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The effect of methotrexate on soluble interleukin-2 receptor levels in rheumatoid arthritiscomment on the article by barrera et al.

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597
LETTERS
indirect immunofluorescence (IIF) techniques, as well as
from our laboratory standardization of the ANCA assay,
which had low interassay variability (19%). The reliability of
this assay, as well as other IIF assays in our immunology/
rheumatology laboratory, obviated the need to test all serial
samples of all patients at the same time. Further, saving sera
over months to years for batch testings, as suggested by
Cohen Tervaert and colleagues, is impractical in clinical
practice. Batch testing for all subjects was also not noted to
be part of the methods employed by those authors (1,2).
Forty-five of our 68 patients (66%) experienced periods of active disease during the study. In 17 of these 45
patients (38%), the disease was initially either in remission or
mild and smoldering, and later relapsed. In only 24% of these
17 patients did a significant rise in ANCA titers precede
disease exacerbations. The prognostic value of ANCA was
evaluated only in this subset, which is a cohort similar to that
reported by Cohen Tervaert et a1 (1). This observatioa
regarding prognostic utility is not influenced by the percent
of patients who had active disease on entry into our study or
the Dutch study, patients for whom ANCA was not evaluated as a prognostic marker.
Correlation of cANCA titer with disease, in general,
can be evaluated throughout periods of changing disease
activity. Cohen Tervaert et a1 have incorrectly deduced that
76% of patients in our study had a change in cANCA titers
that paralleled a change in disease activity. We observed
correlations, in both time and direction, of cANCA titer and
disease activity in 29 of 45 patients, i.e., 64%. However,
among 16 patients who had a 4-fold increase in cANCA titer,
44% (7 patients) did not experience relapse of disease.
We do not believe our results were influenced by the
fact that our study was single-blinded and that the investigators were at times aware of cANCA titer results. This
study was not designed to evaluate treatment efficacy based
on changes in cANCA titers. Our protocol for therapy of
WG includes well-established criteria for active disease (3),
which were applied to the patients in the study. Evaluation
of patients’ disease status and decisions regarding therapy
were not based on cANCA titers.
Cohen Tervaert and colleagues assert that in their
initial study, the mean period between a rise in cANCA level
and clinical exacerbation was 49 days (2). Their experience
(1) includes 20 patients whose disease was in remission or
who had mild, stable disease and were randomized to either
treatment or no-treatmentlobservation groups, following an
asymptomatic rise in cANCA titer. Although none of the
treated patients had a relapse, 9 of 11 untreated patients had
exacerbations. Six flares occurred within 3 months of a rise
in cANCA titer. However, 2 untreated patients did not
relapse at all, and 3 relapsed 1.1-2 years after the titer rise.
Clinical flares were treated with immunosuppressive therapy. The frequency and severity of side effects did not differ
between the 2 groups. Based on this limited experience,
those authors would have us treat patients based purely on
asymptomatic increases in ANCA titer. Their own experience indicates that this practice would lead to immunosuppressive therapy in some patients who would not express
clinically apparent disease for 2 or more years.
The association of cANCA and active WG is well
established and, in the appropriate clinical setting, has
diagnostic importance. However, we and others (4,5) maintain that the limited prognostic value of a rising ANCA titer
in an asymptomatic patient should not be the sole criterion
used to initiate potentially toxic and perhaps unnecessary
therapy.
Gail Kerr, MD
National Institutes of Health
Bethesda, MD
Gary S . Hoffman, MD
Cleveland Clinic Foundation
Cleveland, OH
1. Cohen Tervaert JW, Huitema MG, Hen6 RJ, Sluiter WF, The
2.
3.
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TH, van der Hem GK, Kallenberg CGM: Prevention of relapses
in Wegener’s granulomatosis by treatment based on antineutrophi1 cytoplasmic antibody titre. Lancet 336:709-711, 1990
Cohen Tervaert JW, van der Woude FJ, Fauci AS, Ambrus JL,
Velosa J, Keane WF, Meijer S, van der Giessen M, The TH, van
der Hem GK, Kallenberg CGM: Association between active
Wegener granulomatosis and anticytoplasmic antibodies. Arch
Intern Med 149:2461-2465, 1989
Hoffman GS, Kerr G S , Leavitt RY, Hallahan CW, Lebovics RS,
Travis WD, Rottem M, Fauci AS: Wegener’s granulomatosis: an
analysis of 158 patients. Ann Intern Med 116:488-498, 1992
Hagen EC, Ballieux BEPB, van Es LA, Daha MR, van der
Woude FJ: Antineutrophil cytoplasmic autoantibodies: a review
of the antigens involved, the assays, and the clinical and possible
pathogenetic consequences. Blood 81: 1996-2002, 1993
Petersson E, Heigl 2: Antineutrophil cytoplasmic antibody
(c-ANCA and p-ANCA) titers in relation to disease activity in
patients with necrotizing vasculitis: a longitudinal study. Clin
Nephrol 37:219-228, 1992
The effects of methotrexate on soluble interleukin-2
receptor levels in rheumatoid arthritis: comment on
the article by Barrera et a1
To the Editor:
We read with interest the article by Barrera et a1 (1)
concerning cytokine levels in rheumatoid arthritis (RA)
patients receiving methotrexate (MTX) and azathioprine
(AZA) therapy (1). Those authors observed that MTX therapy caused a significant reduction in circulating levels of
soluble interleukin-2 receptor (sIL-2R) and interleukind
(IL-6) that was associated with clinical improvement, while
AZA did not affect sIL-2R levels but did reduce IL-6 levels.
We have also measured circulating levels of s I L - ~ R ,
by enzyme-linked immunosorbent assay (T Cell Sciences,
Cambridge, MA), and IL-6, by B9 bioassay (2), in RA
patients receiving MTX or AZA. Although we observed a
decrease in circulating levels of sIL-2R between week 0
(1,175 unitslml; interquartile range [IQRI 692-1,400; n = 16)
and week 12 (880 unitslml; IQR 370-1,135; n = 15) and week
24 (740 unitslml; IQR 440-1,150; n = 1l), in patients receiving MTX, this decrease was only statistically significant at
week 12. There was also a decrease in circulating levels of
IL-6 at 12 weeks of MTX therapy (n = 19), which was
statistically significant, but the levels increased again at
week 24 (Crilly et al: unpublished observations). In this same
patient group, there was clinical improvement as assessed by
the Ritchie articular index (RAI), pain score (PS), and
LETTERS
598
duration of morning stiffness (MS). Similarly, we found AZA
therapy did not significantly alter circulating levels of sIL-2R
or IL-6 at either 12 or 24 weeks of therapy (n = 18 and 14,
respectively), although there was clinical improvement as
assessed by the RAI, PS, and MS (Crilly et al: unpublished
observations).
Bascd on our findings as well as those reported by
Dooley et al (3), we believe that it is still not totally clear
whether MTX has the ability to influence sJL-2R levels in
RA patients. Dooley et al reported that not only MTX, but
also placebo, treatment caused a significant reduction in
circulating levels of sIL-2R in patients with RA. When their
patients were grouped as responders and nonresponders at
completion of the study, the sIL-2R levels were similar
regardless of the treatment given. Because a placebo treatment group was not included in Barrera’s study, we would
question their findings with regard to this.
We believe the findings by Dooley et al (3), along
with our own results, suggest that MTX does not influence
lymphocyte activity in RA patients, as assessed by sIL-2R
levels. This is perhaps not surprising since drugs like MTX
and AZA suppress bone marrow function in vivo, and it has
been suggested that they work by reducing the number of
mature monocytes available for recruitment to the joint (4).
We have also observed that other second-line agents also
thought to specifically target macrophage activity and function decrease IL-6 but not sIL-2R levels (5,6). In contrast,
we have found that cyclosporin A, a drug which is known to
specifically target T cell function, reduces circulating levels
of sIL-2R as well as IL-6 (7). We believe, therefore, that the
effect of MTX on sIL-2R levels is still open to debate.
Anne Crilly, PhD
Rajan Madhok, MD, MRCP
University of Glasgow Department of Medicine
Glasgow, Scotland
1.
2.
3.
4.
5.
6.
7.
Barrera P, Boerbooms AMT, Janssen EM, Sauerwein RW,
Gallati H, Mulder J, de Boo T, Demacker PNM, van de Putte
LBA, van der Meer JWM: Circulating soluble tumor necrosis
factor receptors, interleukin-2 receptors, tumor necrosis factor a,
and interleukin-6 levels in rheumatoid arthritis: longitudinal
evaluation during methotrexate and azathioprine therapy. Arthritis Rheum 36: 1070-1079, 1993
Aarden LA, DeGroot ER, Schaap OL, Lansdorp PM: Production
of hybridoma growth factor by human monocytes. Eur J Immuno1 17:1411-1416, 1987
Dooley MA, Pisetsky DS, Dawson DV, Polisson RP: Soluble
serum IL-2 receptor levels in refractory RA: trends during MTX
therapy (abstract). Arthritis Rheum 34 (suppl9):S36, 1991
Hamilton JA: Rheumatoid arthritis: opposing actions of haemopoietic growth factors and slow-acting anti-rheumatic drugs.
Lancet 342536539, 1993
Madhok R, Crilly A, Murphy E, Smith J, Watson J, Capell HA:
Gold therapy lowers interleukin-6 levels in rheumatoid arthritis.
J Rheumatol 20:630-633, 1993
Crilly A, Madhok R, Watson J, Capell HA: Serum concentrations of soluble interleukin 2 receptor in patients with rheumatoid
arthritis: effect of second line drugs. Ann Rheum Dis 52:5&60,
1993
Crilly A, Madhok R, Dougados M, Watson J, Capell HA,
Sturrock RD: IL-6 and soluble IL-2 receptor levels in RA
patients receiving cyclosporin therapy (abstract). Clin Rheumatol
12:47, 1993
Reply
To the Editor:
The comments by Crilly and Madhok are especially
interesting in light of their recently published abstract about
sIL-2R and interleukin-6 (IL-6) measurements in RA (1). In
that study, sIL-2R and IL-6 were measured at 0, 12, and 24
weeks in patients treated with MTX or placebo. In patients
treated with MTX, a significant reduction in sIL-2R (n = 16;
P = 0.0008) and IL-6 (n = 20; P = 0.018) was observed after
12 weeks. The levels of sIL-2R (n = 11) and IL-6 (n = 14)
remained low after 24 weeks, but this was not statistically
significant. In patients treated with placebo, no significant
changes in sIL-2R or IL-6 were observed after 12 or 24
weeks. They concluded that “the clinical benefits in patients
receiving MTX may in part be due to modulation of cytokines such as IL-6 and sIL-2R.”
In their comment on our article, Crilly and Madhok
show very similar data on MTX-treated patients compared,
this time, with AZA-treated patients (where no changes in
sIL-2R and IL-6 levels occurred). Inconsistent with their
previous statement, they now question the effects of MTX
on sIL-2R levels. Some of the discrepancies between their
findings and ours might be due to the different study structure. We conducted a double-blind, randomized study including a considerable number of patients with active RA,
refractory to intramuscular gold and/or D-penicillamine.
Data concerning patient selection and study definition in
the study by Crilly and Madhok are lacking and the nonsignificant decrease in sIL-2R levels after 24 weeks of MTX
treatment may be due to the small numbers of patients at
this time.
For ethical reasons, a placebo group was not included in our study since MTX (2) and AZA (3) have been
demonstrated to be superior to placebo in clinical trials.
Levels of sIL-2R in patients treated with placebo did not
change during 24 weeks in the study by Crilly et al (l), while
Dooley et al(4) found a significant decrease in sIL-2R levels
both in patients treated with MTX and those treated with
placebo for 18 weeks. Furthermore, Dooley et al found no
significant differences in sIL-2R levels among responders
and nonresponders at study completion. Interpretation of
the data in this abstract (4) is difficult since the data given
concern the whole patient group (MTX and placebo) and no
definition of outcome (responder or nonresponder) is provided. Comparing patient groups in a cross-sectional way at
a given time (i.e., study completion) may underestimate
differences, since interindividual variations in sIL-2R levels
are marked, and exceed by more than 5-fold the variation in
a given patient over a period of time (Barrera et al: unpublished results). Therefore, measurements at several time
points or analysis of percentages of changes from baseline
might be more adequate.
Finally, the mechanism of action of MTX has yet to
be elucidated. Besides an effect on lymphocyte activation (as
measured by sIL-~R),effects on monocytes (9,polymorphonuclear cell chemotaxis (6), proliferating synovial cells
(7), and angiogenesis (8) have been suggested. The field open
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