Case Presentation

22-year-old male presents to the rheumatology department for evaluation of Idiopathic Recurrent Pericarditis (IRP). He had his first episode of diagnosed pericarditis 3 years prior, with no prodromal viral illness. He described positional chest pain, and was found to have diffuse ST elevations on ECG, along with moderate pericardial effusion on echocardiogram and elevated inflammatory markers. He was initially treated with NSAIDs and colchicine with relief. He had 3 recurrences in the first year and was started on glucocorticoids. He hasn't been able to wean off of the steroids and has since developed elevated blood pressure, weight gain and borderline diabetes. He has no other evidence of a systemic autoimmune or autoinflammatory condition such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis. He has no family history of IRP or another rheumatologic condition. On physical exam he is cushingoid in appearance, and has no evidence of synovitis. He remains chest pain free as long as he is on prednisone 10 mg daily or higher doses. He comes to the department of rheumatology for evaluation of additional treatment options.

Idiopathic Recurrent Pericarditis Background

In the United States the vast majority of pericarditis episodes are considered idiopathic and often presumed to be post viral¹. Once the diagnosis of pericarditis is made, it is categorized based on the duration of symptoms. If a patient has one episode of pericarditis with symptoms present for less than 1 month, it is referred to as acute pericarditis. If the symptoms last for more than 4 months, it is classified as incessant. If the patient is free of symptoms for 4 weeks and then there has a return of symptoms along with objective evidence of pericarditis, then it is considered recurrent pericarditis². The time frames given for these categories are arbitrary, but it is important to be able to classify a patient as recurrent or not.

In general, after an initial occurrence of acute pericarditis, the probability of developing another recurrence within 18 months is 15-30%,^{3, 4} and in patients who have 1 recurrence there is a 25-50% chance of additional recurrences⁵. At this point it is difficult to predict which patients will have a greater likelihood of recurrence, although a few studies give us clues. One study showed myocardial involvement may portent a better prognosis in terms of recurrence risk. The study consisted of 486 patients with acute pericarditis, myocardial involvement was associated with a decreased risk of recurrence compared to pericarditis alone (11% vs 32%)⁶. Another study found the use of corticosteroids in pericarditis prior to use of colchicine increases the risk of recurrence as well as the length required to treat the recurrence⁷. Other risk factors for recurrence that have been established is poor response to non-steroidal anti-inflammatories after 1 week of treatment, as well as persistently elevated high-sensitivity C-reactive protein⁸.

The morality rate of pericarditis is low, and complications such as tamponade and constrictive pericarditis occur in less than 1%⁹. The morbidity of IRP; however, is high, as the patients are often subjected to prolonged courses of glucocorticoids and non-steroidal anti-inflammatory with the multiple associated side effects.

Evidence of Autoimmune Etiology

Multiple lines of evidence suggest an immune-mediated etiology to IRP. An immune response causing the inflammation seen in pericarditis was suggested with the observation of pericarditis occurring weeks after a viral infection¹⁰. Other precipitating injuries can also result in pericarditis such as cardiac trauma from pacemaker placement or myocardial infarction. Anti-heart and anti-intercalated disk antibodies have been shown to have an association with pericarditis, but it's unclear whether these are pathogenic or an epiphenomenon, as the antibodies are also found in patients with other types of cardiac injury including dilated cardiomyopathy and myocarditis¹¹. IRP is associated with other chronic autoimmune diseases such as Systemic Lupus Erythematosus (SLE)¹². There is an association with ANA and IRP; in one study 43% of patients with IRP had a positive ANA versus 9% of healthy controls¹³.

Other lines of evidence for the etiopathogenesis of IRP suggest an autoinflammatory etiology. Autoinflammatory conditions are predominantly driven by deregulation of the innate immune system. Suggestion of an autoinflammation etiology arises because of the similar phenotype of seemingly unprovoked episodes of inflammation in IRP and Familial Mediterranean Fever (FMF) or tumor necrosis factor receptor-associated periodic syndrome (TRAPS). FMF is an autosomal recessive disorder caused by a mutation of the Mediterranean fever gene (MEFV) which encodes pyrin¹⁴. TRAPS is an autosomal dominant autoinflammatory disorder and it is caused by mutations in the TNFRSF1A gene which codes for a tumor necrosis factor (TNF)-α receptor. Both cause systemic inflammation, and patients experience, fevers, serositis, joint pain, and abdominal pain, yet they differ in regards to their duration, associated symptoms and responses to treatment options such as colchicine and prednisone¹⁵ .

There is an association of autoinflammatory diseases and recurrent pericarditis, as many of the patients with an autoinflammatory disease have recurrent pericarditis. In one series of 158 patients with the diagnosis of TRAPS, 12% of the patients had been diagnosis with pericarditis¹⁶. In another case series of 89 patienst with TRAPS, 27% of the patients had pericardial and or pleural inflammation¹⁵. In a large registry of FMF patients in Turkey, out of 2,468 patients, 2.6% had at least 1 episode of pericarditis¹⁷. Another study of 30 patients with FMF, an echocardiogram was performed and 26% of the patients were found to have pericardial involvement with the majority of patients being asymptomatic¹⁸.

The above studies demonstrated a link between two established autoinflammatory conditions and recurrent pericarditis. What about patients with recurrent pericarditis and no systemic symptoms? In a study by Cantarini et al, 131 patients with Idiopathic Recurrent Pericarditis were evaluated for the gene mutation that causes TRAPS (TNFRSF1A) and 6% of the patients with IRP were found to have a mutation in the gene¹⁹. Importantly, these patients did not have systemic symptoms suggesting an underlying autoinflammatory syndrome. This suggests that in a subset of patients, IRP may represent an incomplete phenotype of an underlying autoinflammatory condition.

Response to Rheumatologic Medications

Further evidence of the underlying immune mediated etiology of IRP is the response seen to rheumatic medications such as NSAIDs, Colchicine, Corticosteroids, azathioprine, IVIG and most recently interleukin 1 inhibitors (IL-1)such as anakinra.

Colchicine inhibits microtubule polymerization as well as inhibits factors that induce chemotaxis in neutrophils. It also inhibits expression of E-selectin on endothelial cells which is required for the adhesion of neutrophils and subsequent chemotaxis²⁰. Colchicine is used in multiple rheumatologic diseases including FMF, calcium pyrophosphate disease, gout, behcet's disease and recurrent pericarditis. It is one of the first line agents used in treating patients with both acute pericarditis as well as IRP^{2, 4}.

Promising agents in the treatment of IRP is the IL-1 receptor antagonists. IL-1 receptor antagonists are used for IRP because inflammation in IRP is driven by aberrant production of IL-1 through the cell's inflammasome. The inflammasome is a macromolecular structure that forms in the cytosole of innate immune cells. It is composed of sensor molecules that react to a variety of stimuli, including infections, reactive oxygen species, as well as monosodium urate crystals in gout. Once activated, the inflammasome generates IL-1 and IL-18 in response to the stimuli²¹. Inappropriate constitutive activation of the inflammasome is implicated in the pathophysiology of multiple autoinflammatory diseases including FMF²². Activation of inflammasome is being evaluated in the pathogenesis of IRP. There are multiple case reports and case series of patients with IRP who have had rapid successful responses to the IL-1 inhibitor anakinra^23-27.

Patient Evaluation

In evaluating a patient with IRP a thorough history for evidence of an underlying rheumatologic systemic disease is prudent. Testing for ANA in patients with IRP is not currently recommended, as we have seen many patients with IRP have a positive ANA but at this point, it would not change therapy unless there is a clinically high suspicion for SLE or another underlying systemic autoimmune condition. Testing for anti-heart and anti-intercalated disk antibodies is also not recommended at this time either as their clinical relevance is unclear. Asking about family history of fevers of unknown origin and episodic serositis is important in evaluating a patient's risk of having an underlying systemic autoinflammatory syndrome.

IRP is a disease of low mortality but high morbidity. Many of these patients are on prolonged immunosuppressant medications, placing them at risk for multiple side effects. Considering the medications used in treatment of these patients and the likely underlying immune-mediated etiology, it's paramount that collaboration exists between cardiologists and rheumatologists in taking care of these patients.

References

1. Imazio M, Gaita F, LeWinter M. Evaluation and Treatment of Pericarditis: A Systematic Review. JAMA. 2015 Oct 13;314(14):1498-506.
2. Imazio M, Adler Y, Charron P. Recurrent Pericarditis: Modern Approach in 2016. Curr Cardiol Rep. 2016 Jun;18(6):50,016-0727-8.
3. Imazio M, Bobbio M, Cecchi E, Demarie D, Demichelis B, Pomari F, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation. 2005 Sep 27;112(13):2012-6.
4. Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013 Oct 17;369(16):1522-8.
5. Imazio M, Bobbio M, Cecchi E, Demarie D, Pomari F, Moratti M, et al. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch Intern Med. 2005 Sep 26;165(17):1987-91.
6. Imazio M, Brucato A, Barbieri A, Ferroni F, Maestroni S, Ligabue G, et al. Good prognosis for pericarditis with and without myocardial involvement: results from a multicenter, prospective cohort study. Circulation. 2013 Jul 2;128(1):42-9.
7. Artom G, Koren-Morag N, Spodick DH, Brucato A, Guindo J, Bayes-de-Luna A, et al. Pretreatment with corticosteroids attenuates the efficacy of colchicine in preventing recurrent pericarditis: a multi-centre all-case analysis. Eur Heart J. 2005 Apr;26(7):723-7.
8. Imazio M, Brucato A, Maestroni S, Cumetti D, Dominelli A, Natale G, et al. Prevalence of C-reactive protein elevation and time course of normalization in acute pericarditis: implications for the diagnosis, therapy, and prognosis of pericarditis. Circulation. 2011 Mar 15;123(10):1092-7.
9. Imazio M, Cecchi E, Demichelis B, Ierna S, Demarie D, Ghisio A, et al. Indicators of poor prognosis of acute pericarditis. Circulation. 2007 May 29;115(21):2739-44.
10. Gold RG. Post-viral pericarditis. Eur Heart J. 1988 May;9 Suppl G:175-9.
11. Caforio AL, Brucato A, Doria A, Brambilla G, Angelini A, Ghirardello A, et al. Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis. Heart. 2010 May;96(10):779-84.
12. Tincani A, Rebaioli CB, Taglietti M, Shoenfeld Y. Heart involvement in systemic lupus erythematosus, anti-phospholipid syndrome and neonatal lupus. Rheumatology (Oxford). 2006 Oct;45 Suppl 4:iv8-13.
13. Imazio M, Brucato A, Doria A, Brambilla G, Ghirardello A, Romito A, et al. Antinuclear antibodies in recurrent idiopathic pericarditis: prevalence and clinical significance. Int J Cardiol. 2009 Aug 21;136(3):289-93.
14. Yoshioka K, Furumitsu Y, Sano T, Miyamoto T, Agematsu K. Acute pericarditis as the first manifestation of familial Mediterranean fever: a possible relationship with idiopathic recurrent pericarditis. Intern Med. 2014;53(15):1659-63.
15. Ravet N, Rouaghe S, Dode C, Bienvenu J, Stirnemann J, Levy P, et al. Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene. Ann Rheum Dis. 2006 Sep;65(9):1158-62.
16. Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014 Dec;73(12):2160-7.
17. Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005 Jan;84(1):1-11.
18. Dabestani A, Noble LM, Child JS, Krivokapich J, Schwabe AD. Pericardial disease in familial Mediterranean fever: an echocardiographic study. Chest. 1982 May;81(5):592-5.
19. Cantarini L, Lucherini OM, Brucato A, Barone L, Cumetti D, Iacoponi F, et al. Clues to detect tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among patients with idiopathic recurrent acute pericarditis: results of a multicentre study. Clin Res Cardiol. 2012 Jul;101(7):525-31.
20. Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015 Dec;45(3):341-50.
21. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015 Jul;21(7):677-87.
22. Gurung P, Kanneganti TD. Autoinflammatory Skin Disorders: The Inflammasomme in Focus. Trends Mol Med. 2016 Jul;22(7):545-64.
23. D'Elia E, Brucato A, Pedrotti P, Valenti A, De Amici M, Fiocca L, et al. Successful treatment of subacute constrictive pericarditis with interleukin-1beta receptor antagonist (anakinra). Clin Exp Rheumatol. 2015 Mar-Apr;33(2):294-5.
24. Jain S, Thongprayoon C, Espinosa RE, Hayes SN, Klarich KW, Cooper LT, et al. Effectiveness and Safety of Anakinra for Management of Refractory Pericarditis. Am J Cardiol. 2015 Oct 15;116(8):1277-9.
25. Lazaros G, Vasileiou P, Danias P, Koutsianas C, Vlachopoulos C, Tousoulis D, et al. Effusive-constrictive pericarditis successfully treated with anakinra. Clin Exp Rheumatol. 2015 Nov-Dec;33(6):945.
26. Lazaros G, Vasileiou P, Koutsianas C, Antonatou K, Stefanadis C, Pectasides D, et al. Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases. Ann Rheum Dis. 2014 Dec;73(12):2215-7.
27. Baskar S, Klein AL, Zeft A. The Use of IL-1 Receptor Antagonist (Anakinra) in Idiopathic Recurrent Pericarditis: A Narrative Review. Cardiol Res Pract. 2016;2016:7840724.

Keywords: Abdominal Pain, Anti-Inflammatory Agents, Non-Steroidal, Arthritis, Rheumatoid, Autoimmune Diseases, Blood Pressure, C-Reactive Protein, Cardiomyopathy, Dilated, Chest Pain, Cytoskeletal Proteins, Diabetes Mellitus, Electrocardiography, Endothelial Cells, Immunoglobulins, Intravenous, Immunosuppressive Agents, Inflammasomes, Interleukin-1, Interleukin 1 Receptor Antagonist Protein, Interleukin-18, Lupus Erythematosus, Systemic, Myocardial Infarction, Myocarditis, Pericardial Effusion, Pericarditis, Pericarditis, Constrictive, Polymerization, Prednisone, Reactive Oxygen Species, Receptors, Interleukin-1, Receptors, Tumor Necrosis Factor, Type I, Risk Factors, Serositis, Synovitis, Tumor Necrosis Factor-alpha, Uric Acid, Weight Gain

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