CORRESPONDENCE
of this antitumour necrosis factor drug
and the limits of many studies assessing
the usefulness of disease-modifying
antirheumatic drugs (DMARDs) in
this disease.
Mease and colleagues quote the
results of a 1-year prospective,
controlled, randomised trial comparing
ciclosporin and methotrexate,2 but the
reference cited is incorrect. The
reference they use3 corresponds to a
study showing that patients with
psoriatic arthritis taking ciclosporin are
less likely than those on methotrexate
to continue long-term treatment.
Patients who continued to take
methotrexate had a median survival
(23 months) longer than patients
taking other DMARDs. We believe
that these results, which show that
methotrexate has a more favourable
risk/benefit ratio than other DMARDs
currently used in the treatment of
psoriatic arthritis, support the choice of
Mease and colleagues to treat patients
who had psoriatic arthritis with
etanercept plus methotrexate. The
assessment of cumulative probability of
taking this combination of drugs
requires long-term studies because the
rate of withdrawal of DMARDs in this
group of patients is lower than 20%
after 12 weeks of treatment, but more
than 90%, except for methotrexate,
after 5 years.3
*Antonio Spadaro, Valeria Riccieri,
Egisto Taccari
Department of Medical Therapy, Rheumatology
Unit, University of Rome (La Sapienza), Viale
del Policlinico 155, 00161 Rome, Italy
1 Mease PJ, Goffe BS, Metz J,
VanderStoep A, Finck B, Burge DJ.
Etanercept in the treatment of psoriatic
arthritis and psoriasis: a randomised trial.
Lancet 2000; 356: 385–90.
2 Spadaro A, Riccieri V, Sili Scavalli A,
Sensi F, Taccari E, Zoppini A. Comparison
of cyclosporin A and methotrexate in the
treatment of psoriatic arthritis: a one-year
prospective study. Clin Exp Rheumatol 1995;
13: 589–93.
3 Spadaro A, Taccari E, Mohtadi B,
Roccieri V, Sensi F, Zoppini A. Life-table
analysis of cyclosporin treatment in psoriatic
arthritis: comparison with other disease-
modifying antirheumatic drugs. Clin Exp
Rheumatol 1997; 15: 609–14.
Author’s reply
Sir—The 60 patients in our study were
entered by seasoned rheumatologists who
were aware of the difficult issues involved
in case definition of psoriatic arthritis,
and used the previously described criteria
by J M H Moll and V Wright,1 and D
Gladman.2 They were specifically
charged not to enter patients who could
have simultaneous presence of psoriasis
and an arthritis other than psoriatic
2096
For personal use only. Not to be reproduced without permission of The Lancet.
arthritis, such as rheumatoid arthritis,
ankylosing spondylitis, or other form of
arthropathy.
Because of the long duration of
psoriatic arthritis in our study
population (average >10 years) and the
requirement that patients had
responded inadequately to previous
treatments, our patients generally had
more severe disease and polyarticular
involvement, a characteristic pattern
previously noted by D Gladman.3 The
issue is of relative severity, not of
accuracy in classification. Because
dactylitis was present in a few patients,
we could not offer statistically
meaningful information about change in
this clinical element during the 3
months of the study. Patients who
presented in an oligoarticular fashion
did not have significantly different
outcomes from those with a more
polyarticular presentation.
Heterogeneity in the presentation of
psoriatic arthritis, which represents a
challenge for correct identification of
study patients, was a challenge to which
we carefully attended. We applaud the
efforts of B Fournie and colleagues4 and
D McGonagle and colleagues,5 whose
papers were published after we had
designed and done our study, to bring
us better tools for case definition of
psoriatic arthritis to improve the
sensitivity and specificity of disease
classification.
We apologise to Antonio Spadaro
and colleagues for the incorrect
reference.
Philip J Mease
First Hill Medical Building, 515 Minor Avenue
#300, Seattle, Washington 98104, USA
1 Moll JMH, Wright V. Psoriatic arthritis.
Semin Arthritis Rheum 1973; 3: 55–78.
2 Gladman DD. Psoriatic arthritis. Bailliere’s
Clin Rheumatol 1995; 9: 319–29.
3 Gladman DD. Natural history of psoriatic
arthritis. Bailliere’s Clin Rheumatol 1994; 8:
379–94.
4 Fournie B, Crognier L, Arnaud C, et al.
Proposed classification criteria of psoriatic
arthritis: a preliminary study in 260 patients.
Rev Rhum Engl Ed 1999; 66: 446–56.
5 McGonagle D, Conaghan PG, Emery P.
Psoriatic arthritis: a unified concept twenty
years on. Arthritis Rheum 1999; 42:
1080–86.
Sleep deprivation and
growth-hormone secretion
Sir—Gabrielle Brandenberger and
colleagues (Oct 21, p 1408)1 report that
after sleep deprivation in young adults
(age 20–26 years), blunting of the
normal sleep-related growth-hormone
(GH) pulse is compensated during the
day. They conclude that this finding
argues against the belief that sleep
disorders in children can inhibit growth
through a daily GH deficit.
The experiments seem well
performed. In support of the data, we
have seen in young men that during the
recovery night after 36 h of total sleep
deprivation, the nocturnal GH pulse
was even increased 2·5-fold compared
with that at baseline before sleep
deprivation (unpublished data). The
effects of acute sleep-deprivation
experiments in young and healthy
people, however, might differ from the
effects that sleep disorders may have on
GH secretion.
We measured serum GH
concentrations every 30 min over 24 h
(2000–2000 h) in a patient with nearly
complete sleep loss due to cerebral
Whipple’s disease.2 In the absence
of any structural damage to the
hypothalamus or pituitary, GH
secretion was flattened with no major
pulses (peak GH concentraton
0–3·8 ng/mL). This finding is in
accordance with the observation of
flattening of GH secretion in patients
with fatal familial insomnia (FFI).3 In
contrast to a major GH pulse during the
night in age-matched controls, two
patients with FFI showed clear
flattening of GH secretion with
advanced disease in the absence of
any histopathological abnormalities of
the hypothalamus or pituitary after
death. These cases support the view
that insomnia can lower GH secretion.
Although these examples are of
extreme sleep disturbance, there are
also hints that chronic insomnia of a
lower degree can disturb GH secretion.
Vgontzas and colleagues4 measured
urinary GH in 15 young adults (age
<40 years) who had chronic insomnia.
Urinary GH was undetectable in
12 people and detectable in only three
who showed a relatively low degree
of sleep disturbance. Normal values
of 24 h urine GH secretion (at age
19–43 years) range from 0·2 ng/g to
14·8 ng/g creatinine.
A major concern for all studies,
including that of Brandenberger and
colleagues,1 is that GH secretion is
dependent on age and decreases greatly
in older people.5 Extrapolation of
findings to children is, therefore,
difficult. We conclude that studies of
GH secretion (eg, by urine sampling) in
children with sleep disorders must be
done before a sleep-disorder-related
GH deficit can be definitively excluded.
*Klaus Lieb, Martin Reincke,
Dieter Riemann, Ulrich Voderholzer
Departments of *Psychiatry and
Psychotherapy, Internal Medicine, University of
Freiburg Medical School, D-79104 Freiburg,
Germany
(e-mail: klaus_lieb@psyallg.ukl.uni-freiburg.de)
THE LANCET • Vol 356 • December 16, 2000

1 Brandenberger G, Gronfier C, Chapotot F,
Simon C, Piquard F. Effect of sleep
deprivation on overall 24 h growth-
hormone secretion. Lancet 2000; 356: 1408.
2 Lieb K, Maiwald M, Berger M,
Voderholzer U. Insomnia for 5 years. Lancet
1999; 354: 1966.
3 Portaluppi F, Cortelli P, Avoni P, et al.
Dissociated 24-hour pattern of
somatotropin and prolactin in fatal familial
insomnia. Neuroendocrinology 1995; 61:
731–37.
4 Vgontzas AN, Tsigos C, Bixler EO, et al.
Chronic insomnia and activity of the stress
system: a preliminary study. J Psychosom
Res 1998; 45: 21–31.
5 Voderholzer U, Laakmann G, Hinz A, et al.
Dependency of growth hormone (GH)
stimulation following releasing hormones
on the spontaneous 24-hour GH secretion
in healthy male and female subjects.
Psychoneuroendocrinology 1993; 18: 365–81.
Endotoxin-lipoprotein
hypothesis
Sir—Matthias Rauchhaus and
colleagues (Sept 9, p 930)1 test the
so-called endotoxin-lipoprotein hypo-
thesis, in which they postulate that high
concentrations of cholesterol are
beneficial in patients with chronic heart
failure. They report that high
concentrations of serum lipoproteins
can bind and detoxify bacterial lipo-
polysaccharide (endotoxin), although
this effect is not unequivocally
evident.2,3 They suggest that in this way
high concentrations of lipoproteins can
lead to lower proinflammatory cytokine
production. On the basis of these
findings, Rauchhaus and colleagues
propose that non-lipid-lowering statins
could be developed for patients with
chronic heart failure. We present some
of our experimental data.
We studied the effects of statin
therapy and hyperlipoproteinaemia on
cytokine production in whole-blood
samples and showed no association
between high concentrations of LDL
cholesterol and pro-inflammatory
cytokine production on stimulation
with endotoxin.4 Patients with familial
hypercholesterolaemia and high levels
of LDL cholesterol exhibited low
in-vitro production of the
proinflammatory cytokine tumour
necrosis factor ␣ (TNF␣) compared
with normolipidaemic controls.
After 6 weeks of statin therapy
(20 mg atorvastatin daily), LDL
cholesterol concentrations decreased
43% in the patients with familial
hypercholesterolaemia (figure). Despite
the strong decrease in LDL cholesterol,
no significant changes in TNF␣
production were noted. To further
assess the influence of the LDL
cholesterol on the production of
TNF␣, we incubated an extra blood
THE LANCET • Vol 356 • December 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
30 000
Cytokines (pg/mL)
20 000
10 000
10·0
LDL cholestrol (mmol/L)
7·5
5·0
2·5
0 465–73.
e s’
lin
se
Ba
s er c
Changes in endotoxin-stimulated
production of TNF␣, interleukin 10, and
LDL cholesterol in whole blood after
6 weeks of statin treatment
sample of the patients with familial
hypercholesterolaemia, obtained after
statin therapy, with the patient’s own
LDL that was harvested before medical
treatment by ultracentrifugation. This
method mimicked the effect of the new
type (non-lipid-lowering) statin that
Rauchhaus and colleagues propose.
Addition of the patient’s own LDL did
not affect cytokine production in whole-
blood samples (figure). We found,
therefore, no straightforward effect of
LDL cholesterol concentrations on
cytokine production.
We also thought that increased LDL
cholesterol concentrations might have a
positive effect on the anti-inflammatory
cytokine interleukin 10, a direct
inhibitor of TNF␣. High LDL
cholesterol concentrations would have a
beneficial effect on the survival of
patients with chronic heart failure.
Interleukin 10 production did not,
however, vary with the changes in LDL
cholesterol concentrations (figure), and
this mechanism does not explain the
positive correlation between high lipid
concentrations and prolonged survival.
Use of LDL apheresis rather than
statins to lower lipids also shows that
lowering of LDL cholesterol does not
affect the production of cytokines.
Circulating concentrations of TNF␣ do
not differ significantly before and after
LDL apheresis in patients with
nephrotic syndrome.5 Moreover, TNF␣
CORRESPONDENCE
TNF␣ production in endotoxin-stimulated
Interleukin 10 mononuclear cells isolated from these
LDL cholesterol patients does not change significantly.
The available data suggest that
variation of LDL probably does not
directly affect production of pro-
inflammatory cytokines in human
beings.
*M F Mohrschladt, A H M Smelt,
R G J Westendorp
Department of General Internal Medicine, Leiden
University Medical Centre, PO Box 9600, 2300
RC Leiden, Netherlands
(e-mail: m.f.mohrschladt@lumc.nl)
1 Rauchhaus M, Coats AJS, Anker SD. The
endotoxin-lipoprotein hypothesis. Lancet
2000; 356: 930–33.
2 Schlichting E, Hendriksen T, Lyberg T.
Lipoproteins do not modulate the tissue
factor activity, plasminogen activator or
tumour necrosis factor production induced
by lipopolysaccharide stimulation of human
monocytes. Scand J Clin Lab Invest 1994; 54:
in
ek py at L 3 Brito BE, Romano EL, Grunfeld C.
st LD ol
we era ’
s s r Increased lipopolysaccharide-induced
6 th ek plu ste tumour necrosis factor levels and death in
at
in we py ole hypercholesterolemic rabbits. Clin Exp
t 6 a h
th Immunol 1995; 101: 357–61.
4 Mohrschladt MF,
Weverling-Rijnsburger AWE,
de Man FHAF, Stoeken D-J, Smelt AHM,
Westendorp RGJ. Hyperlipoproteinemia
affects cytokine production in whole blood
samples ex-vivo: the influence of lipid-
lowering therapy. Atherosclerosis 2000; 148:
413–19.
5 Sakurai M, Muso E, Matsuchima H,
Ono T, Sasayama S. Rapid normalization of
interleukin-8 production after low-density
lipoprotein apheresis in steroid resistant
nephrotic syndrome. Kidney Int Suppl 1999;
56 (suppl 71): 210–12.
Sir—Rauchhaus and colleagues1
contend that in patients with chronic
heart failure reduction of LDL
concentration could be harmful
because this substance binds to and
inactivates cytokine-releasing lipopoly-
saccharide complexes. Central to their
argument is the role of the cholesterol-
lowering statin drugs, which also
exhibit independent anti-inflammatory
and anti-proliferative properties.
Rauchhaus and colleagues propose
that statin-like molecules that did not
lower cholesterol but that retained
these other beneficial properties would
constitute good candidates to test the
hypothesis. We suggest, however, that
such non-cholesterol-lowering statins
would not display the necessary
ancillary properties.
The primary action of statins at the
molecular level is competitive
inhibition of the enzyme 3-hydroxy-3-
methyl-glutaryl coenzyme A (HMG
CoA) reductase, which catalyses the
conversion of HMG CoA to
mevalonate, the rate-limiting step in
the pathway leading to cholesterol
biosynthesis (the mevalonate pathway).
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