Download (VAS), physician`s global assessment (five grades), erythrocyte

Letters to the Editor
1. Martinez-Lavin M, Pineda C, Valdez T et al. Primary hypertrophic
osteoarthropathy. Semin Arthritis Rheum 1988;17:156–62.
2. Levine AC, Ren M, Huber GK, Kirschenbaum A. The effect of
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administration is associated with a high rate of treatment-limiting
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Rheumatology 2000;39:1159–1161
Clinical protocol for monitoring of targeted therapies in
rheumatoid arthritis
S, We read with interest the editorial ‘Targeted therapies in rheumatoid arthritis: the need for action’ [1]. In
support of the ideas raised, we would like to report our
initial experiences of a clinical protocol for rapid evaluation of the response to new treatment modalities in
patients with rheumatoid arthritis (RA).
In Sweden, the new biological anti-tumour necrosis
factor a drugs infliximab (Remicade) and etanercept
( Enbrel ) have been available for use in RA since March
1999, provided that permission is granted for the individual patient by the Medical Products Agency. The
requirements are that the patient has established active
RA which is not responding to at least two diseasemodifying anti-rheumatic drugs (DMARDs), and that
standardized monitoring is provided. Thus we were
offered a unique opportunity to test the hypothesis that
a standardized clinical protocol can yield rapidly available, useful, early information about the efficacy and
other features of new anti-rheumatic drugs. This could
reveal information not apparent in clinical trials, which
do not always reflect the performance of the drug in
real life [2]. Furthermore, since two novel drugs with
the same principal cytokine target had become available,
we also wanted to be able to compare these drugs in
the population of patients we see in our daily practice,
i.e. patients selected on the basis of current disease
activity but with very different backgrounds concerning
previous treatment, concomitant diseases and functional
impairment and disability.
The patients are evaluated at initiation of treatment,
at week 2 and week 6, and thereafter every 3rd month
for Enbrel and every 2nd month for Remicade, to
comply with the administration regimens. The evaluations are performed immediately before a new infusion/
injection. At initiation and at the follow-up evaluations
the mean weekly dosage for the previous 2 weeks of the
biological treatment is recorded. Concomitant treatment
with DMARDs, oral glucocorticoids, the numbers of
swollen and tender joints (28-joint count), pain [visual
analogue scale ( VAS )], patient’s overall assessment
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( VAS ), physician’s global assessment (five grades),
erythrocyte sedimentation rate and C-reactive protein
are recorded. The number of intra-articular glucocorticoid injections administered, any unforeseen medical
observations, permanent and temporary drug withdrawal, surgical operations, and drug side-effects since
the last measuring point are recorded.
To improve the quality of the data on the forms,
these are thoroughly evaluated before the data are
entered into the computer. A computer application has
been developed for data handling (PC, MS Access). The
application calculates disease activity score (DAS28) [3]
and the following response criteria: American College
of Rheumatology (ACR) 20, ACR 50, European League
Against Rheumatism ( EULAR)/WHO 20, EULAR/
WHO 50, that is 20 or 50% improvement compared
with the values at inclusion [4, 5]. These validated
response criteria are compared with the improvement in
DAS28, reduction in Health Assessment Questionnaire
score and reduction in oral prednisolone by 20 and 50%.
For the individual patient, a graphical representation of
the measured variables over time and a calculation of
the extent of their fulfilment of the different response
criteria are presented to the treating physician within
24 h as a tool for treatment decisions ( Fig. 1). For the
whole patient cohort, the application can plot graphically the mean values of the variables over time and the
percentages of patients fulfilling the different response
criteria. These data are presented to the rheumatologists
at regular intervals to encourage participation by all
clinicians.
The treatment regimens are those recommended by
the drug manufacturers, i.e. 25 mg subcutaneously twice
weekly for Enbrel, and infusion of 3 mg/kg of Remicade
at initiation, after 2 weeks and 6 weeks, and every 8
weeks thereafter.
Our experience to date includes all patients treated
with either Enbrel or Remicade at the Department of
Rheumatology at Lund University Hospital. So far, 74
patients have commenced treatment with Enbrel. Fortyone of these have been monitored for at least 3 months.
Only 10 patients are being treated with Remicade and
six of these have been treated for 3 months. The patient
characteristics are shown in Table 1.
This clinical protocol combined with the computer
system produces information regarding treatment effiT 1. Patient characteristics
Included (n)
Males/females (n)
RA/JCA (n)
Treated for 3 months (n)
Disease duration (yr; mean)
Age (yr; mean)
Previous DMARDs (mean)
Ongoing DMARDs (mean)
Ongoing prednisolone (mg/week; mean)
JCA, juvenile chronic arthritis.
Enbrel
Remicade
73
19/55
67/6
41
15.7
51.9
4.6
1.3
47.6
10
2/8
6/0
6
12.4
49.9
3.9
1.1
55.4
1160
Letters to the Editor
F. 1. Graphical presentation of clinical, laboratory and drug variables as presented to the treating physician. Note the framed
upper right part, where fulfilment of the response criteria is presented. The vertical axes are not optimal for every variable, but
represent a compromise to fit a one-page sheet.
cacy in a rapid and easily accessible way. Although the
patients represent a selection of previously treatmentresistant patients (Table 1), the clinical response rate is
impressive. Thus, an ACR response of 20% was found
in 80% of the patients and a response of 50% in 46% of
the patients (Fig. 2).
The protocol is also designed for studying the effects
of withdrawal of the drugs. Patients who have failed to
show significant improvement at the 20% level (i.e. ACR
20) are monitored with the same protocol as at initiation
of treatment and the computer application calculates
worsening of the response criteria at the 20 and 50%
levels.
In Sweden, the social security system allows therapeutic decisions to rely heavily on the estimated medical
need and the economic status of the patient does not
influence treatment decisions. However, due to the profound influence on the economy of the medical system
of these treatment principles, it is extremely important
to be able to document the cost–benefit ratio of the
introduction of these drugs to prove their utility also
from a health economics perspective. Accordingly, the
protocol also includes a socioeconomic part, which
includes a survey of the working/sick leave status, surgery,
and hospitalization, as well as the generic instruments
EuroQol and the Nottingham Health Profile.
The immediate feedback to the treating physician,
with graphical presentation of the measured variables
as well as information about the fulfilment of the response
criteria, has been well received by the staff and is considered very helpful in the care of these patients. The rapid
and powerful on-line presentation of the therapeutic
Letters to the Editor
2.
3.
4.
5.
F. 2. Percentage of patients on Enbrel fulfilling the ACR
criteria for response at 20% (ACR 20) and 50% (ACR 50).
Number at time 0 = 73; 0.5 months = 72; 1.5 months = 48;
3 months = 41.
response has made the system attractive to a number of
regional rheumatological centres. Patients from these
centres are now being included in the database.
This system for monitoring the effects of targeted
therapies in clinical practice can easily be applied also
in monitoring the effects of conventional DMARDs.
The computer-assisted system offers rapid and convenient feedback of treatment results to the physician as
well as easy access to up-to-date compilations of treatment results for all patients or subgroups of patients.
We believe that our system represents a significant step
towards the fulfilment of some of the requirements
outlined in the editorial [1]. Thus, it is possible to
evaluate the effects of therapy, define strict criteria for
efficacy/inefficacy, and evaluate each patient accordingly
and measure the worsening of symptoms after withdrawal of the drug in a standardized fashion. The system
also facilitates the creation of regional immunotherapy
centres, where the data base may be centralized and
give rapid feedback to each participating unit. The units
do not necessarily require the computer facilities, but
the system ensures that the drugs are administered
according to strict criteria and monitored uniformly.
We fully agree with the authors of the editorial that
there is an urgent need for action by rheumatologists in
order to ensure that novel treatment modalities are
being offered to patients who are in most need of such
treatments, at the lowest possible risk and at a cost
acceptable to the providers. This will be possible only
by careful monitoring of treatment effects on all aspects
of the disease. The system presented should be a useful
tool in these efforts.
P. G, T. S
Lund University Hospital, Department of Rheumatology,
S-221 85 Lund, Sweden
Accepted 30 March 2000
Correspondence to: P. Geborek.
1. Emery P, Panayi G, Sturrock R, Williams B. Targeted therapies in
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rheumatoid arthritis: the need for action. Rheumatology
1999;38:911–2.
Wolfe F, Lassere M, van der Heijde D, Stucki G, Saure-Almazor M,
Pincus T et al. Peliminary core set of domains and reporting
requirements for longitudinal observational studies in rheumatology. J Rheumatol 1999;26:484–9.
van der Heijde DM, Jacobs JW. The original ‘DAS’ and the
‘DAS28’ are not interchangeable: comment on the articles by
Prevoo et al. Arthritis Rheum 1998;41:942–3.
Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D,
Goldsmith C et al. American College of Rheumatology preliminary
definition of improvement in rheumatoid arthritis. Arthritis Rheum
1995;38:727–35.
van Gestel AM, Prevoo MLL, van’t Hof MA, van Rijswijk MH,
van de Putte LBA, van Riel PLCM. Development and validation
of the European League against Rheumatism response criteria for
rheumatoid arthritis. Comparison with the preliminary American
College of Rheumatology and the World Health Organization/
International League against Rheumatism criteria. Arthritis Rheum
1996;39:34–40.
Rheumatology 2000;39:1161
Reply
The authors are to be congratulated on undertaking an
effectiveness study of the new anti-TNF therapies. They
demonstrate the value of monitoring by experienced
physicians and the study will provide information on
the effectiveness and withdrawal rate of these drugs.
Furthermore, it will allow economic modelling, which
is crucial if these drugs are to be made available via
State funding.
The potential to monitor conventional DMARDs is
also of great interest and we look forward to further
information on this system.
P. E, G. P1, R. D. S2,
B. D. W3
Leeds Teaching Hospitals, Leeds, 1Guy’s Hospital,
London, 2Royal Infirmary, Glasgow and University
Hospital of Wales, Cardiff, UK
Accepted 30 March 2000
Correspondence to: P. Emery, University of Leeds,
36 Clarendon Road, Leeds LS2 9JT, UK.
Rheumatology 2000;39:1161–1163
Do sex hormones play a role in fibromyalgia?
S, Fibromyalgia (FM ) is a chronic musculoskeletal
disorder characterized by widespread pain, exquisite
tenderness at specific anatomical sites (i.e. tender points)
and other clinical manifestations, such as fatigue, sleep
disturbance and irritable bowel syndrome [1]. Despite
increasing research efforts, considerable debate remains
concerning the role of peripheral and central factors in
the aetiopathogenesis of FM [2]. Nevertheless, there is
no explanation for the higher frequency in women,
which suggests that sex hormones may have a role in
the expression of the disease.
Recent studies have demonstrated elevated levels of
substance P (SP) in cerebrospinal fluid obtained from
FM patients [3, 4]. SP is a peptide which has a role in
the neurotransmission of pain from the periphery to the