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Long-term treatment with every-other-w eek methotrexate in rheumatoid arthritis patients with sustained disease improvementComment on the article by kremer et al.

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samples did not have proportions of dendritic cells as high as
those reported by Thomas et al (l), we still observed the RA
SF MNC to have a markedly enhanced ability to function as
stimulator cells in the allogeneic MLR, compared with blood
MNC. More importantly, however, it is uncertain how
relevant these MLR results are to the presumed high level of
immune reactivity manifested by MNC at sites of autoimmune disease activity.
We observed in our study that the RA SF B cells, T
cells, and monocytes expressed significantly higher levels of
surface molecules that are important in cognate cell-cell
interactions and that can facilitate cellular autoimmune
activation. We believe it is too early to dismiss the pathophysiologic significance of this finding. First, it is not known
whether one or more cell types is involved in the initiation,
progression, and/or maintenance of in vivo autoimmunity.
Second, activated, autoreactive B cells, although relatively
less potent stimulator cells in an MLR, are capable of
invoking a more potent response to specific antigens than are
resident dendritic cells. For example, rheumatoid factor
(RF)-expressing B cells are highly efficient at concentrating
and presenting antigens contained within immune complexes
(4-6). Furthermore, the mutation patterns of the immunoglobulin genes of RF-producing B cells in RA synovium
suggest that these cells are participating in, and are products
of, an antigen-driven response (7). It is plausible that such B
cells may be activating T cells while in turn being activated
by autoreactive T cells, leading to a vicious cycle of cellular
autoimmune activation.
Finally, we agree that it is important to assess the
relative expression levels and functional significance of
CD86 on RA S F MNC subsets. However, despite recent
reports suggesting that the signal delivered via CD86 may
differ qualitatively or quantitatively from that delivered via
CD80, it is still uncertain whether CD86 plays a more
important role than CDSO in autoimmune T cell activation.
In fact, a recent study by Kuchroo and colleagues actually
implied the opposite (8). Those investigators reported that
expression of CD80 by antigen-presenting cells may induce a
Thl-like T cell response to a specific antigen, characterized
by the production of interferon-y, tumor necrosis factor p,
and a cellular, or delayed-type hypersensitivity-dominated,
immune response. In contrast, they noted that Th2-like
responses were induced by CD86-mediated interactions. In
the model used in their studies, i.e., murine experimental
autoimmune encephalomyelitis (EAE), blocking of CD80
(B7-1) apparently effected a dramatic reduction in autoimmune disease pathology, while blocking of CD86 (B7-2)
interactions with its ligands enhanced the autoimmune response. To be sure, more studies are required to confirm
these findings in other systems and to define the discrete
roles played by CD80 versus CD86 in the initiation andor
progression of EAE and other autoimmune diseases.
Regardless of the identity of the most important
antigen-presenting cell(s) in the RA synovium, we believe
that our work and that of Thomas et a1 (l), Kuchroo et al
(S), and others (for review, see ref. 9) suggests that there
may be therapeutic advantage gained in blocking the enhanced expression of CD80 on potential antigen-presenting
cells in the treatment of a subset of human autoimmune
Erik A. Ranheim
Thomas J. Kipps, MD, PhD
University of California Sun Diego
La Jolla, CA
1. Thomas R, Davis LS, Lipsky PE: Rheumatoid synovium is
enriched in mature antigen-presenting dendritic cells. J lmmunol
13-2623, 1994
2. Zvaifler NJ, Steinman RM, Kaplan G, Lau LL, Rivelis M:
Identification of immunostimulatory dendritic cells in the synovial effusions of patients with rheumatoid arthritis. J Clin lnvest
76:78!%300, 1985
3. Steinman RM: The dendritic cell system and its role in immunogenicity. Annu Rev Immunol9:271-296, 1991
4. Carson DA, Chen PP, Kipps TJ: New roles for rheumatoid
factor. J Clin Invest 87:379-383, 1991
5 . Roosnek E, Lanzavecchia A: Efficient and selective presentation
of antigen-antibody complexes by rheumatoid factor B cells. J
Exp Med 173:487489, 1991
6. Tighe H, Chen PP, Tucker R, Kipps TJ, Roudier J, Jirik FR,
Carson DA: Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice. J
Exp Med 177:109-118, 1993
7. Olee T, Lu EW, Huang DF, Soto-Gil RW, Deftos M, Kozin F,
Carson DA, Chen PP: Genetic analysis of self-associating immunoglobulin G rheumatoid factors from two rheumatoid synovia
implicates an antigen-driven response. J Exp Med 175:831-842,
8. Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS, Sobel
RA, Weiner HL, Nabavi N, Glimcher LH: B7-I and B7-2
costimulatory molecules activate differentially the Thl/Th2 developmental pathways: application to autoimmune disease therapy. Cell 80:707-718, 1995
9. Linsley PS, Ledbetter JA: The role of the CD28 receptor during
T cell responses to antigen. Annu Rev Immunol 11:191-212, 1993
Long-term treatment with every-other-week
methotrexate in rheumatoid arthritis patients with
sustained disease improvement: comment on the
article by Kremer et a1
To the Editor:
I read with interest the report by Kremer and colleagues on every-other-week methotrexate (MTX) in the
treatment of rheumatoid arthritis (RA) (Kremer JM, Davies
JMS, Rynes RI, Fink S, Lawrence DA, Petrillo GF, Mullaly
PM: Every-other-week methotrexate in patients with rheumatoid arthritis: a double-blind, placebo-controlled prospective study. Arthritis Rheum 38:601-607, 1995). Now it is time
to let the other shoe drop.
I have previously reported on pulse MTX treatment
results from our Arthritis, Rheumatism and Aging Medical
Information System databank experience (Roth SH: Comparison of pulse methotrexate therapy with gold salt therapy
in rheumatoid arthritis [abstract]. Arthritis Rheum 24 [suppl
4]:S71, 1981). Those of us who have been treating RA
patients with MTX for decades have learned that a significant percentage of them will improve so much that the MTX
may no longer be required. Thus, as a prelude to discontin-
uation of the treatment, I will prescribe every-other-week
treatment. For that subset of patients who tolerate this
without disease recrudescence over a few months, I will then
invariably discontinue the MTX. I find that in almost every
case there is no difference in disease course in this stable
group without it. The clear understanding is that if there is
any recrudescence of disease activity the MTX can be
reinstituted, and more often than not, after a period of years
rather than months, it is.
RA has a variable course. The controlled observations from the empirical study by Kremer et a1 are useful.
But it is appropriate to consider what their findings may
actually mean in terms of long-term management. Can we
justify every-other-week MTX in patients who no longer
may need it? It would be useful to more definitively answer this
question as a key issue in the long-term management of RA.
Sanford H. Roth, MD
Arthritis Center, Ltd.
Phoenix, AZ
To the Editor:
My colleagues and I wish to thank Dr. Roth for his
thoughtful comments. We agree that RA is a disease with a
variable course. We believe Dr. Roth makes the point that
because of this variability, we may be prescribing everyother-week MTX to patients who would do well without it.
We had previously found in a double-blind placebocontrolled study that even patients whose RA is stable with
long-term weekly MTX have flares within 1 month of switching to MTX placebo (1). Our own practice experience has
been that significant flares in clinical disease activity occur
within several weeks of withholding MTX, for whatever
reasons. The impetus for the every-other-week treatment
study was, however, derived from a somewhat different
experience. In a study of the immunologic effects of MTX,
we had observed that not all patients had severe flares in
disease activity when MTX was withheld for 1 month (2).
We therefore posited that perhaps certain patients might be
able to take the drug every other week.
Since we were unable to identify any clinical or
demographic features that predicted which patients could
successfully switch to every-other-week MTX (3), we believe that Dr. Roth’s empirical approach is valid. As long as
patients are willing to accept the risk of a significant flare in
their disease activity, every-other week or less frequent
MTX dosing might be tried in individuals who are well and
whose disease is judged to be stable. This approach raises
other important issues, such as how these alternative dosing
schemes would affect radiographic progression and maintenance of functional status, questions which can be answered
only by long-term comparative trials. In the meantime, there
are no data upon which to formulate a decision as to which
patient may experience success with an alternative MTX
dosing regimens.
Joel M. Kremer, MD
Albany Medical College
Albany, N Y
1 . Kremer JM, Rynes RI, Batholomew LE: Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate
therapy. Am J Med 82:781-786, 1987
2. Kremer JM, Lawrence DA, Petrillo GF, Litts LL, Mullaly PM:
Immune effects of stopping and restarting methotrexate in patients with rheumatoid arthritis: a double blind prospective study
(abstract). Arthritis Rheum 37(suppl 9):S252, 1994
3. Kremer JM, Davies JMS, Rynes RI, Fink S, Lawrence DH,
Petrillo GF, MullaIy PM: Every-other-week methotrexate in
patients with rheumatoid arthritis: a double-blind, placebocontrolled prospective study. Arthritis Rheum 38:601407, 1995
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