Lupus (2004) 13, 679682

www.lupus-journal.com

Evaluation of systemic lupus erythematosus activity

during pregnancy
G Ruiz-Irastorza1 and MA Khamashta2
1

Service and Department of Internal Medicine, Hospital de Cruces, University of the Basque Country, Bizkaia, Spain; and
2
Lupus Research Unit, The Rayne Institute, St Thomas Hospital, London, UK

Due to our increasing knowledge on the pathophysiological basis of autoimmunity and the
development of combined medical obstetric clinics, pregnancy is becoming common among women
with systemic lupus erythematosus (SLE). However, whether lupus worsens during pregnancy
continues to be a controversial issue. SLE assessment during pregnancy is sometimes difficult due to
physiological changes during this period, and common tools for measuring lupus activity during
pregnancy were not available until recently. Several lupus activity scales in common use have been
adapted for pregnancy [systemic lupus erythematosus in pregnancy activity index (SLEPDAI),
modified lupus activity measurement (m-SLAM) and lupus activity index in pregnancy (LAI-P)]. All
of them take into account the influence of pregnancy on clinical manifestation and common
biochemical tests. LAI-P also accounts for specific manifestations of antiphospholipid syndrome in
order not to score them as due to SLE activity. LAI-P has recently been validated for use in SLE
pregnancy and could be used in future studies. However, daily assessment and management of
individual pregnant women with lupus still relies on the clinical skills of attending
physicians. Lupus (2004) 13, 679 682.
Key words: activity scales; gravida; lupus flare

Introduction
Pregnancy is a very special period in every womans life.
This is especially true in women with systemic lupus
erythematosus (SLE). For many years, patients with SLE
have been advised against pregnancy. Fortunately, owing
to the increasing knowledge of disease pathophysiologic
mechanisms and the development of clinics with
combined obstetric and medical care, pregnancy has
become a normal event in women with lupus.
Normal does not mean uneventful, however. Lupus
pregnancies should be considered as high risk, even
though many women do not experience major
complications. Potential adverse events include thrombosis, miscarriage and toxemia in patients with
antiphospholipid antibodies (aPL), neonatal lupus in
babies born to mothers with anti-Ro antibodies, toxicity
of drugs used in SLE and flares of lupus activity whose
severity may range from mild to life threatening.

Correspondence: Munther A Khamashta, Lupus Research Unit, The Rayne

Institute, St Thomas Hospital, London SE1 7EH, UK. E-mail:
munther.khamashta@kcl.ac.uk
# Arnold 2004

Lupus activity during pregnancy: an

unresolved issue
From the immunological point of view, pregnancy
represents a vulnerable period for increased lupus
activity.1 Adaptation of maternal tolerance in order to
prevent rejection of fetal tissues derive to a Th2 profile,2
with increased expression of cytokines such as
interleukins 10 and 4 which have been involved in
SLE pathophysiology.3 Thus, it would not be surprising
that, as opposed to rheumatoid arthritis, SLE worsens
during pregnancy.
It is well known that the studies focusing on lupus
activity during pregnancy have failed to obtain
consensus.4 18 These studies were heterogeneous in
many aspects and also subject to a number of potential
biases such as the following:
. The high number of miscarriages in some series
made a lupus flare less likely due to the substantial
reduction in the period at risk. The exclusion of the
puerperium had a similar effect.
. Routine prophylactic treatment with prednisone
during pregnancy may not prevent all flares and
10.1191/0961203304lu1099oa

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680

.
.
.

.
.

add substantial toxicity, but could undoubtedly have

influenced flare rates in some series.
The practise of withdrawing hydroxychloroquine
during pregnancy was common in some clinics and
could have led to reactivations of SLE in pregnant
women.
Studies focused on obstetric aspects may have
underestimated mild flares.
A closer monitoring of pregnant lupus women
compared with controls may have increased the
detection of flares in the former group.
If patients diagnosed with SLE during the index
pregnancy or starting pregnancy during SLE flare
were not excluded, flare rates would increase in the
pregnancy group.
Historical control populations have been frequently
used, usually with limited information regarding
follow-up and lupus activity definitions.
Features of the antiphospholipid syndrome (APS)
can mimic some manifestations of inflammatory
lupus activity (i.e., thrombocytopenia, cerebral
vasculitis, cutaneous vasculitis). The attribution of
such clinical manifestations to one or another (APS
or SLE) can modify the figures substantially.

The above limitations have certainly contributed to the

heterogeneity shown by the studies. However, the major
reason for discrepancy has been the lack of a common
tool for assessing SLE activity in pregnant women. While
most clinical decisions can be successfully taken based
on the expert judgement of the physician looking after
lupus patients, consensus is required in order to compare
research results from different groups and countries.
Quantification of SLE activity using some of the
available scales [e.g., Systemic Lupus Erythematosus
Disease Activity Index (SLEDAI), Systemic Lupus
Activity Measure (SLAM), British Isles Lupus
Assessment Group (BILAG), European Community
Lupus Activity Measure (ECLAM).] is now standard
practice in lupus studies. However, all such scales have
been validated in nonpregnant populations.19 In
pregnant women, physiologic changes, such as low
grade proteinuria, joint pains, bland effusions,
chloasma, fatigue or thrombocytopenia, can also be
SLE-related. On the contrary, complement levels and
erythrocyte sedimentation rate rise during pregnancy,
limiting the usefulness of normal cut-off values during
this period. Modification of activity scales specific for
pregnant patients is, therefore, necessary.

Proposals for activity scales for

lupus in pregnancy
Important attention was paid to the issue of SLE
activity in pregnancy during the Second International
Lupus

Conference on Sex Hormones, Pregnancy and the

Rheumatic Diseases, held in Trondheim, Norway, in
1998. Then, several groups decided to start working on
modifications of lupus activity scales in use, aiming to
adapt them to pregnancy.
Proposals for modified scales were published in the
Lupus journal in 1999.20 The group of RamseyGoldman from Chicago modified the SLAM (mSLAM); Buyon et al. from New York, modified the
version of SLEDAI developed for the SELENA study,
focused on the effects of hormonal therapy on women
with SLE (SELENA SLEDAI) and named SLEPDAI
(SLE-Pregnancy Disease Activity Index). Finally,
Khamashta and Ruiz-Irastorza from London produced
the Lupus Activity Index in Pregnancy (LAI-P),
modified from the original LAI, created by Petri et al.21
and previously used in our study focused on lupus
flares during pregnancy.7
m-SLAM removed items contained in the original
SLAM to avoid confusion with physiologic changes
during pregnancy, such as weight loss and erythrocyte
sedimentation rate.20
SLEPDAI took into account physiologic changes of
pregnancy that could affect several descriptors:
seizures, cranial nerve disorder, headache, stroke,
cutaneous vasculitis, arthritis, hematuria, proteinuria,
pyuria, rash, alopecia, pleurisy, serum complement
levels, thrombocytopenia and leukopenia.20
In order to increment homogeneity with SLEPDAI,
LAI-P descriptors assumed SLEPDAI definitions for
common items: fever, rash, arthritis, serositis, neurologic disease (including psychosis, organic brain
syndrome, seizure, stroke and retinal and eye changes),
myositis, cutaneous vasculitis, proteinuria and complement levels. However, a major difference between
both scales was the specific exclusion of patients with
antiphospholipid antibodies from scoring clinical
manifestations such as seizures, stroke, optic neuritis
and thrombocytopenia unless features of lupus activity
were measured in other organ systems.20 This change
represented an effort to decrease false positives due to
thrombosis rather than to inflammation. LAI-P and its
complete definitions are available at the Arthritis and
Rheumatism Arthritis Care & Research web site at
(http://www.interscience.wiley.com/jpages/00043591:1/suppmat/index.html).

Validation of activity scales for

lupus in pregnancy
Validation of activity scales in a representative
population of patients with SLE is mandatory before
they can be considered helpful for clinical practice and
research. To be considered valid, an index must

SLE during pregnancy

G Ruiz-Irastorza and MA Khamashta

681

demonstrate to be sensitive to changes in disease

activity,22 and also show good sensitivity, specificity,
predictive values and likelihood ratios in detecting a
disease flare.23 However, any study of this type deals
with the major limitation of the lack of a gold standard
for a lupus flare. Previous validation studies in
nonpregnant patients have used visual analog scales
(VAS) generically named physician global assessment
(PGA) after Petri et al.s first definition in 1991.21
Thus, measures of activity using the scale in evaluation
must be compared with rather a subjective appreciation of disease status by the clinician looking after
SLE patients.
Bearing in mind this intrinsic limitation, a validation
study of LAI-P has been recently completed.24 A group
of 38 pregnant women with SLE was enrolled at three
lupus pregnancy clinics in London, Birmingham and
New York. A modified version of PGA, consisting in a
VAS with three levels (0 no activity, 1 mildmoderate activity, 2 severe activity), was used as
gold standard. The utility of LAI-P was assessed during
pregnancy and the puerperium at three levels:
1) Measuring the sensitivity to changes in lupus
activity using the standardized response mean
(SRM), as defined by Corzillius et al.22
2) Establishing the association between PGA and LAIP by logistic regression models.
3) Calculating the sensitivity, specificity, predictive
values and likelihood ratios for diagnosing a lupus
flare.
Results of the study showed LAI-P to have a high
sensitivity to changes in SLE activity (SRM 1.6), a
strong and significant association with PGA values (R 2
ranging from 0.40 to 0.76) and good diagnostic indices
(sensitivity 0.93, specificity 0.98, positive predictive
value 0.88, negative predictive value 0.99, positive
likelihood ratio 49 and negative likelihood ratio 0.07).
Accordingly, LAI-P can be considered a helpful tool to
measure SLE activity during pregnancy and the
puerperium, which can be readily used in research
studies focused on lupus flares in pregnant women,
allowing homogeneous definitions that may ease
comparisons among different studies.24

Assessment of SLE activity during

pregnancy in clinical practice
Despite availability of ad hoc activity indices,
management of pregnant women with SLE still relies
on the clinical skills of caring doctors. As already
commented, laboratory markers are less useful during
pregnancy. Thus correct diagnosis relies mainly on

clinical grounds. Nevertheless, most flares of lupus

activity can be recognized by experienced physicians.
The most stressing situation is differentiating a
renal flare during the second half of pregnancy from
pre-eclampsia.25 In this setting, finding an active
urinary sediment, especially with blood casts, is
most discriminative.1,25 On the other hand, rising uric
acid levels points to pre-eclampsia.25 The finding of
increased anti-DNA antibody titres and/or decreased
complement levels may be useful. However, both have
been recently shown to have low predictive power as
diagnostic tools for flares in the general SLE
population.26,27 Although complement kept some
utility in renal and hematological flares, the normal
increase of C3 and C4 levels as pregnancy advances
makes its role less certain. Thus, it is not always
possible to differentiate pre-eclampsia from a renal
lupus flare on clinical grounds.

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