of “rheumatoid arthritis”: Type A versus
type B disease. J Clin Rheumatol 1997;3:334-8.
7 Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Roger VL,
Jacobsen SJ, et al. Increased unrecognized coronary heart disease and
sudden deaths in rheumatoid arthritis: A population-based cohort study.
Arthritis Rheum 2005;52:402-11.
8 Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of
thromboembolic cardiovascular events with naproxen among patients with
rheumatoid arthritis. Arch Intern Med 2002;162:1105-10
9 Rahme E, Pilote L, Lelorier J. Association between naproxen use
and protection against myocardial infarction. Arch Intern Med
2002;162:1111-5.
I read with interest the article by Katz et al on the prevalence and
predictors of disability in valued life activities among individuals with
rheumatoid arthritis (1).
It is encouraging that patient based assessments are being explored
among rheumatic diseases. Rheumatoid arthritis (RA) and osteoarthritis
(OA) have received the most attention in this regard. It is thus
reassuring that...
I read with interest the article by Katz et al on the prevalence and
predictors of disability in valued life activities among individuals with
rheumatoid arthritis (1).
It is encouraging that patient based assessments are being explored
among rheumatic diseases. Rheumatoid arthritis (RA) and osteoarthritis
(OA) have received the most attention in this regard. It is thus
reassuring that in this study, the Health Assessment Questionnaire (HAQ)
was predictive (B 2.44 for "unable" , 6.4 for "affected" and 0.56 for
"difficulty) of the overall valued activity disability.
I have some comments and queries. The study population is comprised
of individuals receiving treatment from rheumatologists, and had expressed
their interest in RA research. This may be a surrogate for people with
positive health behaviors, compliance and better educational status.
Patients that visit a rheumatologist may not reflect the general RA
patient population, as they may have better access to medical care,
especially for those 65 years or older (Medicare). In such recruitment, we
not only compromise generalizability of the results, but also the
variation in the disease spectrum. It would have been helpful to include
educational status and ethnicity data, since lower educational level is
known to be associated with work disability (2). Furthermore, lower socio
economic status is related with disease severity, more co morbidity and
higher mortality in RA (3).
The mean age of the study participants was 60 years and mainly
comprised of women, the subgroups that also have a higher prevalence of
osteoarthritis (OA). Can patients differentiate between limitations due to
RA or their coexistent OA or other co-morbidities (obesity, cardiac or
pulmonary disease, vision etc)? More than 50% of the subjects had one or
more co-morbidities, as mentioned in Table 2; however the multiple
regression models did not include co-morbidities as an independent
variable in the models for VLA.
Knowledge about the distribution of the data and range for age,
duration of disease and HAQ scores would have been helpful. Standard
deviations that are larger than the mean scores, on the difficulty ratings
(Table 3), may suggest the presence of outliers or lack of data. Table 3,
indicates the problem with fewer observations in the difficulty ratings in
the last two columns for "a lot" and "unable".
Lastly, it is not evident from the methods section about the recall
period used for VLA assessments. The methods section notes a six months
recall period for development of the VLA scale. However, it has since been
revised as mentioned by the authors. If six month recall period was also
used for this study, it may be too long a period for 60 years old patients
to recall. Similarly, detail about the method used for (physician/patient)
assessment of the number of swollen/painful joints would add to our
knowledge, to ascertain if this is was a completely patient based
assessment or included additional physician assessment.
It would be nice to see a similar study in early RA patients, so that
modifiable factors (including clinical information such as lag period
between disease onset to its diagnosis, time taken to start the treatment
with disease modifiers, and period between onset of disease and
therapeutic remission, presence of erosions, nodules, ESR/CRP, access to
health care, satisfaction with treatment, compliance, education,
ethnicity)which can predict potential disability in VLA, can be
determined, so that we can devise ways to prevent potential disability.
Sincerely
Meenakshi Jolly, MD, MS
References
1) Katz PP, Morris A, Yelin EH. Prevalence and predictors of disability in
valued life activities among individuals with rheumatoid arthritis. Ann
Rheum Dis 2006;65:763-769
2) Morales-Romero J, Gonzalez-Lopez L, Celis B et al. Factors associated
with permanent work disability in Mexican Patients with Rheumatoid
Arthritis. A case control study. J Rheumatol 2006;33:1247-9
3) Harrison MJ, Tricker KJ, Davies L et al. The relationship between social
deprivation, disease outcome measures, and response to treatment in
patients with stable, long standing rheumatoid arthritis. J Rheumatol
2005;32:2330-6.
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...
With great interest, we read the recently published article by Heckert et al regarding the tendency of recurrence of joint inflammation in patients with rheumatoid arthritis (RA) based on the sub-analysis of the BeSt study 1. In this study, the authors found that joint swelling in RA patients tended to recur in the same joints over time (OR 2.37, 95% CI 2.30 to 2.43, p<0.001). We congratulate the teams for their great work. Meanwhile, the important and interesting findings prompt us to think about the possible underlying mechanisms, which was just simply explained in the discussion. The authors pointed out that previous exposure to inflammatory triggers might mount a local alert state in the joint, promoting site-specific recurrence of inflammation. 2 We agree to their hypothesis, and would like to comment on the possible mechanisms in more depth from the aspect of Resident memory T cells (TRM) to the clinical findings.
Show MoreTRM cells have been recognized as a group of sentinels maintained in diverse anatomic compartments which resident in the tissue niche for a long-term in both human and mouse models. TRM requires distinct signals for the maintenance and survival in specific tissues. 3 4 It has been found that TRM is associated with the onset, progression and relapse of autoimmune diseases, such as psoriasis, spondylarthritis and lupus. 5-7 Recently, TRM which residents in the synovium was proved to be essential for the flare of arthritis in the animal model of recur...
Dear Editor:
The surveys were conducted in 1970s. At that time the majority of Finns drank traditional boiled coffee. The use of decaffeinated coffee was exceptional. In the Mini-Finland Health Survey, there was a negative correlation between daily cups of tea and coffee (age and sex adjusted partial r= -0.30, p...
This potentially valuable information about a relationship between coffee consumption and the presence of the rhematoid factor is difficult to evaluate because of a lack of clarity in definitions. What is meant by "coffee"? Is coffee, caffeinated or decaffeinated? This is an obvious distinction that readers need to consider these findings.
Also, it would have been interesting to have information ab...
Dear Editor
I was intrigued when I heard the report of this paper in view of the widely held belief that copper jewellery is also beneficial in the treatment of arthritis.
In the case of the gold rings it has to be remembered that gold rings are seldom pure gold. Even 22 carat gold rings are 22/24 parts gold, the rest being copper.
In view of this what evidence is there that the gold and not the...
I am wondering why, in this day and age, researchers into the long term effects/links of infections and the possible connection with potentially devastating conditions do not use PCR testing for the identification of these infecting or trigger organisms? My understanding is that PCR testing is far more sensitive than indirect methods of detecting the body's response to the bug concerned.
I would be inte...
Dear Editor,
I read with intrest this work and indeed I ask authors why do we search for indirect signs when the direct one is well seen by this ultrasonographic modality? Many new imaging machians introduced in this field and I notice that we try to find what the old machians dose. The plain X ray show bone errosion late and when the authors use the US modality the try to see what the plain X ray shows and in my...
Dear Editor,
Davis et al [1] emphasize the necessity of a uniform definition of the term "disease duration" for the case of ankylosing spondylitis (AS) because different definitions have been used in the past. Besides the duration since disease onset (time of first symptoms), the duration since the time of diagnosis of AS has also sometimes been named "disease duration" [2]. We very much support the initiative fo...
Dear Editor,
The article by Björnådal et al.[1] addresses an issue which has become increasingly recognized in the past decade.[2-4] They took a somewhat unique approach, examining cause of parental death. The authors[1] are to be congratulated for excluding individuals with alternative (to rheumatoid arthritis) discharge diagnoses, recognizing the 'lumping' character of the current ACR criteria[5] and partially ob...
Dear Editor,
I read with interest the article by Katz et al on the prevalence and predictors of disability in valued life activities among individuals with rheumatoid arthritis (1).
It is encouraging that patient based assessments are being explored among rheumatic diseases. Rheumatoid arthritis (RA) and osteoarthritis (OA) have received the most attention in this regard. It is thus reassuring that...
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