Intravenous Immunoglobulin Therapy for Refractory Recurrent Pericarditis M. Rosa del Fresno, Julio E. Peralta, Miguel Ángel Granados, Eugenia Enríquez, Nerea Domínguez-Pinilla and Jaime de Inocencio Pediatrics; originally published online October 6, 2014; DOI: 10.1542/peds.2013-3900
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2014/09/30/peds.2013-3900
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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CASE REPORT
Intravenous Immunoglobulin Therapy for Refractory Recurrent Pericarditis AUTHORS: M. Rosa del Fresno, MD,a Julio E. Peralta, MD,b Miguel Ángel Granados, MD,b Eugenia Enríquez, MD,a Nerea Domínguez-Pinilla, MD,a and Jaime de Inocencio, MD, PhDa aPediatric Rheumatology Unit and bDivision of Pediatric Cardiology, Department of Pediatrics, Hospital Universitario Doce de Octubre, Madrid, Spain
KEY WORDS recurrent pericarditis, intravenous immunoglobulins, child, pericardial effusion/therapy ABBREVIATIONS IL—interleukin IVIG—intravenous immunoglobulin RP—recurrent pericarditis TNF—tumor necrosis factor Drs del Fresno, Peralta, and Domínguez-Pinilla conceptualized the work, carried out the collection and interpretation of the patients’ data, performed the literature review, and drafted the initial manuscript; Drs Granados, Enríquez, and de Inocencio participated in data acquisition and revised the manuscript critically; and all authors approved the final manuscript as submitted.
abstract Recurrent pericarditis is a troublesome complication of idiopathic acute pericarditis and occurs more frequently in pediatric patients after cardiac surgery (postpericardiotomy syndrome). Conventional treatment with nonsteroidal antiinflammatory drugs, corticosteroids, and colchicine is not always effective or may cause serious adverse effects. There is no consensus, however, on how to proceed in those patients whose disease is refractory to conventional therapy. In such cases, human intravenous immunoglobulin, immunosuppressive drugs, and biological agents have been used. In this report we describe 2 patients with refractory recurrent pericarditis after cardiac surgery who were successfully treated with 3 and 5 monthly high-dose (2 g/kg) intravenous immunoglobulin until resolution of the effusion. Our experience supports the effectiveness and safety of this therapy. Pediatrics 2014;134:e1–e6
www.pediatrics.org/cgi/doi/10.1542/peds.2013-3900 doi:10.1542/peds.2013-3900 Accepted for publication Apr 28, 2014 Address correspondence to M. Rosa del Fresno, MD, Pediatric Rheumatology Unit, Department of Pediatrics, Hospital Universitario Doce de Octubre, Avenida de Córdoba s/n, 28041, Madrid, Spain. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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Recurrent pericarditis (RP) is a chronic disease characterized by repeated episodes of pericardial effusion. After an episode of acute pericarditis, up to 36% of the patients develop recurrences.1,2 In children, almost 50% of the cases occur after cardiac surgery.3 RP is a condition that is difficult to manage and often results in the frustration of patients, families, and treating physicians. The guideline on pericardial syndrome by the European Society of Cardiology, updated in 2012,4 recommends nonsteroidal antiinflammatory drugs with additional colchicine as the first line of therapy, with the use of low-dose steroids for those who do not respond. It is not uncommon, however, for patients to become steroid-dependent or to continue to have pericardial effusion. In such cases, several therapies have been successfully used, including immunosuppressive agents such as azathioprine or methotrexate,2–5 interleukin (IL)-1 receptor antagonist,6–10 anti–tumor necrosis factor (anti-TNF) drugs,11 and intravenous immunoglobulin (IVIG).12–15 Herein, we report on 2 children with refractory postpericardiotomy syndrome who were successfully treated with IVIG.
and worsening of the effusion. The pericardial effusion improved gradually, allowing prednisone tapering after 2 weeks. Eleven weeks after surgery, the pericardial effusion was resolved and prednisone was stopped.
Patient 2
thy was transferred to our institution in November 2011 for corrective surgery (fibromuscular ring resection and placement of an infundibular patch). After surgical repair, he developed mild to moderate asymptomatic pericardial effusion. Acute-phase reactants were not elevated. His electrocardiogram was normal, except for tall P waves in leads I, II, and V1 to V3 and an RSR pattern in V1. He was managed at his local hospital with ibuprofen for 2 weeks, followed by prednisone (2 mg/kg per day) and colchicine (0.75 mg/day). In February 2012, oral methotrexate was added because of worsening effusion and onset of fatigue, with no effect (Fig 2). After 2 months, methotrexate was stopped. Several unsuccessful attempts were made to taper prednisone, requiring doses of ˃0.6 mg/kg per day to keep the effusion under control despite concomitant colchicine therapy. In September 2012, he received his first dose of IVIG (400 mg/kg per day for 4 consecutive days). No significant change in the pericardial effusion was observed and he was transferred to our center.
A 4-year-old boy diagnosed with hypertrophic obstructive cardiomyopa-
In November 2012, IVIG was administered at a dose of 2 g/kg per month. After
Three weeks later, however, she developed a recurrence and exhibited a large pericardial effusion (Fig 1). Prednisone (1 mg/kg per day) and colchicine (0.5 mg/day) were started with no improvement after 8 weeks of therapy. At that time (September 2012), she received IVIG, 2 g/kg per month given as a single dose. After 2 doses, the effusion began to decrease, allowing steroid tapering. By the time she received her third IVIG treatment, the prednisone dose had been decreased to 0.1 mg/kg per day. In January 2013, after 5 doses of IVIG, her disease was in complete remission. IVIG and prednisone were stopped and colchicine was maintained for another 8 weeks. She has discontinued all medications for the last 13 months without recurrences.
CASE REPORTS Patient 1 A 4-year-old girl underwent corrective surgery for tetralogy of Fallot at our center in April 2012. The patient was diagnosed at birth, but surgery was delayed because parents refused surgical treatment. One week later, an echocardiogram revealed a moderate pericardial effusion without elevation of acute-phase reactants or hemodynamic compromise. Her electrocardiogram revealed a broad QRS of 125 ms with RSR pattern and T wave inversion in leads V1 to V4. Indomethacin was started, but 48 hours later it was discontinued due to gastrointestinal intolerance, and prednisone (2 mg/kg per day) was initiated because of increasing serum creatinine levels e2
FIGURE 1 Patient 1 before IVIG therapy. Subcostal echocardiographic view reveals a moderate to severe global pericardial effusion that is more intense behind the atria (arrow). No signs of hemodynamic compromise were noted during the examination. LA, left atrium; LV, left ventricle; PE, pericardial effusion; RA, right atrium.
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CASE REPORT
and anti–intercalated disk autoantibodies, as well as antinuclear antibodies.19,20 In addition, the analysis of pericardial effusions reveals the presence of proinflammatory cytokines, including IL-6, IL-8, and interferon-g.21
FIGURE 2 Patient 2 before IVIG therapy. Subcostal echocardiographic view reveals a moderate pericardial effusion on the right side of the RV and above the LV. There was no chamber compression during the study. LV, left ventricle; PE, pericardial effusion; RV, right ventricle.
the administration of a second 2-g/kg dose of IVIG, the patient developed severe headache and malaise. The effusion, however, resolved and prednisone was discontinued in February 2013. In March, a small recurrence was noted. It was managed with small doses of prednisone (,0.2 mg/kg per day), which did not require further administration of IVIG for its control. This time the effusion resolved quickly, allowing discontinuation of prednisone in July and of colchicine 3 months later.
DISCUSSION RP is a chronic disease characterized by recurrent episodes of fever, chest pain, pericardial friction rubs, electrocardiographic changes, and pericardial effusion. Laboratory tests usually reveal leukocytosis and elevated acute-phase reactants. Relapses may present as an intermittent (symptom-free intervals longer than 6 weeks without therapy) or as an incessant type (discontinuation or attempts to taper off treatment result in early reappearance or worsening
of symptoms), as happened to our 2 patients.16 Recurrences develop in up to 36% of pediatric patients after the first episode of idiopathic acute pericarditis1 and in 50% of children after pericardial injury.3 Age at the time of cardiac surgery is a major factor associated with the development of postpericardiotomy syndrome in pediatric patients. For undetermined reasons, younger children rarely present this complication.17 Post– cardiac injury syndrome develops after pericardial damage caused by cardiac surgery, accidental trauma, or post– myocardial infarction. Much less common causes of RP include certain rheumatic conditions (systemic juvenile idiopathic arthritis, systemic lupus erythematosus) and autoinflammatory diseases (familial Mediterranean fever, TNF receptor– associated periodic syndrome).2 The pathogenesis of the disease is unknown. The most commonly accepted theory is that RP represents an autoimmune phenomenon.18 Patients with the disease have circulating anti–heart
This theory might explain both idiopathic and post–cardiac injury pericarditis. In the first group, a virus could trigger an autoimmune process through a mechanism of molecular mimicry. In the latter, surgery, trauma, or infarction would expose or release cardiac autoantigens and stimulate an immune response. An additional hypothesis that could explain some cases is that recurrent pericarditis represents an autoinflammatory disease due to a genetically determined dysfunction of the innate immune system that causes a dysregulation of the inflammatory process.22,23 Serosal inflammation is a common feature of familial Mediterranean fever and TNF receptor– associated periodic syndrome, and recurrent pericarditis might be the only clinical manifestation at disease onset.24,25 The mainstay of therapy is nonsteroidal antiinflammatory drugs (aspirin, ibuprofen, or indomethacin) for 10 to 14 days with additional colchicine (0.5–1 mg/day) for 6 months.4 If there is intolerance or no response, patients could receive lowdose steroids (0.2–0.5 mg/kg per day). Paradoxically, for this indication, steroids appear to be beneficial only at low doses; in fact, corticosteroids at high doses ($1 mg/kg per day) seem to increase the risk of recurrences.2–4,26 This stepwise approach controls the disease in most patients. There is a small group of patients, however, who are refractory to conventional therapy, such as the 2 presented in this report. In such cases, different immunosuppressive or immunomodulatory drugs have been used on the basis of the suspected autoimmune pathogenesis of the disease, including azathioprine,2–4 methotrexate,5 and, more recently, anti–IL-1
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DEL FRESNO et al
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Male
Male
Male
Male
6
7
8
9
Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Postpericardiotomy syndrome Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Postpericardiotomy syndrome Idiopathic recurrent pericarditis Postpericardiotomy syndrome Postpericardiotomy syndrome
Diagnosis
4
4
35
47
37
22
69
42
30
29
27
12
11
21
28
5
1
6
7
3
6
5
4
6
3
6
8
15
4
5
5
?
19 29
?
Number of Relapses Before IVIG
30
Age at Onset, years
IBU 30 mg/kg per day, COL 0.75 mg/d, PDN 2 mg/kg per day, MTX
COL 0.5 mg/d, PDN 2 mg/kg per day
IBU 1.8 g/d, IND 150 mg/d, COL, PDN 5 mg/d
IND 150 mg/d, ASA 3 g/d, COL
ASA 1.5 g/d, IBU 1.2 g/d, COL, PDN 50 mg/d
IBU 2 g/d, COL, PDN 25 mg/d
IND 150 mg/d, COL, PDN, AZA
IND 150 mg/d, IBU 1.6 g/d, COL, PDN 50 mg/d
ASA 1.5 g/d, IND 150 mg/d, COL, PDN 25 mg/d, MTX
IND 50–100 mg/d, PDN 25 mg/d, MTX, CSA
ASA 1.6 g/d, COL, PDN 35 mg/d, AZA
COL 1 mg/d, PDN 50 mg/d, MTX 15 mg/s, CSA 4 mg/kg per day, AZA 150 mg/d ASA 75 mg/kg per day, PDN 2 mg/kg per day
ASA 1.6 g/d, COL 1 mg/d, PDN 50 mg/d
ASA 3.2 g/d, COL 1 mg/d, PDN 50 mg/d
ASA 4–6 g/d, COL 1 mg/d, PDN 75 mg/d, AZA 150 mg/d, CSA 300 mg/d, CYC 100 mg/d COL 1 mg/d, PDN 50 mg/d, MPIV 160 mg/d 3 3 d, CSA, CYC, MTX COL 1 mg/d, PDN 50 mg/d
Treatments Before IVIGa Number of Cycles 1 1 7 7 ? ($5) 9 1 3 1 1 2 1 1 1 1 2 5 3
Dose/Cycle
0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.4 g/kg per day 3 5 d 0.4 g/kg per day 3 5 d 0.4 g/kg per day 3 5 d 0.4 g/kg per day 3 5 d 2 g/kg per day 31 d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.5g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 2 g/kg per day 3 1 d 0.4 g/kg per day 3 4 d (1 cycle), 2 g/kg per day 3 1 d (2 cycles)
11
13
24
24
12
24
12
36
96
84
156
54
?
?
12
20
32
42
Monitored Time Free From Relapses, months
Malaise, headache
None
None
None
None
None
None
None
None
None
None
Mild headache None
None
None
None
None
None
Adverse Effects
ASA, acetyl salicylic acid; AZA, azathioprine; COL, colchicine; CSA, cyclosporine A; CYC, cyclophosphamide; IBU, ibuprofen; IND, indomethacin; PDN, prednisone; MPIV, intravenous methylprednisolone; MTX, methotrexate; sc, subcutaneous; ?, data not available. a Treatments before IVIG: It is shown highest doses for each treatment.
Male
Female
5
2
Female
4
Female
Male
3
1
Female
2
del Fresno (2013)
Male
1
Male
4
Moretti (2013)
Male
3
Female
Male
2
1
Male
Female
2
1
Male
Gender
1
Patient Number
Wendelin (2008)
Peterlana (2005)
Tona (2003)
Author (Year)
TABLE 1 Previous Case Reports on RP Treated With IVIG
CASE REPORT
receptor antagonist,6–10 anti-TNF agents11 and human IVIG.12–15 With regard to classic immunosuppressive agents, several pediatric case reports, including our patient number 2, suggest that methotrexate is not effective in the treatment of RP.3,11–13,15 Azathioprine has a similar lack of effect in children,11–13,15 although in adults it has proven to be useful.27 Therefore, although both immunosuppressant agents are recommended in most reviews, there are no robust clinical data on their precise role in the management of pediatric disease. More recently, biological therapy has been used to treat this condition. Several reports support the effectiveness of anti–IL-1 (IL-1 receptor antagonist) therapy. In all cases, the concentration of acute-phase reactants was very high when reported and the response to therapy was often dramatic, within the first few days after the initiation of the drug.6–10 There is only 1 case series reporting on 3 patients with RP who re-
ceived anti-TNF therapy.11 It revealed that anti-TNF drugs might be efficacious but require months to show clinical effect and years of continuous therapy. A literature review revealed that in the last 10 years only 4 series have reported the efficacy of IVIG in the therapy for RP. The numbers in those series were small, except from 1 report on a series of 9 patients (Table 1). All the studies showed that IVIG had rapid beneficial effects in patients, independently of their gender, age, diagnosis, dose, and protocol of administration. In most cases, a clinical response was obvious after 1 to 3 doses. Adverse effects were unusual and not serious (Table 1). The major limitations of IVIG include its cost and its route of administration. The use of single monthly doses and its administration in pediatric day hospitals, however, facilitate its use.
inhibition of phagocytosis; blockade of immune-complex access to FcgR; increased expression of FcgRIIB on effector macrophages; Fab binding to anti-idiotypes, specific cytokines, and autoantibodies; and reduction in complement deposition. These actions result in decreases in the production of proinflammatory cytokines; the downregulation of adhesion molecule, chemokine, and chemokine receptor expression; and the neutralization of circulating autoantibodies.
A recent review28 suggested different mechanisms to explain the efficacy of IVIG in autoimmune diseases, including
In conclusion, although the use of IVIG at high doses currently represents an offlabel indication, an increasing number of reports indicate that it is an effective and safe alternative for those patients whose pericarditis is refractory to conventional therapy or who become steroiddependent. Our small series supports that this treatment represents another option in these cases. Prospective randomized studies will be required to fully determine its role in the management of thisdifficultand often frustrating disease.
(anakinra): an unrecognized autoinflammatory disease? Arthritis Rheum. 2009;60(1):264–268 Cantarini L, Lucherini OM, Cimaz R, Galeazzi M. Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment. Clin Exp Rheumatol. 2010;28(5):802 Vassilopoulos D, Lazaros G, Tsioufis C, Vasileiou P, Stefanadis C, Pectasides D. Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). Int J Cardiol. 2012;160(1):66–68 Camacho-Lovillo M, Méndez-Santos A. Successful treatment of idiopathic recurrent pericarditis with interleukin-1 receptor antagonist (anakinra). Pediatr Cardiol. 2013;34 (5):1293–1294 Scardapane A, Brucato A, Chiarelli F, Breda L. Efficacy of an interleukin-1b receptor antagonist (anakinra) in idiopathic recurrent pericarditis. Pediatr Cardiol. 2013;34(8):1989– 1991
11. Nieto González JC, Monteagudo Saez I, López-Longo FJ, Serrano B, Mata Martínez C, Carreño Pérez L. Idiopathic recurrent pericarditis treated successfully with tumour necrosis factor alpha blocking agents (anti-TNF-a). Clin Exp Rheumatol. 2013;31(5): 776–778 12. Tona F, Bellotto F, Laveder F, Meneghin A, Sinagra G, Marcolongo R. Efficacy of highdose intravenous immunoglobulins in two patients with idiopathic recurrent pericarditis refractory to previous immunosuppressive treatment. Ital Heart J. 2003;4(1): 64–68 13. Peterlana D, Puccetti A, Simeoni S, Tinazzi E, Corrocher R, Lunardi C. Efficacy of intravenous immunoglobulin in chronic idiopathic pericarditis: report of four cases. Clin Rheumatol. 2005;24(1):18–21 14. Wendelin G, Fandl A, Beitzke A. High-dose intravenous immunoglobulin in recurrent postpericardiotomy syndrome. Pediatr Cardiol. 2008;29(2):463–464
REFERENCES 1. Ratnapalan S, Brown K, Benson L. Children presenting with acute pericarditis to the emergency department. Pediatr Emerg Care. 2011;27(7):581–585 2. Gaspari S, Marsili M, Imazio M, et al. New insights in the pathogenesis and therapy of idiopathic recurrent pericarditis in children. Clin Exp Rheumatol. 2013;31(5):788–794 3. Raatikka M, Pelkonen PM, Karjalainen J, Jokinen EV. Recurrent pericarditis in children and adolescents: report of 15 cases. J Am Coll Cardiol. 2003;42(4):759–764 4. Seferovic PM, Ristic AD, Maksimovic R, et al. Pericardial syndromes: an update after the ESC guidelines 2004. Heart Fail Rev. 2013;18(3):255–266 5. Zucker N, Levitas A, Zalzstein E. Methotrexate in recurrent postpericardiotomy syndrome. Cardiol Young. 2003;13(2):206–208 6. Picco P, Brisca G, Traverso F, Loy A, Gattorno M, Martini A. Successful treatment of idiopathic recurrent pericarditis in children with interleukin-1beta receptor antagonist
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15. Moretti M, Buiatti A, Merlo M, et al. Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis. Am J Cardiol. 2013; 112(9):1493–1498 16. Soler-Soler J, Sagristà-Sauleda J, PermanyerMiralda G. Relapsing pericarditis. Heart. 2004; 90(11):1364–1368 17. Engle MA, O’Loughlin JE. Complications of cardiac surgery in children. Pediatr Rev. 1987;9(5):147–154 18. Erlich JF, Paz Z. Postpericardial injury syndrome: an autoimmune phenomenon. Clin Rev Allergy Immunol. 2010;38(2-3):156–158 19. Caforio AL, Brucato A, Doria A, et al. Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis. Heart. 2010;96 (10):779–784
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20. Imazio M, Brucato A, Doria A, et al. Antinuclear antibodies in recurrent idiopathic pericarditis: prevalence and clinical significance. Int J Cardiol. 2009;136(3):289–293 21. Pankuweit S, Wädlich A, Meyer E, Portig I, Hufnagel G, Maisch B. Cytokine activation in pericardial fluids in different forms of pericarditis. Herz. 2000;25(8):748–754 22. Maestroni S, Di Corato PR, Cumetti D, et al. Recurrent pericarditis: autoimmune or autoinflammatory? Autoimmun Rev. 2012;12(1): 60–65 23. Cantarini L, Imazio M, Brizi MG, et al. Role of autoimmunity and autoinflammation in the pathogenesis of idiopathic recurrent pericarditis. Clin Rev Allergy Immunol. 2013;44 (1):6–13 24. Okutur K, Seber S, Oztekin E, Bes C, Borlu F. Recurrent pericarditis as the initial mani-
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festation of familial Mediterranean fever. Med Sci Monit. 2008;14(12):CS139–CS141 Cantarini L, Lucherini OM, Brucato A, et al. Clues to detect tumor necrosis factor receptorassociated periodic syndrome (TRAPS) among patients with idiopathic recurrent acute pericarditis: results of a multicentre study. Clin Res Cardiol. 2012;101(7):525–531 Imazio M, Brucato A, Cumetti D, et al. Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation. Circulation. 2008;118(6):667–671 Vianello F, Cinetto F, Cavraro M, et al. Azathioprine in isolated recurrent pericarditis: a single centre experience. Int J Cardiol. 2011; 147(3):477–478 Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012;367(21):2015–2025
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Intravenous Immunoglobulin Therapy for Refractory Recurrent Pericarditis M. Rosa del Fresno, Julio E. Peralta, Miguel Ángel Granados, Eugenia Enríquez, Nerea Domínguez-Pinilla and Jaime de Inocencio Pediatrics; originally published online October 6, 2014; DOI: 10.1542/peds.2013-3900 Updated Information & Services
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Univ Of Wisconsin on October 17, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2014/09/30/peds.2013-3900
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Univ Of Wisconsin on October 17, 2014
CASE REPORT
Intravenous Immunoglobulin Therapy for Refractory Recurrent Pericarditis AUTHORS: M. Rosa del Fresno, MD,a Julio E. Peralta, MD,b Miguel Ángel Granados, MD,b Eugenia Enríquez, MD,a Nerea Domínguez-Pinilla, MD,a and Jaime de Inocencio, MD, PhDa aPediatric Rheumatology Unit and bDivision of Pediatric Cardiology, Department of Pediatrics, Hospital Universitario Doce de Octubre, Madrid, Spain
KEY WORDS recurrent pericarditis, intravenous immunoglobulins, child, pericardial effusion/therapy ABBREVIATIONS IL—interleukin IVIG—intravenous immunoglobulin RP—recurrent pericarditis TNF—tumor necrosis factor Drs del Fresno, Peralta, and Domínguez-Pinilla conceptualized the work, carried out the collection and interpretation of the patients’ data, performed the literature review, and drafted the initial manuscript; Drs Granados, Enríquez, and de Inocencio participated in data acquisition and revised the manuscript critically; and all authors approved the final manuscript as submitted.
abstract Recurrent pericarditis is a troublesome complication of idiopathic acute pericarditis and occurs more frequently in pediatric patients after cardiac surgery (postpericardiotomy syndrome). Conventional treatment with nonsteroidal antiinflammatory drugs, corticosteroids, and colchicine is not always effective or may cause serious adverse effects. There is no consensus, however, on how to proceed in those patients whose disease is refractory to conventional therapy. In such cases, human intravenous immunoglobulin, immunosuppressive drugs, and biological agents have been used. In this report we describe 2 patients with refractory recurrent pericarditis after cardiac surgery who were successfully treated with 3 and 5 monthly high-dose (2 g/kg) intravenous immunoglobulin until resolution of the effusion. Our experience supports the effectiveness and safety of this therapy. Pediatrics 2014;134:e1–e6
www.pediatrics.org/cgi/doi/10.1542/peds.2013-3900 doi:10.1542/peds.2013-3900 Accepted for publication Apr 28, 2014 Address correspondence to M. Rosa del Fresno, MD, Pediatric Rheumatology Unit, Department of Pediatrics, Hospital Universitario Doce de Octubre, Avenida de Córdoba s/n, 28041, Madrid, Spain. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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Recurrent pericarditis (RP) is a chronic disease characterized by repeated episodes of pericardial effusion. After an episode of acute pericarditis, up to 36% of the patients develop recurrences.1,2 In children, almost 50% of the cases occur after cardiac surgery.3 RP is a condition that is difficult to manage and often results in the frustration of patients, families, and treating physicians. The guideline on pericardial syndrome by the European Society of Cardiology, updated in 2012,4 recommends nonsteroidal antiinflammatory drugs with additional colchicine as the first line of therapy, with the use of low-dose steroids for those who do not respond. It is not uncommon, however, for patients to become steroid-dependent or to continue to have pericardial effusion. In such cases, several therapies have been successfully used, including immunosuppressive agents such as azathioprine or methotrexate,2–5 interleukin (IL)-1 receptor antagonist,6–10 anti–tumor necrosis factor (anti-TNF) drugs,11 and intravenous immunoglobulin (IVIG).12–15 Herein, we report on 2 children with refractory postpericardiotomy syndrome who were successfully treated with IVIG.
and worsening of the effusion. The pericardial effusion improved gradually, allowing prednisone tapering after 2 weeks. Eleven weeks after surgery, the pericardial effusion was resolved and prednisone was stopped.
Patient 2
thy was transferred to our institution in November 2011 for corrective surgery (fibromuscular ring resection and placement of an infundibular patch). After surgical repair, he developed mild to moderate asymptomatic pericardial effusion. Acute-phase reactants were not elevated. His electrocardiogram was normal, except for tall P waves in leads I, II, and V1 to V3 and an RSR pattern in V1. He was managed at his local hospital with ibuprofen for 2 weeks, followed by prednisone (2 mg/kg per day) and colchicine (0.75 mg/day). In February 2012, oral methotrexate was added because of worsening effusion and onset of fatigue, with no effect (Fig 2). After 2 months, methotrexate was stopped. Several unsuccessful attempts were made to taper prednisone, requiring doses of ˃0.6 mg/kg per day to keep the effusion under control despite concomitant colchicine therapy. In September 2012, he received his first dose of IVIG (400 mg/kg per day for 4 consecutive days). No significant change in the pericardial effusion was observed and he was transferred to our center.
A 4-year-old boy diagnosed with hypertrophic obstructive cardiomyopa-
In November 2012, IVIG was administered at a dose of 2 g/kg per month. After
Three weeks later, however, she developed a recurrence and exhibited a large pericardial effusion (Fig 1). Prednisone (1 mg/kg per day) and colchicine (0.5 mg/day) were started with no improvement after 8 weeks of therapy. At that time (September 2012), she received IVIG, 2 g/kg per month given as a single dose. After 2 doses, the effusion began to decrease, allowing steroid tapering. By the time she received her third IVIG treatment, the prednisone dose had been decreased to 0.1 mg/kg per day. In January 2013, after 5 doses of IVIG, her disease was in complete remission. IVIG and prednisone were stopped and colchicine was maintained for another 8 weeks. She has discontinued all medications for the last 13 months without recurrences.
CASE REPORTS Patient 1 A 4-year-old girl underwent corrective surgery for tetralogy of Fallot at our center in April 2012. The patient was diagnosed at birth, but surgery was delayed because parents refused surgical treatment. One week later, an echocardiogram revealed a moderate pericardial effusion without elevation of acute-phase reactants or hemodynamic compromise. Her electrocardiogram revealed a broad QRS of 125 ms with RSR pattern and T wave inversion in leads V1 to V4. Indomethacin was started, but 48 hours later it was discontinued due to gastrointestinal intolerance, and prednisone (2 mg/kg per day) was initiated because of increasing serum creatinine levels e2
FIGURE 1 Patient 1 before IVIG therapy. Subcostal echocardiographic view reveals a moderate to severe global pericardial effusion that is more intense behind the atria (arrow). No signs of hemodynamic compromise were noted during the examination. LA, left atrium; LV, left ventricle; PE, pericardial effusion; RA, right atrium.
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CASE REPORT
and anti–intercalated disk autoantibodies, as well as antinuclear antibodies.19,20 In addition, the analysis of pericardial effusions reveals the presence of proinflammatory cytokines, including IL-6, IL-8, and interferon-g.21
FIGURE 2 Patient 2 before IVIG therapy. Subcostal echocardiographic view reveals a moderate pericardial effusion on the right side of the RV and above the LV. There was no chamber compression during the study. LV, left ventricle; PE, pericardial effusion; RV, right ventricle.
the administration of a second 2-g/kg dose of IVIG, the patient developed severe headache and malaise. The effusion, however, resolved and prednisone was discontinued in February 2013. In March, a small recurrence was noted. It was managed with small doses of prednisone (,0.2 mg/kg per day), which did not require further administration of IVIG for its control. This time the effusion resolved quickly, allowing discontinuation of prednisone in July and of colchicine 3 months later.
DISCUSSION RP is a chronic disease characterized by recurrent episodes of fever, chest pain, pericardial friction rubs, electrocardiographic changes, and pericardial effusion. Laboratory tests usually reveal leukocytosis and elevated acute-phase reactants. Relapses may present as an intermittent (symptom-free intervals longer than 6 weeks without therapy) or as an incessant type (discontinuation or attempts to taper off treatment result in early reappearance or worsening
of symptoms), as happened to our 2 patients.16 Recurrences develop in up to 36% of pediatric patients after the first episode of idiopathic acute pericarditis1 and in 50% of children after pericardial injury.3 Age at the time of cardiac surgery is a major factor associated with the development of postpericardiotomy syndrome in pediatric patients. For undetermined reasons, younger children rarely present this complication.17 Post– cardiac injury syndrome develops after pericardial damage caused by cardiac surgery, accidental trauma, or post– myocardial infarction. Much less common causes of RP include certain rheumatic conditions (systemic juvenile idiopathic arthritis, systemic lupus erythematosus) and autoinflammatory diseases (familial Mediterranean fever, TNF receptor– associated periodic syndrome).2 The pathogenesis of the disease is unknown. The most commonly accepted theory is that RP represents an autoimmune phenomenon.18 Patients with the disease have circulating anti–heart
This theory might explain both idiopathic and post–cardiac injury pericarditis. In the first group, a virus could trigger an autoimmune process through a mechanism of molecular mimicry. In the latter, surgery, trauma, or infarction would expose or release cardiac autoantigens and stimulate an immune response. An additional hypothesis that could explain some cases is that recurrent pericarditis represents an autoinflammatory disease due to a genetically determined dysfunction of the innate immune system that causes a dysregulation of the inflammatory process.22,23 Serosal inflammation is a common feature of familial Mediterranean fever and TNF receptor– associated periodic syndrome, and recurrent pericarditis might be the only clinical manifestation at disease onset.24,25 The mainstay of therapy is nonsteroidal antiinflammatory drugs (aspirin, ibuprofen, or indomethacin) for 10 to 14 days with additional colchicine (0.5–1 mg/day) for 6 months.4 If there is intolerance or no response, patients could receive lowdose steroids (0.2–0.5 mg/kg per day). Paradoxically, for this indication, steroids appear to be beneficial only at low doses; in fact, corticosteroids at high doses ($1 mg/kg per day) seem to increase the risk of recurrences.2–4,26 This stepwise approach controls the disease in most patients. There is a small group of patients, however, who are refractory to conventional therapy, such as the 2 presented in this report. In such cases, different immunosuppressive or immunomodulatory drugs have been used on the basis of the suspected autoimmune pathogenesis of the disease, including azathioprine,2–4 methotrexate,5 and, more recently, anti–IL-1
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DEL FRESNO et al
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Male
Male
Male
Male
6
7
8
9
Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Postpericardiotomy syndrome Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Idiopathic recurrent pericarditis Postpericardiotomy syndrome Idiopathic recurrent pericarditis Postpericardiotomy syndrome Postpericardiotomy syndrome
Diagnosis
4
4
35
47
37
22
69
42
30
29
27
12
11
21
28
5
1
6
7
3
6
5
4
6
3
6
8
15
4
5
5
?
19 29
?
Number of Relapses Before IVIG
30
Age at Onset, years
IBU 30 mg/kg per day, COL 0.75 mg/d, PDN 2 mg/kg per day, MTX
COL 0.5 mg/d, PDN 2 mg/kg per day
IBU 1.8 g/d, IND 150 mg/d, COL, PDN 5 mg/d
IND 150 mg/d, ASA 3 g/d, COL
ASA 1.5 g/d, IBU 1.2 g/d, COL, PDN 50 mg/d
IBU 2 g/d, COL, PDN 25 mg/d
IND 150 mg/d, COL, PDN, AZA
IND 150 mg/d, IBU 1.6 g/d, COL, PDN 50 mg/d
ASA 1.5 g/d, IND 150 mg/d, COL, PDN 25 mg/d, MTX
IND 50–100 mg/d, PDN 25 mg/d, MTX, CSA
ASA 1.6 g/d, COL, PDN 35 mg/d, AZA
COL 1 mg/d, PDN 50 mg/d, MTX 15 mg/s, CSA 4 mg/kg per day, AZA 150 mg/d ASA 75 mg/kg per day, PDN 2 mg/kg per day
ASA 1.6 g/d, COL 1 mg/d, PDN 50 mg/d
ASA 3.2 g/d, COL 1 mg/d, PDN 50 mg/d
ASA 4–6 g/d, COL 1 mg/d, PDN 75 mg/d, AZA 150 mg/d, CSA 300 mg/d, CYC 100 mg/d COL 1 mg/d, PDN 50 mg/d, MPIV 160 mg/d 3 3 d, CSA, CYC, MTX COL 1 mg/d, PDN 50 mg/d
Treatments Before IVIGa Number of Cycles 1 1 7 7 ? ($5) 9 1 3 1 1 2 1 1 1 1 2 5 3
Dose/Cycle
0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.4 g/kg per day 3 5 d 0.4 g/kg per day 3 5 d 0.4 g/kg per day 3 5 d 0.4 g/kg per day 3 5 d 2 g/kg per day 31 d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.5g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 0.5 g/kg per day 3 5 d 2 g/kg per day 3 1 d 0.4 g/kg per day 3 4 d (1 cycle), 2 g/kg per day 3 1 d (2 cycles)
11
13
24
24
12
24
12
36
96
84
156
54
?
?
12
20
32
42
Monitored Time Free From Relapses, months
Malaise, headache
None
None
None
None
None
None
None
None
None
None
Mild headache None
None
None
None
None
None
Adverse Effects
ASA, acetyl salicylic acid; AZA, azathioprine; COL, colchicine; CSA, cyclosporine A; CYC, cyclophosphamide; IBU, ibuprofen; IND, indomethacin; PDN, prednisone; MPIV, intravenous methylprednisolone; MTX, methotrexate; sc, subcutaneous; ?, data not available. a Treatments before IVIG: It is shown highest doses for each treatment.
Male
Female
5
2
Female
4
Female
Male
3
1
Female
2
del Fresno (2013)
Male
1
Male
4
Moretti (2013)
Male
3
Female
Male
2
1
Male
Female
2
1
Male
Gender
1
Patient Number
Wendelin (2008)
Peterlana (2005)
Tona (2003)
Author (Year)
TABLE 1 Previous Case Reports on RP Treated With IVIG
CASE REPORT
receptor antagonist,6–10 anti-TNF agents11 and human IVIG.12–15 With regard to classic immunosuppressive agents, several pediatric case reports, including our patient number 2, suggest that methotrexate is not effective in the treatment of RP.3,11–13,15 Azathioprine has a similar lack of effect in children,11–13,15 although in adults it has proven to be useful.27 Therefore, although both immunosuppressant agents are recommended in most reviews, there are no robust clinical data on their precise role in the management of pediatric disease. More recently, biological therapy has been used to treat this condition. Several reports support the effectiveness of anti–IL-1 (IL-1 receptor antagonist) therapy. In all cases, the concentration of acute-phase reactants was very high when reported and the response to therapy was often dramatic, within the first few days after the initiation of the drug.6–10 There is only 1 case series reporting on 3 patients with RP who re-
ceived anti-TNF therapy.11 It revealed that anti-TNF drugs might be efficacious but require months to show clinical effect and years of continuous therapy. A literature review revealed that in the last 10 years only 4 series have reported the efficacy of IVIG in the therapy for RP. The numbers in those series were small, except from 1 report on a series of 9 patients (Table 1). All the studies showed that IVIG had rapid beneficial effects in patients, independently of their gender, age, diagnosis, dose, and protocol of administration. In most cases, a clinical response was obvious after 1 to 3 doses. Adverse effects were unusual and not serious (Table 1). The major limitations of IVIG include its cost and its route of administration. The use of single monthly doses and its administration in pediatric day hospitals, however, facilitate its use.
inhibition of phagocytosis; blockade of immune-complex access to FcgR; increased expression of FcgRIIB on effector macrophages; Fab binding to anti-idiotypes, specific cytokines, and autoantibodies; and reduction in complement deposition. These actions result in decreases in the production of proinflammatory cytokines; the downregulation of adhesion molecule, chemokine, and chemokine receptor expression; and the neutralization of circulating autoantibodies.
A recent review28 suggested different mechanisms to explain the efficacy of IVIG in autoimmune diseases, including
In conclusion, although the use of IVIG at high doses currently represents an offlabel indication, an increasing number of reports indicate that it is an effective and safe alternative for those patients whose pericarditis is refractory to conventional therapy or who become steroiddependent. Our small series supports that this treatment represents another option in these cases. Prospective randomized studies will be required to fully determine its role in the management of thisdifficultand often frustrating disease.
(anakinra): an unrecognized autoinflammatory disease? Arthritis Rheum. 2009;60(1):264–268 Cantarini L, Lucherini OM, Cimaz R, Galeazzi M. Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment. Clin Exp Rheumatol. 2010;28(5):802 Vassilopoulos D, Lazaros G, Tsioufis C, Vasileiou P, Stefanadis C, Pectasides D. Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). Int J Cardiol. 2012;160(1):66–68 Camacho-Lovillo M, Méndez-Santos A. Successful treatment of idiopathic recurrent pericarditis with interleukin-1 receptor antagonist (anakinra). Pediatr Cardiol. 2013;34 (5):1293–1294 Scardapane A, Brucato A, Chiarelli F, Breda L. Efficacy of an interleukin-1b receptor antagonist (anakinra) in idiopathic recurrent pericarditis. Pediatr Cardiol. 2013;34(8):1989– 1991
11. Nieto González JC, Monteagudo Saez I, López-Longo FJ, Serrano B, Mata Martínez C, Carreño Pérez L. Idiopathic recurrent pericarditis treated successfully with tumour necrosis factor alpha blocking agents (anti-TNF-a). Clin Exp Rheumatol. 2013;31(5): 776–778 12. Tona F, Bellotto F, Laveder F, Meneghin A, Sinagra G, Marcolongo R. Efficacy of highdose intravenous immunoglobulins in two patients with idiopathic recurrent pericarditis refractory to previous immunosuppressive treatment. Ital Heart J. 2003;4(1): 64–68 13. Peterlana D, Puccetti A, Simeoni S, Tinazzi E, Corrocher R, Lunardi C. Efficacy of intravenous immunoglobulin in chronic idiopathic pericarditis: report of four cases. Clin Rheumatol. 2005;24(1):18–21 14. Wendelin G, Fandl A, Beitzke A. High-dose intravenous immunoglobulin in recurrent postpericardiotomy syndrome. Pediatr Cardiol. 2008;29(2):463–464
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DEL FRESNO et al
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Intravenous Immunoglobulin Therapy for Refractory Recurrent Pericarditis M. Rosa del Fresno, Julio E. Peralta, Miguel Ángel Granados, Eugenia Enríquez, Nerea Domínguez-Pinilla and Jaime de Inocencio Pediatrics; originally published online October 6, 2014; DOI: 10.1542/peds.2013-3900 Updated Information & Services
including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/early/2014/09/30 /peds.2013-3900
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