Resistant or recurrent acute pericarditis: a new therapeutic opportunity? Claire Massardier, Claire Dauphin, Eschalier Romain, Jean Ren´e Lusson, Martin Soubrier PII: DOI: Reference:
S0167-5273(14)01912-3 doi: 10.1016/j.ijcard.2014.09.192 IJCA 18968
To appear in:
International Journal of Cardiology
Received date: Accepted date:
27 September 2014 29 September 2014
Please cite this article as: Massardier Claire, Dauphin Claire, Romain Eschalier, Lusson Jean Ren´e, Soubrier Martin, Resistant or recurrent acute pericarditis: a new therapeutic opportunity?, International Journal of Cardiology (2014), doi: 10.1016/j.ijcard.2014.09.192
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title : Resistant or recurrent acute pericarditis: a new therapeutic opportunity? Auteurs : Claire Massardier*,MD, Claire Dauphin*, MD, Romain Eschalier*,MD, Jean René Lusson*,
SC R
IP
T
PhD, Martin Soubrier**PhD.
* CHU Clermont-Ferrand, Hôpital Gabriel Montpied, Service de cardiologie et maladies
**
NU
vasculaires, Clermont-Ferrand, F-63003, France.
CHU Clermont-Ferrand, Hôpital Gabriel Montpied, Service de rhumatologie, Clermont-
Claire Dauphin
CE P
Corresponding author :
TE
D
MA
ferrand, F-63003, France.
AC
Pole de cardiologie – CHU Clermont-Ferrand Hopital Gabriel Montpied F – 63003 Clermont-Ferrand Tel: +33 4 73 75 14 10 Fax: +33 4 73 75 19 34
E-mail : [email protected]
ACCEPTED MANUSCRIPT
Introduction:
IP
T
Treatment of recurrent (15%-30%) or resistant (5%) idiopathic pericarditis is difficult. It is based on the combination NSAID plus colchicine, and, in case of failure, on corticosteroids, with the risk of
SC R
corticosteroid dependence. Immunosuppressive agents are used in cases in which the abovementioned treatments are inefficacious [1,2].
NU
In 2009, Picco et al reported, for the first time, the efficacy of anakinra, an interleukin-1 receptor
MA
antagonist in 3 children [3]. Subsequently, other publications confirmed its efficacy in children and then in [4-8].
D
We report our observations for 2 patients, aged 60 and 65 years, who had idiopathic pericarditis
TE
resistant to standard treatment, complicated by signs of pericardial constriction, who responded
Case 1:
CE P
rapidly and favorably to treatment with anakinra, chosen over corticosteroids.
AC
A 60-year-old, obese, female patient with insulin-requiring diabetes and hypertension, presented with acute pericarditis with fever and significant biological inflammation (CRP at 337mg/L) that had recurred when aspirin treatment was discontinued.
The clinical examination found signs of
pericardial constriction. Echocardiography found circumferential pericardial effusion, with a measured width of 2 cm, of inflammatory appearance, with compression of right chambers (figures 1a, 2a). Investigations to identify the cause (including laboratory tests and chest CT scan) were negative. After failure of standard treatment (persistence of effusion and signs of constriction, CRP of 102 at D7), a combination of aspirin plus colchicine at recommended doses, anakinra was initiated, in preference to NSAIDs and to corticosteroids in this diabetic patient. There followed a rapid (D3 of treatment) favorable clinical response (resumption of diuresis, disappearance of precordialgia and dyspnea), as well as regression of biological inflammation (CRP at discharge from hospital (D12 of
ACCEPTED MANUSCRIPT treatment): 7.5mg/L) and effusion. At 2 months of treatment, the patient remained asymptomatic, without inflammation and pericardial effusion (figure 1b, 2b). Tolerance to anakinra was satisfactory.
T
The patient was gradually weaned from the treatment: aspirin between the third and fifth month of
IP
treatment, then anakinra between the 5th and 9th month, and finally colchicine, discontinued in the
SC R
fifteenth month. Case 2:
NU
A 65-year-old female patient, with a history of rheumatoid arthritis stable on methotrexate after successive treatment with gold salts, Plaquenil, corticosteroids, NSAID, anti-TNF alpha, monoclonal
MA
antibody, developed an acute inflammatory pericarditis, resistant to treatment of aspirin plus colchicine then NSAID plus colchicine. After 1 month of standard treatment, chest pain was still
D
present, dyspnea had developed, and the biological inflammation had increased (CRP 124 after one
TE
month of NSAID, 15.6 after 6 days of the NSAID plus colchicine combination), and on echocardiography, left ventricular dysfunction and signs of adiastole had developed. Pericardial
CE P
constriction was confirmed by cardiac catheterization and myocardial biopsies did not find any signs of myocarditis. The chest CT scan confirmed the inflammatory nature of the pericardium. Anakinra
AC
was started, in combination with colchicine and an NSAID (naproxen) and we observed gradual improvement of symptoms, reduction in biological inflammation (CRP < 2.9 at D6) and the disappearance of echographic signs of constriction. Three months after the start of treatment, naproxen could be reduced. Weaning from anakinra was started at the 6th month of treatment, after discontinuation of NSAID. Discussion: After a first episode of pericarditis, between 15% and 30% of patients develop recurrent or resistant pericarditis. 80% of cases of this inflammatory pathology remain idiopathic [9-10]
ACCEPTED MANUSCRIPT A recurrent or resistant pericarditis may also be the first clinical manifestation of various pathologies with an auto-inflammatory component: systemic inflammatory diseases or familial auto-
T
inflammatory diseases [9].
IP
Treatment is based on possible cause, and on combinations of aspirin or other NSAID plus colchicine,
SC R
the only molecule shown to have efficacy in preventing recurrences [1, 11].
In case of failure or contraindication to NSAIDs or in certain situations (pregnancy, systemic
NU
inflammatory disease for which they are indicated…), corticosteroids are indicated; in general, the treatment is rapidly efficacious, but it carries the risks of corticosteroid dependence and several side
MA
effects.
The third line of treatment, and often in cases of corticosteroid dependence, is an
TE
D
immunosuppressive agent.
Since 2009, following Picco et al [3], several authors have reported the efficacy of anakinra in
5,6].
CE P
children, then in adults, in cases of failure with corticosteroids or of corticosteroid dependence [4,
AC
This was confirmed by Finetti [7] in a retrospective study involving 15 corticosteroid-dependent patients, of whom 3 were adults: IL1-blocking agents led to a clinical improvement in 2.2 days, weaning from corticosteroids in 2 months, at the cost of an extended treatment of 12 months, and resumption of the treatment for recurrences in 2/3 of cases. More recently, Lazaros reported the same remarkable efficacy of anakinra in 10 adult patients, with regression of symptoms in 2 days, normalization of CRP in 6 days, weaning from corticosteroids in 37 days, but 70% recurrence during weaning from anakinra, most often necessitating resumption of the treatment and continuation of a small dose over the long term [8].
ACCEPTED MANUSCRIPT We reported the cases of 2 patients, in whom we chose anakinra over corticosteroids after failure of usual recommended treatments. Given that treatment duration has not been defined for this type of
T
case, the anakinra treatment was extended and stopped in a gradual manner after total weaning
IP
from anti-inflammatory agents and then colchicine.
SC R
As in the literature, anakinra led to rapid regression of clinical and paraclinical signs of pericarditis. The improvement was maintained over time, enabling gradual weaning from the concomitant antiinflammatory treatment. The onset of action was approximately 3 days, the duration of treatment 9
NU
months.
MA
Anakinra was well-tolered and these two patients remain symptom-free today. In the first patient, corticosteroids were avoided because of the presence of diabetes. The second
D
patient had RA, without simultaneous signs of joint inflammation. The involvement of the
TE
pericardium in RA is often independent of joint involvement and carries with it the risk of progression
CE P
to myocardial constriction. Anakinra was chosen for its activity on both RA and the pericardium, and obviated the need for corticosteroids, the treatment usually recommended, given the lack of efficacy
Conclusion:
AC
of classic RA treatments on the pericardium.
The treatment of recurrent or resistant pericarditis is difficult and must be tailored to each patient [1]. Anakinra, an interleukin-1 inhibitor, may be an alternative to corticosteroids, especially in patients with a contraindication to corticosteroid therapy. The therapeutic protocol, the duration of treatment, still need to be defined, in order to prevent the high recurrence rates reported in the literature. Additional studies are required to determine whether early use of anakinra, before corticosteroids and early in the course of the disease, can reduce the recurrence rate and hence the duration of treatment.
ACCEPTED MANUSCRIPT
IP
T
References:
SC R
[1] Imazio M. Treatment of recurrent pericarditis. Expert Rev Cardiovasc Ther 2012;1165-72. [2] Lilly LS. Treatment of acute and recurrent idiopathic pericarditis. Circulation 2013;127:1723–6.
NU
[3] Picco P, Brisca G, Traverso F, et al. Successful treatment of idiopathic recurrent pericarditis in
disease? Arthritis Rheum 2009;60:264–8.
MA
children with interleukin-1beta receptor antagonist (anakinra): an unrecognized autoinflammatory
D
[4] Scardapane A, Brucato A, Chiarelli F, Breda L. Efficacy of an interleukin-1beta receptor antagonist
CE P
TE
(Anakinra) in idiopathic recurrent pericarditis. Pediatr Cardiol 2013;36:1989–93.
[5] Camacho-Lovillo M, Mendez-Santos A. Successful treatment of idiopathic recurrent pericarditis
AC
with interleukin-1 receptor antagonist (Anakinra). Pediatr Cardiol 2013;34:1293–4.
[6] Vasileiou P, Lazaros G, Tsioufis C, et al. Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). Int J Cardiol 2012;160:66– 8. [7] Finetti M, Insalaco A, Cantarini L, Meini A, Breda L, Alessio M, D’Alessandro M, Picco P, Martini A, Gattorno M et al. Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroiddependent and colchicine-resistant recurrent pericarditis. J Petriatr 2014;164:1425-31.e1. [8] Lazaros G, Vasileiou P, Koutsianas C, et al. Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases. Ann Rheum Dis 2014 Aug 27.
ACCEPTED MANUSCRIPT
[9] Brucato A, Brambilla G, Moreo A, et al. Long-term outcomes in difficult-to-treat patients with
IP
T
recurrent pericarditis. Am J Cardiol 2006;98:267–71.
SC R
[10] Shabetai R. Recurrent pericarditis: recent advances and remaining questions. Circulation 2005; 112:1921–3.
[11] Imazio M, Belli R, Brucato A, et al. Efficacy and safety of colchicine for treatment of multiple
NU
recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised
AC
CE P
TE
D
MA
trial. Lancet 2014;383:2232–7.
ACCEPTED MANUSCRIPT
CE P
TE
D
MA
NU
SC R
IP
T
FIGURE 1a
AC
CT scan with injection of contrast at admission : For chambers view : circonferential pericardial effusion, discrete pericardial contrast enhancement
ACCEPTED MANUSCRIPT
CE P
TE
D
MA
NU
SC R
IP
T
FIGURE 2a
AC
Transthoracic echocardiography at admission : apical view : Circonferential pericardial effusion, with compression of the right chamber
ACCEPTED MANUSCRIPT
AC
CE P
TE
D
MA
NU
SC R
IP
T
FIGURE 1b
CT scan after 3 months of treatment : For chamber view : Normal pericardium
ACCEPTED MANUSCRIPT
CE P
TE
D
MA
NU
SC R
IP
T
FIGURE 2 b
AC
Transthoracic echocardiography: apical view after 3 months of treatment : Normal pericardium.
S0167-5273(14)01912-3 doi: 10.1016/j.ijcard.2014.09.192 IJCA 18968
To appear in:
International Journal of Cardiology
Received date: Accepted date:
27 September 2014 29 September 2014
Please cite this article as: Massardier Claire, Dauphin Claire, Romain Eschalier, Lusson Jean Ren´e, Soubrier Martin, Resistant or recurrent acute pericarditis: a new therapeutic opportunity?, International Journal of Cardiology (2014), doi: 10.1016/j.ijcard.2014.09.192
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title : Resistant or recurrent acute pericarditis: a new therapeutic opportunity? Auteurs : Claire Massardier*,MD, Claire Dauphin*, MD, Romain Eschalier*,MD, Jean René Lusson*,
SC R
IP
T
PhD, Martin Soubrier**PhD.
* CHU Clermont-Ferrand, Hôpital Gabriel Montpied, Service de cardiologie et maladies
**
NU
vasculaires, Clermont-Ferrand, F-63003, France.
CHU Clermont-Ferrand, Hôpital Gabriel Montpied, Service de rhumatologie, Clermont-
Claire Dauphin
CE P
Corresponding author :
TE
D
MA
ferrand, F-63003, France.
AC
Pole de cardiologie – CHU Clermont-Ferrand Hopital Gabriel Montpied F – 63003 Clermont-Ferrand Tel: +33 4 73 75 14 10 Fax: +33 4 73 75 19 34
E-mail : [email protected]
ACCEPTED MANUSCRIPT
Introduction:
IP
T
Treatment of recurrent (15%-30%) or resistant (5%) idiopathic pericarditis is difficult. It is based on the combination NSAID plus colchicine, and, in case of failure, on corticosteroids, with the risk of
SC R
corticosteroid dependence. Immunosuppressive agents are used in cases in which the abovementioned treatments are inefficacious [1,2].
NU
In 2009, Picco et al reported, for the first time, the efficacy of anakinra, an interleukin-1 receptor
MA
antagonist in 3 children [3]. Subsequently, other publications confirmed its efficacy in children and then in [4-8].
D
We report our observations for 2 patients, aged 60 and 65 years, who had idiopathic pericarditis
TE
resistant to standard treatment, complicated by signs of pericardial constriction, who responded
Case 1:
CE P
rapidly and favorably to treatment with anakinra, chosen over corticosteroids.
AC
A 60-year-old, obese, female patient with insulin-requiring diabetes and hypertension, presented with acute pericarditis with fever and significant biological inflammation (CRP at 337mg/L) that had recurred when aspirin treatment was discontinued.
The clinical examination found signs of
pericardial constriction. Echocardiography found circumferential pericardial effusion, with a measured width of 2 cm, of inflammatory appearance, with compression of right chambers (figures 1a, 2a). Investigations to identify the cause (including laboratory tests and chest CT scan) were negative. After failure of standard treatment (persistence of effusion and signs of constriction, CRP of 102 at D7), a combination of aspirin plus colchicine at recommended doses, anakinra was initiated, in preference to NSAIDs and to corticosteroids in this diabetic patient. There followed a rapid (D3 of treatment) favorable clinical response (resumption of diuresis, disappearance of precordialgia and dyspnea), as well as regression of biological inflammation (CRP at discharge from hospital (D12 of
ACCEPTED MANUSCRIPT treatment): 7.5mg/L) and effusion. At 2 months of treatment, the patient remained asymptomatic, without inflammation and pericardial effusion (figure 1b, 2b). Tolerance to anakinra was satisfactory.
T
The patient was gradually weaned from the treatment: aspirin between the third and fifth month of
IP
treatment, then anakinra between the 5th and 9th month, and finally colchicine, discontinued in the
SC R
fifteenth month. Case 2:
NU
A 65-year-old female patient, with a history of rheumatoid arthritis stable on methotrexate after successive treatment with gold salts, Plaquenil, corticosteroids, NSAID, anti-TNF alpha, monoclonal
MA
antibody, developed an acute inflammatory pericarditis, resistant to treatment of aspirin plus colchicine then NSAID plus colchicine. After 1 month of standard treatment, chest pain was still
D
present, dyspnea had developed, and the biological inflammation had increased (CRP 124 after one
TE
month of NSAID, 15.6 after 6 days of the NSAID plus colchicine combination), and on echocardiography, left ventricular dysfunction and signs of adiastole had developed. Pericardial
CE P
constriction was confirmed by cardiac catheterization and myocardial biopsies did not find any signs of myocarditis. The chest CT scan confirmed the inflammatory nature of the pericardium. Anakinra
AC
was started, in combination with colchicine and an NSAID (naproxen) and we observed gradual improvement of symptoms, reduction in biological inflammation (CRP < 2.9 at D6) and the disappearance of echographic signs of constriction. Three months after the start of treatment, naproxen could be reduced. Weaning from anakinra was started at the 6th month of treatment, after discontinuation of NSAID. Discussion: After a first episode of pericarditis, between 15% and 30% of patients develop recurrent or resistant pericarditis. 80% of cases of this inflammatory pathology remain idiopathic [9-10]
ACCEPTED MANUSCRIPT A recurrent or resistant pericarditis may also be the first clinical manifestation of various pathologies with an auto-inflammatory component: systemic inflammatory diseases or familial auto-
T
inflammatory diseases [9].
IP
Treatment is based on possible cause, and on combinations of aspirin or other NSAID plus colchicine,
SC R
the only molecule shown to have efficacy in preventing recurrences [1, 11].
In case of failure or contraindication to NSAIDs or in certain situations (pregnancy, systemic
NU
inflammatory disease for which they are indicated…), corticosteroids are indicated; in general, the treatment is rapidly efficacious, but it carries the risks of corticosteroid dependence and several side
MA
effects.
The third line of treatment, and often in cases of corticosteroid dependence, is an
TE
D
immunosuppressive agent.
Since 2009, following Picco et al [3], several authors have reported the efficacy of anakinra in
5,6].
CE P
children, then in adults, in cases of failure with corticosteroids or of corticosteroid dependence [4,
AC
This was confirmed by Finetti [7] in a retrospective study involving 15 corticosteroid-dependent patients, of whom 3 were adults: IL1-blocking agents led to a clinical improvement in 2.2 days, weaning from corticosteroids in 2 months, at the cost of an extended treatment of 12 months, and resumption of the treatment for recurrences in 2/3 of cases. More recently, Lazaros reported the same remarkable efficacy of anakinra in 10 adult patients, with regression of symptoms in 2 days, normalization of CRP in 6 days, weaning from corticosteroids in 37 days, but 70% recurrence during weaning from anakinra, most often necessitating resumption of the treatment and continuation of a small dose over the long term [8].
ACCEPTED MANUSCRIPT We reported the cases of 2 patients, in whom we chose anakinra over corticosteroids after failure of usual recommended treatments. Given that treatment duration has not been defined for this type of
T
case, the anakinra treatment was extended and stopped in a gradual manner after total weaning
IP
from anti-inflammatory agents and then colchicine.
SC R
As in the literature, anakinra led to rapid regression of clinical and paraclinical signs of pericarditis. The improvement was maintained over time, enabling gradual weaning from the concomitant antiinflammatory treatment. The onset of action was approximately 3 days, the duration of treatment 9
NU
months.
MA
Anakinra was well-tolered and these two patients remain symptom-free today. In the first patient, corticosteroids were avoided because of the presence of diabetes. The second
D
patient had RA, without simultaneous signs of joint inflammation. The involvement of the
TE
pericardium in RA is often independent of joint involvement and carries with it the risk of progression
CE P
to myocardial constriction. Anakinra was chosen for its activity on both RA and the pericardium, and obviated the need for corticosteroids, the treatment usually recommended, given the lack of efficacy
Conclusion:
AC
of classic RA treatments on the pericardium.
The treatment of recurrent or resistant pericarditis is difficult and must be tailored to each patient [1]. Anakinra, an interleukin-1 inhibitor, may be an alternative to corticosteroids, especially in patients with a contraindication to corticosteroid therapy. The therapeutic protocol, the duration of treatment, still need to be defined, in order to prevent the high recurrence rates reported in the literature. Additional studies are required to determine whether early use of anakinra, before corticosteroids and early in the course of the disease, can reduce the recurrence rate and hence the duration of treatment.
ACCEPTED MANUSCRIPT
IP
T
References:
SC R
[1] Imazio M. Treatment of recurrent pericarditis. Expert Rev Cardiovasc Ther 2012;1165-72. [2] Lilly LS. Treatment of acute and recurrent idiopathic pericarditis. Circulation 2013;127:1723–6.
NU
[3] Picco P, Brisca G, Traverso F, et al. Successful treatment of idiopathic recurrent pericarditis in
disease? Arthritis Rheum 2009;60:264–8.
MA
children with interleukin-1beta receptor antagonist (anakinra): an unrecognized autoinflammatory
D
[4] Scardapane A, Brucato A, Chiarelli F, Breda L. Efficacy of an interleukin-1beta receptor antagonist
CE P
TE
(Anakinra) in idiopathic recurrent pericarditis. Pediatr Cardiol 2013;36:1989–93.
[5] Camacho-Lovillo M, Mendez-Santos A. Successful treatment of idiopathic recurrent pericarditis
AC
with interleukin-1 receptor antagonist (Anakinra). Pediatr Cardiol 2013;34:1293–4.
[6] Vasileiou P, Lazaros G, Tsioufis C, et al. Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). Int J Cardiol 2012;160:66– 8. [7] Finetti M, Insalaco A, Cantarini L, Meini A, Breda L, Alessio M, D’Alessandro M, Picco P, Martini A, Gattorno M et al. Long-term efficacy of interleukin-1 receptor antagonist (anakinra) in corticosteroiddependent and colchicine-resistant recurrent pericarditis. J Petriatr 2014;164:1425-31.e1. [8] Lazaros G, Vasileiou P, Koutsianas C, et al. Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases. Ann Rheum Dis 2014 Aug 27.
ACCEPTED MANUSCRIPT
[9] Brucato A, Brambilla G, Moreo A, et al. Long-term outcomes in difficult-to-treat patients with
IP
T
recurrent pericarditis. Am J Cardiol 2006;98:267–71.
SC R
[10] Shabetai R. Recurrent pericarditis: recent advances and remaining questions. Circulation 2005; 112:1921–3.
[11] Imazio M, Belli R, Brucato A, et al. Efficacy and safety of colchicine for treatment of multiple
NU
recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised
AC
CE P
TE
D
MA
trial. Lancet 2014;383:2232–7.
ACCEPTED MANUSCRIPT
CE P
TE
D
MA
NU
SC R
IP
T
FIGURE 1a
AC
CT scan with injection of contrast at admission : For chambers view : circonferential pericardial effusion, discrete pericardial contrast enhancement
ACCEPTED MANUSCRIPT
CE P
TE
D
MA
NU
SC R
IP
T
FIGURE 2a
AC
Transthoracic echocardiography at admission : apical view : Circonferential pericardial effusion, with compression of the right chamber
ACCEPTED MANUSCRIPT
AC
CE P
TE
D
MA
NU
SC R
IP
T
FIGURE 1b
CT scan after 3 months of treatment : For chamber view : Normal pericardium
ACCEPTED MANUSCRIPT
CE P
TE
D
MA
NU
SC R
IP
T
FIGURE 2 b
AC
Transthoracic echocardiography: apical view after 3 months of treatment : Normal pericardium.
