Boers, M.

Kirwan, J

J R, Kirwan

Boers, M

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Low dose prednisolone for treatment of RA

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Authors’ reply
We thank Dr Smith for alerting readers and
us to the existence of his excellent paper that
came out after our study was done and
during the preparation of our manuscript.
Our study described asymptomatic sub-
jects,1 a somewhat different group from that
in Dr Smith’s study2—namely, patients with
unexplained knee pain with clinically and
arthroscopically normal knee joints. It is
fascinating that in his study arthroscopy
could not detect moderate inflammation seen
in some biopsies. Thus, some synovitis can be
present even when examinations and gross
arthroscopy are normal. Future studies of
patients like ours and those of Smith et al
would benefit from longer follow up. What
was the final cause of the knee pain that led
to the need for arthroscopy? Will the cellular
pattern be consistent, resolving, or progres-
sive in some patients? Do the infiltrates seen
in some ‘‘normal subjects’’ have any prog-
nostic significance?
It appears that our two studies1 2 with
many similar findings reinforce the point,
also noted before by Lindblad and Hedfors,3
that there may be more variability in synovial
histology and immunohistochemistry than
many may have appreciated.
J A Singh, H R Schumacher
Minneapolis VA Medical Center, Minneapolis, USA
Correspondence to: Dr J A Singh; singh046@umn.edu
References
1 Singh JA, Arayssi T, Duray P, Schumacher HR.
Immunohistochemistry of normal human knee
synovium: a quantitative study. Ann Rheum Dis
2004;63:785–90.
2 Smith MD, Barg E, Weedon H, Papengelis V,
Smeets T, Tak PP, et al. Microarchitecture and
protective mechanisms in synovial tissue from
clinically and arthroscopically normal knee joints.
Ann Rheum Dis 2003;62:303–7.
3 Lindblad S, Hedfors E. The synovial membrane of
healthy individuals—immunohistochemical
overlap with synovitis. Clin Exp Immunol
1987;69:41–7.
Low dose prednisolone for
treatment of RA
We read with interest the report of the
WOSERACT trial1 that compared the addition
of 7 mg daily prednisolone or placebo to
sulfasalazine in early rheumatoid arthritis
(RA). A number of important aspects of the
trial have been dealt with well: the sample
size is adequate; appropriate attention has
been paid to confounders; two separate and
independent readers scored the radiographs;
the 2 year trial was of adequate length; and
the completeness of the data is satisfactory.
Given these strengths, it is all the more
disappointing that the results of the main
outcome, radiographic damage, cannot be
adequately interpreted as they are reported.
Indeed, the validity of these results is open to
serious doubt. We feel there is a real possibility
of a type II statistical error (missing a true
difference between treatment arms). There are
two (possibly three) reasons for this.
Firstly, there is an absolute difference
between the x ray scores of the two readers
of about 40 Sharp points. This raises strong
doubts over the proficiency of either or both
readers. In early RA Sharp scores are typically
very low, with most patients scoring 0 and
only a few with higher scores. Scores of 80,
let alone 159, after one year of RA are
without precedent in the literature, and even
the baseline medians of 6 and 8 recorded for
the conservative reader are quite high. In
contrast with the authors, we cannot be
‘‘reassured’’ by their assertion that ‘‘the
change in x ray score was consistent between
the two readers’’: these data are simply not
provided in the report. All we have is an
unsatisfactory correlation of absolute scores
between readers of 0.8 (whereas in most
trials the intraclass correlation coefficient
(the recommended and more severe test of
reliability between readers) exceeds 0.9), and
the comparison between readers of differ-
ences between the median start and end
scores in the two study groups. Unfor-
tunately, the difference between medians at
baseline and end point is not the same as the
median change.
Secondly, most trials choose two readers
who read either with sequence known or
unknown (the jury is still out on which is the
preferred method), and report the mean of
these two readings. This report has two
readers, each of whom uses a different one
of these options, and this makes it impossible
to pool the results. Also, even with sequence
unknown, films should be read as sets (all
films belonging to one patient assessed
simultaneously), not totally at random.
Reading totally at random strongly decreases
the signal to noise ratio.2 Which method did
the ‘‘random’’ reader apply exactly?
A third concern is with the analysis,
although this may only be a question of the
way in which the data are presented.
Although the authors state that the main
outcome measure is the change in radio-
graphic damage, they only report medians
and ranges of the absolute scores in the
groups. From our reading of the report, we
fear the analysis has (statistically) compared
the distributions of these absolute scores
rather than their changes.
This is an important study, and has the
potential to add valuable information to our
understanding of the best way to treat RA,
but in its present form the radiographic
results are more likely to cloud the issues
than clarify them. We suggest that the
radiographs are made available to be re-read
by two new, experienced readers, with either
the sequence known or unknown to both. We
also suggest that the analysis should present
the median, range, etc, of the changes in each
group, and the test of the difference between
these. (If they have a skewed distribution,
then either transformation before parametric
analysis or the use of non-parametric meth-
ods would be the best way to compare the
groups.)
There are other difficulties with the study,
although these are less important than the
essential concerns noted above. For example,
we are baffled by the statement in the
introduction that the COBRA combination3
‘‘showed radiological advantage over sulfa-
salazine alone but the study was not powered
to detect differences in x ray change’’. In fact,
the differences in x ray change were among
the key findings of the COBRA study, and
have since been shown to increase over time.4
So the study was not only adequately
powered but also showed an unexpectedly
large effect.
The authors diminish the value of the
report by inappropriate interpretation of their
secondary data, especially on the adverse
effects. In the discussion they comment,
‘‘While observed toxicity from corticosteroids
in terms of hypertension, weight gain, and
osteoporosis could be reduced by active
assessment and prompt intervention, there
is no room for complacency’’. However, in
their results section they report that, ‘‘Low
dose aspirin and treatment for ischaemic
heart disease remained similar, whereas the
use of antihypertensive agents increased in
both groups, as did prescription of lipid
lowering agents. The use of any treatment
for osteoporosis also increased in both
groups’’ In fact there was no difference
between the groups and thus there was no
observed toxicity from glucocorticoids in their
study. Further, the authors make no com-
ment on their observation that (many) more
patients in the placebo group than in the
glucocorticoid group stopped sulfasalazine
treatment owing to side effects.
In relation to weight gain, inappropriate
attention to within-group changes leads the
authors to conclude that body weight
‘‘increased significantly’’ in the glucocorti-
coid group (median gain 4 kg), with only a
‘‘borderline increase’’ in the placebo group
(median gain 3 kg). Body mass index is
handled in the same way. However, the only
really relevant comparisons, those between
groups, do not even show a trend to
significance (all p values >0.10). As with
the radiographic findings, the presentation of
the table suggests end point results were
compared rather than change scores.
Our interpretation of the clinical results
contradicts that of the investigators, and we
conclude that the effects on symptoms are in
line with previous reports of limited and
temporary advantages for disease activity,
blunting of sulfasalazine toxicity, and extre-
mely limited side effects when appropriate
caution is applied. It is not possible to assess
adequately the main results on x ray progres-
sion, which are at variance with several
previously published studies,3–8 and we urge
the authors to allow a second read of the
radiographs so that their important dataset
can be added to the existing evidence.
J Kirwan
University of Bristol Academic Rheumatology Unit,
Bristol Royal Infirmary, Bristol BS2 8HW, UK
M Boers
Department of Clinical Epidemiology and Biostatistics,
VU University Medical Centre, Amsterdam, The
Netherlands
Correspondence to: Dr J Kirwan; john.kirwan@
bristol.ac.uk
References
1 Capell HA, Madhok R, Hunter JA, Porter D,
Morrison E, Larkin J, et al. Lack of radiological
and clinical benefit over two years of low dose
prednisolone for rheumatoid arthritis: results of a
randomised controlled trial. Ann Rheum Dis
2004;63:797–803.
2 Van der Heijde D, Boonen A, Boers M, Kostense P,
van Der Linden S. Reading radiographs in
chronological order, in pairs or as single films has
important implications for the discriminative
power of rheumatoid arthritis clinical trials.
Rheumatology (Oxford) 1999;38:1213–20.
3 Boers M, Verhoeven AC, Markusse HM, van de
Laar MA, Westhovens R, van Denderen JC, et al.
Randomised comparison of combined step-down
prednisolone, methotrexate and sulphasalazine
with sulphasalazine alone in early rheumatoid
arthritis [see comments] [published erratum
appears in Lancet 1998;351:220]. Lancet
1997;350:309–18.
4 Landewe RB, Boers M, Verhoeven AC,
Westhovens R, van De Laar MA, Markusse HM,
et al. COBRA combination therapy in patients
with early rheumatoid arthritis: long-term
PostScript 1533
www.annrheumdis.com
structural benefits of a brief intervention. Arthritis
Rheum 2002;46:347–56.
5 Kirwan JR, Arthritis and Rheumatism Council Low
Dose Glucocorticoid Study Group. The effect of
glucocorticoids on joint destruction in rheumatoid
arthritis. N Engl J Med 1995;333:142–6.
6 Hickling P, Jacoby RK, Kirwan JR. Joint
destruction after glucocorticoids are withdrawn in
early rheumatoid arthritis. Br J Rheumatol
1998;37:930–6.
7 Rau R, Wassenberg S, Zeidler H. Low dose
prednisolone therapy (LDPT) retards
radiographically detectable destruction in early
rheumatoid arthritis—preliminary results of a
multicenter, randomized, parallel, double blind
study. Z Rheumatol 2000;59(suppl 2):II/90–6.
8 van Everdingen AA, Jacobs JW, Siewertsz Van
Reesema DR, Bijlsma JW. Low-dose prednisone
therapy for patients with early active rheumatoid
arthritis: clinical efficacy, disease-modifying
properties, and side effects: a randomized,
double-blind, placebo-controlled clinical trial.
Ann Intern Med 2002;136:1–12.
Authors’ reply
We agree with John Kirwan and Maarten
Boers that the assessment of radiographic
damage in the WOSERACT study is of
importance.1 The method of reading radio-
graphs has evolved since this study was
planned in 1995.2 Because we consider that
‘‘the jury is out’’, on the optimal way to read
radiographs in studies the films were read (a)
at random by one reader and (b) in sequence
by the other reader, and the same conclusion
was reached. This strengthens rather than
weakens the case for a true result.
The study of Paulus et al,3 in which there
was no beneficial effect on radiographic
outcome in 197 patients with rheumatoid
arthritis (RA), supports the WOSERACT
study findings. It was unfortunate that in
the Arthritis and Rheumatism Council (ARC)
low dose corticosteroid study the two groups
were not well matched at the outset, making
interpretation of the true effect of predniso-
lone at 2 years and of the subsequent report
difficult.4 5
The COBRA study6 used a high initial
corticosteroid dose and the effects contri-
buting to prompt disease control were
multifactorial. It is similarly not possible
to extrapolate from the study of van
Everdingen et al,7 because they used a
protocol of steroid without initial disease
modifying antirheumatic drug, which is not a
practice supported by current guidelines on
RA management.
There was considerable discussion among
the WOSERACT investigators about the
approach to glucocorticoid side effects. It
was decided that management of these
would be the responsibility of the individual
consultant, who remained unaware of the
treatment assignment. For this reason there
is likely to be a great deal of background
noise. This issue was not a primary end point
of our study but information is available from
other studies.8 We do agree that the blunting
of sulfasalazine toxicity in the active group is
of interest, although it would be inappropri-
ate to advocate the use of prednisolone for
this reason alone.
At a time when multiple treatments are
increasingly used in early RA it is vital to be
certain what contribution, if any, oral corti-
costeroids might make. The fact that both the
ARC study and ours showed no sustained
clinical benefit, makes x ray interpretation all
the more important.
Thus we suggest that with John Kirwan
and Marten Boers an approach is made to the
ARC (the original sponsors of the 1995
study), or to EULAR, for sufficient funding
to allow independent readers and statisti-
cians to evaluate all appropriate datasets.
This would allow films from relevant studies
to be copied and made available as a central
repository for future study. The films from
the study of Rau et al9 would also be useful for
this initiative.
H Capell, J Hunter, R Madhok, E Morrison,
J Larkin on behalf of the WOSERACT group
Centre for Rheumatic Diseases, Glasgow, UK
Correspondence to: Dr H A Capell; hilary.capell@
northglasgow.scot.nhs.uk
References
1 Capell HA, Madhok R, Hunter JA, Porter D,
Morrison E, Larkin J, et al. Lack of radiological
and clinical benefit over two years of low dose
prednisolone for rheumatoid arthritis: results of a
randomised controlled trial. Ann Rheum Dis
2004;63:797–803.
2 van der Heijde D, Boonen A, Boers M, Kostense P,
van der Linden S. Reading radiographs in
chronological order, in pairs or as single films has
important implications for the discriminative
power of rheumatoid arthritis clinical trials.
Rheumatology (Oxford) 1999;38:1213–20.
3 Paulus HE, Di Primeo D, Sanda M, Lynch JM,
Schwartz BA, Sharp JT, et al. Progression of
radiographic joint erosion during low dose
corticosteroid treatment of RA. J Rheumatol
2000;27:1632–7.
4 Kirwan JR, Arthritis and Rheumatism Council Low
Dose Glucocorticosteroid Study Group. The effect
of glucocorticosteroids on joint destruction in
rheumatoid arthritis. N Engl J Med
1995;333:142–6.
5 Hickling P, Jacoby RK, Kirwan JR. Joint
destruction after glucocorticostoids are withdrawn
in early rheumatoid arthritis. Br J Rheumatol
1998;37:930–6.
6 Landewe RB, Boers M, Verhoeven AC,
Westhovens R, van De Laar MA, Markusse HM,
et al. COBRA combination therapy in patients
with early rheumatoid arthritis: long-term
structural benefits of a brief intervention. Arthritis
Rheum 2002;46:347–56.
7 van Everdingen AA, Jacobs JW, Siewertsz Van
Reesema DR, Bijlsma JW. Low dose prednisolone
therapy for patients with early active rheumatoid
arthritis: clinical efficacy, disease-modifying
properties, and side-effects: a randomized,
double-blind, placebo-controlled clinical trial.
Ann Intern Med 2002;136:1–12.
8 Fries JF, Williams CA, Ramey D, Bloch DA. The
relative toxicity of disease-modifying
antirheumatic drugs. Arthritis Rheum
1993;36:297–306.
9 Rau R, Wassenberg S, Zeidler H. Low dose
prednisolone therapy (LDPT) retards
radiographically detectable destruction in early
rheumatoid arthritis – preliminary results of a
multicenter, randomized, parallel, double blind
study. Z Rheumatol 2000;59(suppl 2):II/90–6.
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Low dose prednisolone for treatment of RA

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