Immunosuppression as therapy for congestive heart failure

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184 www.thelancet.com Vol 371 January 19, 2008
of other formulations? And what are the long-term 
adverse events? Additional and more long-term data on 
the modifi ed-release formulation are therefore needed, 
although Buttgereit’s study provides proof-of-principle 
for this chronotherapy.
Glucocorticoids are the most eff ective and widely 
used immunosuppressive drugs worldwide in many 
immune-mediated diseases and vasculitides. Might this 
new formulation also have benefi ts in those diseases? 
An interesting second step could be the use of this 
formulation in polymyalgia rheumatica, which is also 
characterised by severe early morning symptoms. 
Ultimately, the relevance of Buttgereit and colleagues’ 
study could go far beyond rheumatic diseases.
*Johannes W J Bijlsma, Johannes W G Jacobs
Department of Rheumatology & Clinical Immunology, 
UniversityMedical Centre Utrecht, 3508 GA Utrecht, Netherlands
j.w.j.bijlsma@umcutrecht.nl
JWJB has received consultancy fees from Nitec. JWGJ declares that he has no 
confl ict of interest.
1 Buttgereit F, Doering G, Schaeffl er A, et al. Effi cacy of modifi ed-release 
versus standard prednisone to reduce duration of morning stiff ness of the 
joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised 
controlled trial. Lancet 2008; 371: 205–14
2 Croff ord LJ, Kalogeras KT, Mastorakos G, et al. Circadian relationships 
between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis 
hormones: failure of IL-6 to cause sustained hypercortisolism in patients 
with early untreated rheumatoid arthritis. J Clin Endocrinol Metab 1997; 
82: 1279–83.
3 Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: implications 
for pathophysiology and therapeutic management. Arthritis Rheum 2007; 
56: 399–408.
4 Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized 
controlled clinical trial of the interleukin-6 receptor antagonist, 
tocilizumab, in European patients with rheumatoid arthritis who had 
an incomplete response to methotrexate. Arthritis Rheum 2006; 
54: 2817–29.
5 Arvidson NG, Gudbjornsson B, Larsson A, Hallgren R. The timing of 
glucocorticoid administration in rheumatoid arthritis. Ann Rheum Dis 
1997; 56: 27–31.
6 Kirwan JR, Bijlsma JW, Boers M, Shea BJ. Eff ects of glucocorticoids on 
radiological progression in rheumatoid arthritis. 
Cochrane Database Syst Rev 2007; 1: CD006356.
7 Van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW. 
Low-dose prednisone therapy for patients with early active rheumatoid 
arthritis: clinical effi cacy, disease-modifying properties, and side eff ects: 
a randomized, double-blind, placebo-controlled clinical trial. 
Ann Intern Med 2002; 136: 1–12.
8 Jacobs JW, Van Everdingen AA, Verstappen SM, Bijlsma JW. Followup 
radiographic data on patients with rheumatoid arthritis who 
participated in a two-year trial of prednisone therapy or placebo. 
Arthritis Rheum 2006; 54: 1422–28.
9 da Silva JAP, Jacobs JWG, Kirwan JR, et al. Safety of low dose 
glucocorticoid treatment in rheumatoid arthritis: published evidence 
and prospective trial data. Ann Rheum Dis 2006; 65: 285–93.
10 Hoes JN, Jacobs JW, Boers M, et al. EULAR evidence-based 
recommendations on the management of systemic glucocorticoid 
therapy in rheumatic diseases. Ann Rheum Dis 2007; 66: 1560–67.
11 Combe B, Landewe R, Lukas C, et al. EULAR recommendations for the 
management of early arthritis: report of a task force of the European 
Standing Committee for International Clinical Studies Including 
Therapeutics (ESCISIT). Ann Rheum Dis 2007; 66: 34–45.
12 Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies 
for treatment of rheumatoid arthritis. Lancet 2007; 370: 1861–74.
13 Verstappen SM, Jacobs JW, van der Veen MJ, et al. Intensive treatment 
with methotrexate in early rheumatoid arthritis: aiming for remission: 
computer assisted management in early rheumatoid arthritis (CAMERA, 
an open-label strategy trial). Ann Rheum Dis 2007; 66: 1443–49.
14 Bakker MF, Jacobs JW, Verstappen SM, Bijlsma JW. Tight control in the 
treatment of rheumatoid arthritis: effi cacy and feasibility. Ann Rheum Dis 
2007; 66 (suppl 3): iii56–60.
15 Bijlsma JW, Weinblatt ME. Optimal use of methotrexate: the advantages 
of tight control. Ann Rheum Dis 2007; 66: 1409–10.
Targeted anti-infl ammatory therapy of congestive 
car diac failure with monoclonal antibodies directed 
against single cytokines, such as tumour necrosis 
factor α, had an inauspicious beginning.1,2 In today’s 
Lancet, Guillermo Torre-Amione and colleagues report 
the results of their multicentre ACCLAIM trial of a 
strat egy to down regulate an entire range of proinfl am-
matory cytokines in patients with chronic heart failure.3 
ACCLAIM recruited more than 2400 patients with 
moderate to severe heart failure. In view of the method-
ology, such a task was not trivial.
Torre-Amione and co-workers took anticoagulated 
blood from patients with congestive heart failure, 
exposed the blood to ozone and ultraviolet light at 
42°C for 20 min, and then injected the blood back into 
the donor intramuscularly on days 1, 2, and 14 and 
then every 28 days for at least 22 weeks. The composite 
primary endpoint was time to hospitalisation for a 
cardiovascular event or death from any cause. This 
composite was not modifi ed by the intervention 
(hazard ratio 0·92, 95% CI 0·80–1·05). However, results 
were more promising in two prespecifi ed subgroups of 
patients with less functionally limiting disease.
The rationale behind ACCLAIM is that the ex-vivo 
treatment promotes apoptosis in leucocytes, which 
leads to generalised immunosuppression on reinjection 
of the apoptotic cells. Generalised immunosuppression, 
in which multiple pathways are activated, should 
decrease the synthesis of proinfl ammatory cytokines 
associated with congestive heart failure, such as tumour 
Immunosuppression as therapy for congestive heart failure
See Articles page 228
Comment
www.thelancet.com Vol 371 January 19, 2008 185
necrosis factor α and C-reactive protein, with associated 
clinical benefi t.
Apoptosis is a normal process in which phagocytes 
recognise apoptotic cells without inducing infl am-
mation. The process is associated with the synthesis 
of anti-infl ammatory cytokines, such as transforming 
growth factor β and interleukin 10, and the absence of 
induction of co-stimulatory molecules. These events 
together are thought to contribute to the maintenance 
of self-tolerance.4 Interactions between cell-surface 
molecules on phagocytes and apoptotic cells bridge this 
interaction, assisted by plasma constituents (fi gure).5 
Mice with impaired phagocytosis develop autoimmune 
diseases,4,6,7 which suggests that phagocytosis of 
apop totic cells is needed to maintain self-tolerance. 
The immunosuppressive cytokines interleukin 10 
and transforming growth factor β in turn facilitate 
the development of regulatory T cells.8 Apoptotic 
cells have thus been used to induce immunological 
tolerance against allogeneic antigens9 and exogenous 
antigens.10
The strengths of Torre-Amione and colleagues’ study 
are the large size and multicentre double-blind design, 
which lend credibility to their fi ndings. Other strategies 
that use small molecules with anti-infl ammatory prop-
erties have not been tested in large studies.11,12 However, 
there are several potential problems with this new 
approach. The method depends on the view that heart 
failure is triggered or maintained by an infl ammatory 
process which is detrimental to the patient. Cytokines 
have multiple eff ects and are synthesised by various 
cell lineages other than immune cells. Thus induction 
of immune tolerance might not aff ect pathways that 
are not mediated by immune activation. Also, the 
chronic infl ammatory process could be benefi cialin 
removing myocytes that are dying or dead for reasons 
other than the immune response. Inhibition of the 
infl ammatory response might also have serious clinical 
consequences, such as susceptibility to opportunistic 
infections and failure to respond to antigenic stimuli 
or to eliminate potentially malignant cells. Although 
no statistical diff erences in these variables were noted 
by the authors during the study period, some of these 
eff ects may be slow to emerge.
The other major issue is that intramuscular delivery 
of dead or dying apoptotic cells or altered cells in 
10 mL of blood, even though autologous, could 
generate autoimmune reactions against altered cells, 
dying red cells, and leucocytes. Autoimmune diseases 
might thus be precipitated, particularly in genetically 
predisposed patients. Thus, while apoptosis may 
favour the induction of tolerance, there is a sinister side 
to apoptosis, such as its role in patients with systemic 
lupus erythematosus and patients with phagocytosis 
defects.
Torre-Amione and co-workers did not study bio-
markers of immunity (humoral or cellular) or infl am-
mation (eg, cytokines), although they do provide a 
rationale for that decision in their discussion. C-reactive 
protein, which refl ects infl ammatory cytokine release, 
was lower in the intervention group than in the 
controls, at least up to week 26, but the diff erence 
between the groups was not statistically signifi cant.
ACCLAIM was not powered to detect diff erences in 
mortality, and the study duration was too short to 
detect new onset of autoimmune diseases. Long-term 
follow-up of patients receiving this type of therapy 
should be mandatory.
Figure: Model for induction of self-tolerance by apoptotic cells
Blood cells that are exposed ex vivo to agents that promote apoptosis, such as ozone and ultraviolet light, 
recruit phagocytic cells when reinjected. Molecules such as the Mer/Gas6 complex bridges interaction with 
phagocytes. Peptides from apoptotic cells that have undergone phagocytosis are then presented by MHC to 
their cognate clone of T cells. Without co-stimulatory signals, anergy and self-tolerance to such self-peptides 
ensue. Phagocytic cells also release transforming growth factor β (TGF β) and interleukin 10 to create 
immunosuppressive milieu. TCR=T-cell receptor.
Phagocytic cell
Mer
Platelets
TGF β
Interleukin 10
Phagocytosed apoptic cells
digested into peptides
Immunosuppressive
milieu
Self peptides
from digested cell
Phosphatidylserine
Primary
T cell
Gas6
Anergy and
tolerance to self
TCR
MHC
No co-stimulationNo co-stimulation
Comment
186 www.thelancet.com Vol 371 January 19, 2008
*Karen Sliwa, Aftab A Ansari
Soweto Cardiovascular Research Unit, CH Baragwanath Hospital, 
University of the Witwatersrand, Johannesburg 2013, South Africa 
(KS); and Department of Pathology and Laboratory Medicine, 
Emory University School of Medicine, Atlanta, GA, USA (AAA)
Sliwa-hahnlek@mdh-africa.org
We declare that we have no confl ict of interest.
1 Mousa SA, Goncharuk O, Miller D. Recent advances of TNF-α antagonists in 
rheumatoid arthritis and chronic heart failure. Expert Opin Biol Ther 2007; 
5: 617–25.
2 Mann DL. Infl ammatory mediators and the failing heart: past, present and 
the foreseeable future. Circ Res 2002; 91: 988–89.
3 Torre-Amione G, Anker S, Bourge RC, for the Advanced Chronic Heart Failure 
CLinical Assessment of Immune Modulation Therapy Investigators. Results of 
a non-specifi c immunomodulation therapy in chronic heart failure (ACCLAIM 
trial): a placebo-controlled randomised trial. Lancet 2008; 371: 228–36.
4 Albert ML. Death-defying immunity: do apoptotic cells infl uence antigen 
processing and presentation. Nat Rev Immunol 2004; 4: 223–31.
5 Lauber K, Blumenthal SG, Waibel M, Wesselborg S. Clearance of apoptotic 
cells: getting rid of the corpses. Mol Cell 2004; 14: 277–87.
In today’s Lancet, the Supplementation with Multiple 
Micronutrients Intervention Trial (SUMMIT) Study 
Group present important fi ndings from their large 
trial of maternal multiple micronutrients administered 
through routine health services in Lombok, Indonesia.1 
Although the reported outcomes do not include mater-
nal or newborn morbidity or biochemistry, the trial 
provides evidence of a reduction in mortality in young 
infants born to mothers who received the supplements. 
Whilst the rigorous promotional and support strategy 
limits the generalisability of this trial, SUMMIT does 
provide important data on the feasibility of delivering 
such an intervention through a routine health system.
Previous studies of multiple micronutrients in preg-
nancy do not show a consistent eff ect on birth out comes 
or infant mortality.2 By contrast, a pooled anal ysis of 
two trials from Nepal3 revealed a statistically signifi cant 
increase in newborn mortality after the use of maternal 
multiple micronutrients, purportedly due to a shift in the 
birthweight distribution4 and potentially higher rates of 
birth asphyxia. The fi nding of increased neonatal mor-
tality is unsupported by a systematic review, including 
data from other studies in diff erent populations.2 Sev eral 
important diff erences merit consideration when com-
paring this disparate evidence. The studies from Nepal 
were not done against a backdrop that included skilled 
atten dance at birth, whereas SUMMIT was specifi cally 
layered on a platform of preventive maternal health 
services and skilled midwives. The SUMMIT population, 
with lower rates of low birthweight, was also not as 
malnourished as those in Nepal. These factors might 
have contributed to the observed eff ects in SUMMIT.
The repertoire of nutritional interventions in preg-
nancy is limited and mainly consists of balanced-energy 
See Articles page 215
Maternal micronutrient defi ciencies in developing countries
WHO region Maternal mortality ratio 
(per 100 000 livebirths)*8
Infant mortality rate 
(per 1000 livebirths)*8
Total fertility rate 
(per woman)*8
Maternal body-mass 
index <18·5 (%)*9,10
Low birthweight 
(%)8,11
Total goitre 
rate (%)10
Iron-defi ciency 
anaemia (%)10
Best estimates of 
vitamin A defi ciency (%)11
Africa 780 (24–2000) 86·5 (11–165) 5·1 (2–7·7) 10·9 (4·5–38·1) 14 (7–25) 18 (5–42) 44 (27–68) 1·5 (0–10)
Americas 110 (5–680) 17 (5–83) 2·3 (1·5–4·4) 3·75 (0·7–9) 9 (5–23) 11 (4–16) 31 (20–54) 5·4 (2·8–8)
South-East Asia 360 (44–740) 52 (12–74) 2·9 (1·9–7·8) 38·1 (26·7–41·2) 15 (7–30) 17·5 (10–26) 45 (26–62) 1·35 (0·7–4·6)
Europe 17 (4–210) 6 (2–81) 1·45 (1·1–3·6) 3·7 (0·2–7·3) 6 (0–16) 21 (11–28) 35 (12–63) No data available
Eastern Mediterranean 120 (7–1900) 24·5 (8–165) 3·3 (1·9–7·3) 3·35 (0·6–31·6) 10 (6–32) 11·5 (0–48) 30 (0–61) 1·6 (0–2·1)
Western Pacifi c 56 (6–650) 23·5 (2–98) 2·8 (0·7–4·6) 14·25 (5·6–21·2) 8·5 (3–20) 12·5 (5–15) 35 (21–48) 0·6 (0–6·9)
*Median (range).
Table: Global prevalence of indices of maternal health and nutrition indicators 
6 Hanayama R, Miyasaka K, Nakaya M, Nagata S. MFG-E8 dependent 
clearance of apoptotic cells, and autoimmunity caused by its failure. 
Curr Dir Autoimmun 2006; 9: 162–72.
7 Mahoney JA, Rosen A. Apoptosis and autoimmunity. Curr Opin Immunol 
2005; 17: 583–88.
8 Kleinclauss F, Perruche S, Masson E, et al. Intravenous apoptotic spleen 
cell infusion induces a TGF-beta-dependent regulatory T cell expansion. 
Cell Death Diff er 2006; 13: 41–52.
9 Xia CQ, Kao KJ. Induction of immune tolerance across major 
histocompatibility complex barrier by transfusion of ultraviolet 
B-irradiated immature dendritic cells. Transfusion 2005; 45: 181–88.
10 Maeda A, Schwarz A, Kernebeck K, et al. Intravenous infusion of sungeneic 
apoptotic cells by photopheresis induces antigen-specifi c regulatory T cell. 
J Immunol 2005; 174: 5968–76.
11 Sliwa K, SkudickyD, Candy G, et al. Randomised investigation of eff ects of 
pentoxifyline on left ventricular performance in idiopathic dilated 
cardiomyopathy. Lancet 1998; 351: 1091–93.
12 Parillo JE, Cunnion RE, Epstein SE, et al. A prospective randomized 
controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 
1989; 321: 1061–68.
	Immunosuppression as therapy for congestive heart failure
	References