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Rheumatoid Synovial T Cells are Functionally Active and can Contribute to the Pathogenesis of Rheumatoid ArthritisComment on the Article by Matthews et al.

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leucovorin supplementation. Our study included 35 patients
who completed 52 weeks of therapy with MTX and leucovorin, whose response as a group to MTX was no different
than the group receiving no leucovorin (placebo). Thus, it is
doubtful that the leucovorin regimen interfered in a clinically
significant manner.
Dr. Morgan et al believe that FA will be easier to use,
safer to use, and have a larger therapeutic window in dosing
than leucovorin. I cannot think of an easier therapy than one
that requires taking only half a tablet or 1 tablet once weekly,
the day after taking MTX. No other supplements are required for the rest of the week. I would think that this kind
of a regimen is rather convenient to the patient.
With regard to safety, leucovorin is safe and is
nontoxic, just as folate is. No doubt, if leucovorin is given in
a sufficient amount, it can interfere with the efficacy of MTX.
In the study by Tishler et al referred to by Dr. Morgan, 9
tablets, or 45 mg, of leucovorin was given within hours of
taking MTX, and this resulted in a flare of the arthritis. This
is a substantial difference between taking either half a tablet
or 1 tablet 24 hours after the MTX. It would be interesting to
know what would happen if one took 9 or 10 tablets of either
5 or 10 mg of FA either simultaneously or within several
hours of taking MTX. In either case, should a flare arise, one
would simply discontinue the supplementation and likely the
MTX would become more effective, as it does after the
reinstitution of therapy following leucovorin rescue for acute
toxicity due to an overdose.
With respect to cost, the 600-fold difference in cost
reported by Morgan et al is, in my experience, an exaggeration. I have recently conducted a survey of local pharmacies in southeastern Florida and found the cost to the patient
to be $5.49 for a 1-month supply of 5 mg/day of folate (more
for 10 mdday), compared with $9.09 and 14.49 monthly for
2.5 mdweek and 5 mg/week leucovorin, respectively. I
acknowledge that although, in dollars, this is not a substantial amount, it still could be meaningful to some patients;
however, this is not really a 600-fold difference, as suggested. One may also speculate that should there be an
increase in usage of folinic acid (leucovorin), it is possible
that the price of the medication could decline, as with other
medications formerly used only rarely.
In regard to the studies of folate conducted by Dr.
Morgan and colleagues, we were trying to draw to attention
the small sample size and short duration of the first study.
The authors themselves acknowledge the restrictions of their
sample size in their report. We reiterate that the dosages of
MTX used in that study do not reflect how MTX is currently
administered to patients with RA. It would be interesting to
see how their FA regimen would work using current MTX
Finally, I look forward to the results of the ongoing
trial of FA supplementation in MTX-treated patients and do
hope that these results prove to be comparable with or even
better than those from our trial. All of our patients will
benefit from such results.
Jeffrey B. Shiroky, MD
Cleveland Clinic Florida
Fort Lauderdale, FL
Rheumatoid synovial T cells are functionally active
and can contribute to the pathogenesis of rheumatoid
arthritis: comment on the article by Matthews et al
To the Editor:
We read with interest the article by Matthews et a1
(1) regarding the increased proportion of CD4+ T cells in
rheumatoid synovium that are CD45RO+ and CD45RBdim.
While our own data are consistent with their results (2), we
disagree with their conclusion that the likelihood that these
synovial T cells have been chronically stimulated implies a
limited role in inflammatory damage to the joint.
In our previous studies (2), we found evidence to
support a conclusion that rheumatoid synovial T cells have
functional potential, and that they are likely to have undergone local differentiation. While the CD45RBdimsynovial T
cells are likely to be in a late stage of differentiation, they still
appear to have the potential to provide help to B cells. Blood
and, in particular, synovial CD45RBdi" T cells had a reduced
capacity to proliferate and to produce interleukin-2 in response to mitogenic stimuli. They effectively promoted the
production of immunoglobulin, and had a reduced capacity
to down-regulate Ig production from normal B cells. These
regulatory activities were noted in both normal and synovial
CD45RBdimT cells despite the observation that synovial T
cells were partially anergized, presumably as a result of local
influences. Although the previous experiments documented
this potential after mitogenic stimulation, recent unpublished
experiments have demonstrated this function to be constitutively expressed by synovial T cells without in vitro manipulation. Thus, synovial T cells very likely stimulate synovial
B cells to secrete the large amounts of Ig, and possibly
rheumatoid factor, that are measurable in rheumatoid synovium (3).
Moreover, we believe that existing data support the
idea that activation and differentiation of T cells occurs
inside the joint. Synovial T cells express activation markers,
including HLA-DR, intercellular adhesion molecule I, and
very late activation antigen 1 (4). Furthermore, in rheumatoid synovial tissue sections, T cells are clustered around
antigen-presenting dendritic cells in proximity to blood vessels (5,6). Finally, in vitro experiments have demonstrated
that migrating CD4+,CD45RO+ T cells are not enriched in
CD45RBdi" cells (7). This suggests that the differentiation of
the majority of the migrating cells to a CD45RBdi" phenotype occurs within the joint-after their activation by antigen
presented by the antigen-presenting cells. Despite the recent
emphasis on the contribution of T cells to rheumatoid
inflammation, the local production of Ig and rheumatoid
factor, with resultant formation of immune complexes,
clearly plays a role in the pathogenesis of this disease (8,9).
Ranjeny Thomas, MBBS
Melissa McIlraith, BS
Laurie Davis, PhD
Peter Lipsky, MD
University of Texas Southwestern Medical School
Dallas, TX
1. Matthews N, Emery P, Pilling D, Akbar A, Salmon M: Subpopulations of primed T helper cells in rheumatoid arthritis. ArthriGs
Rheum 36:603-607, 1993
2. Thomas R, McIlraith M, Davis LS, Lipsky PE: Rheumatoid
synovium is enriched in CD45RBdimmature memory T cells that
are potent helpers for B cell differentiation. Arthritis Rheum
35~1455-1465, 1992
3. Wernick RM, Lipsky PE, Marban-Arcos E, Maliakkal JJ, Edelbaum D, Ziff M: IgG and IgM rheumatoid factor synthesis in
rheumatoid synovid membrane cell cultures. Arthitis Rheum
28:742-752, 1985
4. Cush JJ, Lipsky PE: Phenotypic analysis of synovial tissue and
peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum 31:123&1238, 1988
5. Janossy G, Panayi G, Duke 0, Bofill M, Poulter LW, Goldstein
G: Rheumatoid arthritis: a disease of T-lymphocyte/macrophage
immunoregulation. Lancet 2:839-842, 1981
6. Van-Dinthner-Janssen ACHM, Pals ST, Scheper R, Breedveld
F, Meijer CJLM: Dendritic cells and high endothelial venules in
the rheumatoid synovial membrane. J Rheumatol 17:11-17, 1990
7. Pietschmann P, Cush JJ, Lipsky PE, Oppenheimer-Marks N:
Identification of subsets of human T cells capable of enhanced
transendothelial migration. J Immunol 149:1170-1 178, 1992
8. Korchak HM, Vienne K, Rutherford LE, Weissmann G: Neutrophil stimulation: receptor, membrane, and metabolic events.
Fed Proc 43:274%2754, 1984
9. Cooke TD, Hurd ER, Jasin HE, Bienenstock J, Z f i M: Identification of immunoglobulins and complement in rheumatoid articular collagenous tissues. Arthritis Rheum 18541-551, 1975
Mason has shown that CD45RBdU”cells from blood
proliferate poorly, but support antibody synthesis if stimulated nonspecifically (4). This point made by Thomas et a1 is
therefore not controversial, and indeed is in accord with our
observation of increased IL-4 synthesis. There is, however,
less evidence to support their suggestion that this implies a
role for such effects in the pathologic process of RA.
Mitogenic stimulation of T cells isolated from the synovial
microenvironment does not necessarily indicate a likely
antigen-specific function in vivo. There is very little evidence of local activity of T cells in rheumatoid joints (for
review, see ref. 5 ) , but as Thomas points out, plasma cell
activity is frequently observed. Indeed, experiments using
total lymphoid irradiation for RA, which may considerably
reduce synovial T cell numbers, have little, if any, effect on
rheumatoid factor production (6). It is therefore likely that
the synovium recruits precommitted plasmablasts, and that
synovial T cells have little influence on their function.
To the Editor:
We thank Thomas and colleagues for their interest in
our article. We have shown recently that the CD45RBdU”
state does not indicate a specific subpopulation of primed
cells, but rather, a late stage in the spectrum of progressive
differentiation of T cells; CD45RBbnSh‘primed cells represent the early stage. This progression is associated with
reduced production of interleukin-2 (IL-2) and interferon- y,
and increased production of IL-4. In parallel with the spectrum of differentiation, cells progressively increase their
susceptibility to apoptosis, which is associated with reduced
bcl-2 and increased Fas expression (1,2). This is important
for maintaining homeostatic balance in T cell populations.
As we reported, synovial T cells represent the extreme limit
of differentiation. The accumulation of such cells in synovium appears to reflect a retardation of apoptosis, which
may be associated with factors derived from synovial fibroblasts (1,3).
1. Akbar AN, Borthwick N, Salmon M, Gombert W, Bofill M,
Shamsadeen N, Pilling D, Pett S, Grundy JE, Janossy G: The
significance of low bcl-2 expression by CD45RO T cells in normal
individuals and patients with acute viral infections: the role of
apoptosis in T cell memory. J Exp Med 178:427438, 1993
2. Salmon M, Pilling D, Borthwick NJ, Viner N, Janossy G, Bacon
PA, Akbar AN: The progressive differentiation of primed T cells
is associated with an increasing susceptibility to apoptosisSubmitted
3. Scott S, Pandolfi F, Kurnick J T Fibroblasts mediate T cell
survival: a proposed mechanism for retention of primed T cells.
J Exp Med 172:1873-1878, 1991
4. Mason D: Subsets of CD4+ T-cells defined by their expression of
different isoforms of the leukocyte-common antigen, CD45.
Biochem SOCTrans 20:188-190, 1992
5 . Firestein GS, Zvaifler NJ: How important are T cells in chronic
rheumatoid synovitis? Arthritis Rheum 33:768-771, 1990
6. Hanly JG, Hassan J, Moriarty M, Barry C, Molony J, Casey E,
Whelan A, Feighery C, Bresnihan B: Lymphoid irradiation in
intractable rheumatoid arthritis: a double-blind, randomized
study comparing 750-rad treatment with 2,000-rad treatment.
Arthritis Rheum 29:16-25, 1986
ders, in which he provides a refreshing view of a disability
system that he eloquently describes as having a logical injury
basis that is “recondite at best.”
His presentation of patients with “regional musculoskeletal symptoms~~
emphasizes low back pain and curnulative trauma disorders of the upper extremities. Dr. Hadler
clearly relates the sociomedicd metamorphosis of “a person
with a predicament” occurring in the workplace becoming
Occupational Musculoskeletal Disorders. Nortin M . Hadler.
New York, Raven Press, 1993. 287 P P . Illustrated. Indexed.
Professor Nortin Hadler has prepared another enlightening monograph, Occupational Musculoskeletal Disor-
Mike Salmon, PhD
Darrell Pilling, BSc
Arne N. Akbar, PhD
Paul Emery, MA, MD, FRCP
University of Birmingham
Birmingham, U K
The Royal Free Hospital
London, UK
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