Saturday 20 September 2003
BMJ
Treating acute rheumatic fever
So many years, and yet we do not know if steroids should be used
R
heumatic fever is a delayed complication of
pharyngeal infection with group
haemolytic
streptococci. Susceptible individuals develop a
diffuse inflammatory disease of the heart, joints, brain,
blood vessels, and subcutaneous tissue. Carditis is the
most serious manifestation of the disease. It may culmi-
nate in chronic valvular disease and can lead to heart
failure and ultimately death. The incidence of acute
rheumatic fever has declined in industrialised countries
since the 1950s. However, a resurgence of the disease
has been noted, and new epidemics have been reported
in the United States.1 Acute rheumatic fever continues to
be an important cause of acquired heart disease in
developing countries where it is an endemic disease.2
Open heart surgery may be needed to repair or replace
heart valves in patients with severely damaged valves, the
cost of which is exorbitant and a drain on the meagre
health resources of poor countries.
Because of substantial evidence pointing to the
inflammatory nature of the disease anti-inflammatory
agents such as corticosteroids and aspirin are used for
its treatment. The treatment is, however, controversial.
Several current textbooks recommend the use of
corticosteroids in patients with acute rheumatic fever
and heart failure.3–5 In contrast other authors say that
heart failure in patients with active rheumatic carditis
occurs as a result of a haemodynamically severe valvu-
lar lesion that can be corrected only surgically and not
by giving steroids.6
Substantial contrary evidence points, however,
against treating patients who have acute rheumatic
fever with corticosteroid agents to prevent the compli-
cations of carditis. This evidence against cortico-
steroids is based largely on randomised controlled
studies performed 40-50 years ago and analysed in a
recent Cochrane review.7 Eight randomised controlled
trials describing outcomes in patients given anti-
inflammatory agents were identified in this meta-
analysis. All studies assessed cardiac outcomes in the
form of clinically significant heart murmurs diagnosed
on auscultation or the presence of incompetence of the
aortic or mitral valve diagnosed by using echocardio-
graphy at least one year after treatment with
anti-inflammatory agents. Several corticosteroid
agents—namely adrenocorticotrophic hormone,
cortisone, hydrocortisone, dexamethasone and
prednisone—and intravenous immunoglobulin were
compared with aspirin, placebo, or no treatment in the
various studies. Three of the studies showed a higher
BMJ 2003;327:631–2 risk of cardiac disease at one year after treatment with
BMJ VOLUME 327 20 SEPTEMBER 2003 bmj.com
corticosteroids compared with aspirin. Only one study
showed some advantage for aspirin, although statisti-
cally insignificant, in reducing the risk of cardiac
disease compared with prednisone (relative risk 1.71,
95% confidence interval 0.92 to 3.19).
Overall no significant difference was seen in the
risk of cardiac disease at one year between the groups
treated with corticosteroids or with aspirin (0.87, 0.66
to 1.15). Similarly, use of prednisone (1.78, 0.98 to 3.34)
or intravenous immunoglobulin (0.87, 0.55 to 1.39)
compared with placebo did not reduce the risk of
developing lesions to the heart valve at one year. No
trials compared aspirin with placebo in patients with
carditis in the presence of acute rheumatic fever; the
efficacy of aspirin has therefore not been established.
The reporting of secondary outcomes such as a reduc-
tion in the erythrocyte sedimentation rate and
C reactive protein was too varied and inconsistent to
analyse adequately. Corticosteroids seem superior to
aspirin in the rate at which the erythrocyte sedimenta-
tion rate drops, but this is not a compelling reason to
choose one drug over the other.
Although newer non-steroidal anti-inflammatory
agents such as naproxen8 and high dose methylpred-
nisone9 have been used to treat patients with acute rheu-
matic fever in more recent studies, the outcomes have
not been tested in a randomised and controlled manner.
Ultimately there is no conclusive evidence to
indicate that the use of corticosteroids in patients with
acute rheumatic fever will prevent heart disease in the
long term. It is sad that in this modern day era we have
not found an effective treatment for a disease with an
infectious origin that has such devastating conse-
quences, particularly for patients who live in poor
developing countries. Further randomised controlled
studies examining corticosteroids with less outdated
formulations—for example, prednisone and intra-
venous methylprednisone—are warranted. The avail-
ability and use of echocardiography and other newer
technologies will help greatly in providing more
precise, valid, and objective assessment of changes in
cardiac lesions in future randomised controlled trials.
Antoinette Cilliers paediatric cardiologist
CH Baragwanath Hospital, PO Box 2588, Northcliff, 2115,
Johannesburg, South Africa (amcilliers@icon.co.za)
Competing interests: None declared.
1 Veasy LG, Wiedmeier SE, Orsmond GS, Ruttenberg HD, Boucek MM,
Roth SJ, et al. Resurgence of acute rheumatic fever in the intermountain
area of the United States. N Engl J Med 1987;316:421-7.
631
Editorials
2 Olivier C. Rheumatic fever—is it still a problem? J Antimicrob Chemother
2000;45(suppl 13):s13-21.
3 Abraham MT, Cherian G. In: Chatterjee K, Cheitlin MD, Karliner J, Parm-
ley WM, Rapaport E, Scheinman M, eds. Cardiology: an illustrated
text/reference. New York: Gower Medical Publishing, 1991:10.98-10.116.
4 Ayoub EM. In: Emmanouilides GC, Riemenschneider TA, Allen HD, Gut-
gesell HP, eds. Moss and Adams’ heart disease in infants, children, and adoles-
cents: including the fetus and the young adult. 5th ed. Baltimore: Williams and
Wilkins, 1995:1400-16.
5 El-Said GM, El-Rafaee MM, Sorour KA, El-Said HG. In: Garson A,
Bricker JT, Fischer DJ, Neish SR, eds. The science and practice of pediatric
cardiology. 2nd ed. Baltimore: Williams and Wilkins, 1998:1691-724.
Elucidating the pathogenesis of schizophrenia
DISC-1 gene may predispose to neurodevelopmental changes underlying schizophrenia
G
enetic predisposition to schizophrenia is
evident from family, twin, and adoption
studies.1–3 But whereas genetic factors contrib-
ute to the fundamental mechanisms or vulnerability to
schizophrenia, additional influences including environ-
mental factors are clearly involved in the full manifesta-
tion of symptoms of schizophrenia.4 Thus currently
schizophrenia is best conceptualised as a “multiple hit”
illness similar to cancer. This editorial looks at the
fundamental mechanisms underlying the disease.
The following evidence implies that neurodevelop-
mental abnormalities contribute to susceptibility to
schizophrenia.1 5 6 7 Firstly, clinical studies show that
patients with schizophrenia manifest minor behav-
ioural abnormalities in childhood even before the
onset of schizophrenia.
Secondly, recent advanced imaging techniques such
as magnetic resonance imaging provide reliable
evidence of abnormalities during development of the
central nervous system. Such abnormalities include con-
sistent increases in ventricular size at the onset of schizo-
phrenia, with notable alterations in some areas including
the prefrontal cerebral cortex and hippocampus.
Thirdly, neuropathological studies indicate no
overall loss in the number of neurones but reductions in
the size of neurones. Cytoarchitectonic abnormalities
include variability of cell orientation and decreased syn-
aptic structures. In contrast to neurodegenerative
diseases, in which proliferation of glial cells increases as
neurones degenerate, no glial proliferation occurs in
brains of patients with schizophrenia, implying that the
primary disorder in schizophrenia is neurodevelopmen-
tal rather than neurodegenerative. Abnormalities in
proteins that are key determinants of brain development
and structure are often observed in autopsied brains
from adult patients with schizophrenia. For example,
changes are reported in microtubule associated protein
2 (MAP2), growth associated protein-43 (GAP-43), post-
synaptic density protein 95 (PSD 95), and reelin. Reelin
is a large secreted matrix protein that is involved in neu-
ronal migration, facilitating normal brain architecture
during development, and brains of patients with schizo-
phrenia show a 30–50% reduction in reelin protein
especially in the prefrontal cerebral cortex and
hippocampus. Mutations in the reelin gene are also
associated with a type of lissencephaly with cerebellar
hypoplasia. Such a molecular association with cortical
development disorder implies neurodevelopmental
implications for schizophrenia.
632
6 Kingsley RH, Pocock WA. In: JB Barlow, ed. Prospectives on the mitral valve,
1987:227-45.
7 Cilliers AM, Manyemba J, Saloojee H. Anti-inflammatory treatment for
carditis in acute rheumatic fever. Cochrane Database Syst Rev
2003;(2):CD003176.
8 Uziel Y, Hashkes PJ, Kassem E, Padeh S, Goldman R, Vollach B. The use
of naproxen in the treatment of children with rheumatic fever. J Pediatr
2000;137:269-71.
9 Herdy GVH, Pinto CA, Olivaes MC, Carvalho EA, Tchou H, Cosendey R,
et al. Rheumatic carditis treated with high doses of pulse therapy methyl-
prednisolone. Arq Bras Cardiol 1999;72:604-6.
Altogether it seems that genetic factors that have
roles in cortical development are candidates for the
underlying pathogenesis of schizophrenia. In this
context, attention has recently been focused on a gene
named disrupted in schizophrenia-1 (DISC-1). In a
Scottish family, a chromosome (1;11)(q42.1; q14.3)
translocation with disruption of DISC1 gene inside its
open reading frame segregates with major psychiatric
illnesses with a LOD (logarithm of odds) score of 7.1.8
This translocation interrupts the coding sequence of
DISC-1, leading to loss of the C-terminal 257 amino
acids of the DISC-1 protein. Linkage and association
studies have also identified the DISC-1 locus as a
susceptibility factor for schizophrenia in Finnish families
and white people.9
Expression of DISC-1 displays pronounced devel-
opmental regulation, with concentrations highest in
late embryonic life when the cerebral cortex develops.
DISC-1 interacts with a variety of cytoskeletal proteins
that are important in neurodevelopment.10 A cytoskel-
etal protein, NUDEL (NudE-like), which is one of the
DISC-1 interactors, is associated with cortical develop-
ment and linked to LIS-1 (the disease gene for a form
of lissencephaly) as described above. The mutant form
of DISC-1 in the Scottish family fails to bind NUDEL.
Expression of mutant, but not wild type, DISC-1 in
neuronal PC12 cells reduces neurite outgrowth. As
schizophrenia is thought to reflect defects in cortical
development determined by cytoskeletal proteins, the
cellular disturbances with mutant DISC-1 may be
relevant to psychopathological mechanisms. DISC-1
may be one of several susceptible factors for the
pathogenesis of schizophrenia.
Nevertheless, there is precedence for focusing on
causative factors of rare familial forms of diseases.11
Studies on Alzheimer’s disease and Parkinson’s disease
in the past decade indicate how investigating the genes
involved in rare familial forms of diseases can provide
information on more general sporadic forms of
neuropsychiatric conditions. The biology on amyloid
precursor protein and presenilin has provided key
mechanisms for the more common form of Alzheimer’s
disease. By analogy with this successful approach, focus-
ing on rare forms of schizophrenia and the genes may
also prove successful for more common forms of
schizophrenia. Thus, DISC-1 is expected as a novel
window towards the pathogenesis of schizophrenia.
Classic linkage analysis combined with analysis of
schizophrenia associated single nucleotide poly-
morphisms within the linkage areas has clarified BMJ 2003;327:632–3
BMJ VOLUME 327 20 SEPTEMBER 2003 bmj.com