Complicated Pericarditis

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 68, NO. 21, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2016.07.785

FOCUS SEMINAR: PERICARDIAL AND MYOCARDIAL DISEASE STATE-OF-THE-ART REVIEW

Complicated Pericarditis Understanding Risk Factors and Pathophysiology to Inform Imaging and Treatment Paul C. Cremer, MD,a Arnav Kumar, MD,a Apostolos Kontzias, MD,b Carmela D. Tan, MD,c E. Rene Rodriguez, MD,c Massimo Imazio, MD,d Allan L. Klein, MDa

ABSTRACT Most patients with acute pericarditis have a benign course and a good prognosis. However, a minority of patients develop complicated pericarditis, and the care of these patients is the focus of this review. Specifically, we address risk factors, multimodality imaging, pathophysiology, and novel treatments. The authors conclude that: 1) early high-dose corticosteroids, a lack of colchicine, and an elevated high-sensitivity C-reactive protein are associated with the development of complicated pericarditis; 2) in select cases, cardiovascular magnetic resonance imaging may aid in the assessment of pericardial inflammation and constriction; 3) given phenotypic similarities between recurrent idiopathic pericarditis and periodic fever syndromes, disorders of the inflammasome may contribute to relapsing attacks; and 4) therapies that target the inflammasome may lead to more durable remission and resolution. Finally, regarding future investigations, the authors discuss the potential of cardiovascular magnetic resonance to inform treatment duration and the need to compare steroid-sparing treatments to pericardiectomy. (J Am Coll Cardiol 2016;68:2311–28) © 2016 by the American College of Cardiology Foundation.

C

ompared with other cardiovascular diseases,

The improved understanding of complicated peri-

pericarditis has garnered relatively little in-

carditis is anchored in recent clinical trials, bolstered

terest, in part due to the appropriate focus

by better characterization of pericarditis with multi-

on reducing cardiovascular mortality. In recent de-

modality imaging, and better delineation of the un-

cades, however, as mortality related to cardiac dis-

derlying pathophysiology through molecular studies.

ease has continued to decrease (1), morbidity has

Therefore, given the need for improved diagnosis and

become increasingly important. This trend coincides

management of patients with complicated pericar-

with an increased emphasis on pericarditis, a dis-

ditis, this review focuses on the following questions:

ease often characterized by significant morbidity. Although most patients with acute pericarditis will have resolution, some will develop incessant, recurrent, chronic, or constrictive pericarditis. Many of these patients experience a debilitating chronic disease, and to simplify presentation throughout this review, are referred to as having

complicated

1. Which patients are at risk for complicated disease after acute pericarditis? 2. Which

patients

with

complicated

3. What is the pathological progression of pericarditis, and how is autoinflammatory pericarditis distinct from autoimmune pericarditis?

pericarditis. Listen to this manuscript’s audio summary by JACC Editor-in-Chief

From the aDepartment of Cardiovascular Imaging, Center for the Diagnosis and Treatment of Pericardial Disease, Heart and

Dr. Valentin Fuster.

Vascular Institute, Cleveland Clinic, Cleveland, Ohio; c

pericarditis

benefit from multimodality imaging?

b

Department of Rheumatology, Cleveland Clinic, Cleveland, Ohio;

Department of Anatomic Pathology, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio; and the

d

Cardiology

Department, Maria Vittoria Hospital and Department of Public Health and Pediatrics, University of Torino, Torino, Italy. Dr. Imazio has received institutional research grants from Acarpia and SOBI. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received April 28, 2016; revised manuscript received July 5, 2016, accepted July 12, 2016.

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Complicated Pericarditis

ABBREVIATIONS

4. What are the established treatments for

AND ACRONYMS CMR = cardiac magnetic resonance

CT = computed tomography ECG = electrocardiogram IVIG = intravenous immunoglobulin

MI = myocardial infarction STIR = short-tau inversion recovery

recurrences of pericarditis has provided a useful

pericarditis, and what are the emerging

framework for the conduct of clinical trials (10–12).

therapies for patients with complicated

ETIOLOGY AND EPIDEMIOLOGY OF PERICARDITIS.

disease?

In the United States and Western Europe, most epi-

IDENTIFYING THE PATIENT WHO IS AT RISK FOR PROGRESSION BEYOND LIMITED ACUTE PERICARDITIS

sodes of pericarditis (80% to 90%) are idiopathic and are often presumed to be post-viral (3). Conversely, tuberculosis is the most common cause of pericarditis in the developing world (13,14). Increasing causes of pericarditis are the post-cardiac injury syndromes,

Acute pericarditis is common, and when

which include pericarditis after myocardial infarction

treated with appropriate anti-inflammatory

(MI), percutaneous coronary intervention, electro-

medications, most symptoms resolve within

physiology procedures, or post-pericardiotomy (15).

days to weeks (2,3). However, a significant minority

Less common causes of pericarditis include autoim-

of patients will either experience adverse events

mune diseases, chest irradiation, and active cancer.

related to the initial presentation or will be debili-

To establish the cause of pericarditis, an extensive

tated by recurrent attacks. To aid in the identification

laboratory analysis may increase the yield (16), but is

of these at-risk patients, an understanding of the

not routinely recommended (5). Currently, identifi-

epidemiology, etiologies, and classifications of peri-

cation of the putative viral agent does not inform

carditis is necessary. With this background, risk fac-

prognosis or management. Similarly, testing for

tors for specific complications are better appreciated.

antinuclear antibodies is not recommended, as low

DEFINING THE STAGES OF PERICARDITIS. Pericar-

titer levels are common and nonspecific (17). In pa-

ditis remains a clinical diagnosis with hallmark fea-

tients with a rheumatic disease, involvement of other

tures, including precordial chest pain that is worse

organs is usually apparent before the onset of peri-

with inspiration and when supine, characteristic

carditis (18,19).

ST-segment elevation and PR deviation on electro-

For the clinician, a central initial question is the

cardiogram (ECG), a pericardial friction rub, and

overall likelihood that a patient will develop compli-

a pericardial effusion that is more than trivial (4). A

cated pericarditis. After an episode of acute pericar-

diagnosis of pericarditis requires 2 of these 4 char-

ditis,

acteristics, usually chest pain in conjunction with

pericarditis or a first recurrence within 18 months is

either ECG changes or a pericardial effusion (5–7).

generally 15% to 30% (10,20). In patients who have

Supportive findings, although not included in the

had an initial recurrence of pericarditis, additional

diagnostic criteria, include elevated inflammatory

recurrence occurs in 25% to 50% (11,12). Likewise,

markers or other imaging evidence of pericardial

further exacerbations will develop in 20% to 40% of

inflammation (5,8,9).

patients

Once diagnosed, pericarditis is categorized ac-

the

probability

after

2

or

of

more

developing

previous

incessant

recurrences

(Figure 1) (21).

cording to the duration of symptoms. Pericarditis that

These data regarding the incidence of recurrence

persists for more than 4 to 6 weeks is termed inces-

originate from randomized trials including approxi-

sant, and the presence of symptoms for >3 months is

mately 800 patients, and 80% of patients in these

considered chronic pericarditis. If a patient is free of

trials

symptoms for at least 4 to 6 weeks, relapse is referred

(11,12,20,21). A separate question relates to the risk of

to as recurrent pericarditis (5). As will be discussed,

developing a first episode of pericarditis after cardiac

this distinction may be relevant, as the underlying

injury. In the current era of early reperfusion for

had

an

idiopathic

cause

of

pericarditis

pathophysiology of a patient with idiopathic recur-

acute MI, late pericarditis (Dressler’s syndrome) is

rent pericarditis is likely different from a patient with

uncommon (<0.5%) (22,23). Early pericarditis after

chronic pericarditis related to autoimmune disease.

ST-segment elevation MI has also decreased, with an

In general, however, these distinct time frames are

incidence of approximately 4%, although it is more

admittedly arbitrary and not necessarily mutually

common in patients who present after at least 6 h of

exclusive. A patient with recurrent pericarditis may

symptoms (14%) and in patients with percutaneous

also develop incessant or chronic disease if the

coronary intervention failure (23%) (23). After peri-

symptoms are not controlled. Nonetheless, the num-

cardiotomy, pericarditis is more common, with a

ber and duration of attacks does reflect the morbidity

likely incidence between 10% and 25% (24,25).

of the disease. In addition, the distinction between

An additional risk of pericarditis is the develop-

acute pericarditis, a single recurrence, and multiple

ment of constrictive pathophysiology. In constrictive

Cremer et al.

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Complicated Pericarditis

F I G U R E 1 Incidence of Short-Term Adverse Events and Complicated Disease After an Episode of Acute Pericarditis

Resolution

~15% (31)

Myocardial Involvement A

COMPLICATED

~1-2% (20,30) Acute Pericarditis

Cardiac Tamponade B

Recurrent Pericarditis C

PERICARDITIS

?

~15-30% (10,20)

?

D

Reversible Constrictive Pericarditis

?

? E

? Chronic Constrictive Pericarditis ~1-2% (27)

Multiple Recurrences ~6% (12)

After an episode of acute pericarditis, a minority of patients will develop short-term adverse events, including cardiac tamponade or concomitant myocarditis. Delayed enhancement imaging may delineate associated subepicardial myocardial involvement (A), and transthoracic echocardiography quickly defines the extent of a pericardial effusion (B). With appropriate treatment of acute pericarditis, the long-term prognosis is generally good. However, a subset of patients will develop complicated pericarditis, and a few of these patients will have multiple recurrences. In select cases, delayed enhancement imaging is useful and may demonstrate increased pericardial signal (C). Rarely, patients will develop chronic constrictive pericarditis requiring pericardiectomy, although the incidence of reversible constrictive pericarditis is unknown. Early inspiratory septal shift may aid in the diagnosis of constrictive pericarditis (D) (Online Videos 1, 2, 3, and 4), and the extent of calcification can be defined with computed tomography (E).

pericarditis, diastolic heart failure results from peri-

acute pericarditis is uncommon (1%), and mortality is

cardial restraint that decreases the compliance of the

most often not related to pericarditis (29).

cardiac chambers (26). The eventual development of

Conversely, a direct complication of pericarditis

constrictive pericarditis that is severe enough to

includes extension of the inflammation through the

require surgery after an episode of acute idiopathic

pericardial layers and epicardial fat to involve the

pericarditis is rare, and likely occurs in a minority of

myocardium. When the inflammation predominantly

patients (w1%) (27). However, constrictive pericar-

involves the pericardium, it is termed myoper-

ditis that responds to anti-inflammatory therapy is

icarditis, in distinction to perimyocarditis, in which

likely more common (28), although the incidence of

myocardial inflammation supersedes the pericarditis.

this reversible constrictive pericarditis is unknown.

Clinically, both syndromes require an abnormal troponin level. In perimyocarditis, patients will also

ADVERSE EVENTS FROM ACUTE PERICARDITIS AND

have focal or globally reduced left ventricular systolic

RISKS FOR THE DEVELOPMENT OF COMPLICATED

function (30).

PERICARDITIS. In a patient with acute pericarditis,

Myocardial involvement occurs in approximately

risk stratification is dichotomized into the likelihood

15% of patients with acute pericarditis, and risk fac-

of adverse events from the initial attack and the

tors

likelihood of developing complicated pericarditis in

arrhythmia, and ST-segment elevation on ECG. Of

the ensuing months to years. Even though morbidity

note, myopericarditis generally has a benign course

related to the disabling pain of acute pericarditis may

and is not associated with an increased risk of

be substantial, death in patients hospitalized for

recurrent

include

younger

pericarditis

age,

or

male

pericardial

sex,

fever,

tamponade.

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T A B L E 1 Risks for Developing Complicated Disease After an Episode of

Acute Pericarditis

Treatment-related variables with increased risk in multivariable models

anti-inflammatory treatment (Figure 1) (28). Overall, a history of idiopathic pericarditis remains the most common diagnosis in patients who have a peri-

Corticosteroid use

cardiectomy for constriction, given the predominant

Lack of colchicine

prevalence

of

this

condition,

although

pericar-

diectomy after prior cardiac surgery is increasing (34).

Patient-related variables with increased risk in multivariable models Incomplete response to NSAIDs

Among patients who have a pericardiectomy, those

Elevated high-sensitivity C-reactive protein

with idiopathic pericarditis have the best prognosis.

Patient-related variables without increased risk in multivariable models Younger age

Patients with post-pericardiotomy syndrome have an intermediate outcome, and patients with a

Sex

history of radiation heart disease have the highest

Pericardial effusion

mortality (34). Adapted from data in Imazio et al. (20) and Imazio et al. (33). NSAID ¼ nonsteroidal anti-inflammatory drug.

THE POTENTIAL VALUE OF MULTIMODALITY IMAGING IN COMPLICATED PERICARDITIS

Moreover,

most

patients

with

left

ventricular

dysfunction will have recovery (30,31) (Figure 1).

Most patients with acute pericarditis will have a limited and uncomplicated illness, and echocardiog-

Although the long-term outcome is favorable for

raphy is the first and only imaging test necessary

these patients, they are generally observed in the

(Central Illustration) (35). In this setting, because

hospital. Likewise, patients with large effusions are

many patients have been diagnosed according to

also admitted, and hospitalization can be considered

characteristic chest pain and ECG changes, echocar-

in certain patients with fever, a subacute course,

diography is performed primarily for risk stratifica-

trauma, anticoagulation, or a failure of outpatient

tion. Specifically, echocardiography may identify a

anti-inflammatory agents (5,6). After the patient has

pericardial effusion, evidence of pericardial tampo-

been risk stratified according to the likelihood of

nade, wall motion abnormalities, or features of peri-

developing a short-term adverse event, the next

cardial constriction (Figure 1B) (8).

question relates to the risk of later developing

After this initial risk stratification, only a minority

complicated pericarditis. These risks can be catego-

of patients will develop complicated pericarditis.

rized as either patient- or treatment-related (Table 1).

Some of these patients may benefit from further im-

In regard to treatment, early use of corticosteroids

aging, primarily directed at 2 questions that may

has been consistently associated with recurrence

remain unresolved after clinical evaluation and

(32,33), and relapse is especially hastened with high-

echocardiography. First, does the patient still have

dose short courses. Colchicine has reduced re-

significant pericardial inflammation? Second, does

currences of pericarditis and has become a mainstay

the patient have constrictive pathophysiology? In

of treatment. In regard to patient-related factors, at

general, compared with echocardiography, cardiac

1 week after acute pericarditis, an incomplete

magnetic resonance (CMR) has a predominant role in

response to nonsteroidal anti-inflammatory agents

the evaluation of pericardial inflammation. For

and a persistently elevated high-sensitivity C-reac-

constriction, CMR is typically an adjuvant test when

tive protein (CRP) are both associated with risk of

echocardiographic data are ambiguous.

recurrence (33). Of note, other patient-related fac-

To appropriately select patients with complicated

tors, including younger age, female sex, and peri-

pericarditis for CMR to address either of these ques-

cardial effusion, have not been associated with

tions, clinicians should understand the sequences

recurrent pericarditis (33).

used to evaluate the pericardium and also how these

The risks for developing constrictive pericarditis

images correlate with the progressive pathology of

are less well defined, primarily because the diagnosis

pericarditis. Even though a detailed discussion of

is less common and the epidemiology is not as

CMR is beyond the scope of this review (36), the

well understood. Moreover, most data relate to pa-

limitations of current techniques should be empha-

tients who have had a pericardiectomy, and these

sized (Table 2). Nonetheless, despite these limita-

patients may represent only a subset of patients

tions, emerging evidence indicates that the stage and

who have constrictive pathophysiology. In some pa-

severity of pericardial inflammation is better assessed

tients, the constrictive pathophysiology may not be

with CMR. This improved assessment may subse-

severe enough to require surgery, whereas other

quently lead to better care for the patient with

patients may have constriction that resolves with

complicated pericarditis.

Cremer et al.

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Complicated Pericarditis

C ENTR AL I LL U STRA T I O N Complicated Pericarditis: Clinical Stages of Pericarditis With Imaging and Treatment Considerations

Clinical Stages of Pericarditis With Imaging and Treatment Considerations Stage of pericarditis

Acute

First recurrence

Multiple recurrences

Imaging

• Echocardiogram for pericardial

• Echocardiogram for constriction

Same as for

myocardial involvement, constriction

Colchicineresistant or steroid dependent Same as for

• CMR in select cases for pericardial

• NSAIDS (weeks)

• NSAIDS

• Colchicine (3 mos.)

• Colchicine

Same as for Plus possible CT for extent of and preoperative planning

or constriction Treatment

Constrictive

• NSAIDS + Colchicine + Prednisone (>6 mos., taper steroid as tolerated) • Consider steroidsparing agent (warrants further study)

• NSAIDS + Colchicine + Prednisone + Steroidsparing agent

• Intensify medical therapy • Pericardiectomy if “burnt out”

taper steroid as tolerated) • Consider pericardiectomy (warrants further study)

Cremer, P.C. et al. J Am Coll Cardiol. 2016;68(21):2311–28.

All patients with acute pericarditis should have an echocardiogram for short-term risk stratification, and subsequent echocardiograms can be performed if there is concern for constrictive pericarditis. In recurrent pericarditis, CMR imaging has an emerging role to assess for pericardial inflammation if the clinical evaluation is equivocal and to assess for constrictive pathophysiology if the echocardiogram is indeterminate. CT is primarily employed to assess pericardial calcification and for preoperative planning. The mainstay of treatment is NSAIDs and colchicine with the addition of low-dose corticosteroids in patients with multiple recurrences. Steroidsparing agents can be added in refractory cases. Early use of steroid-sparing agents and pericardiectomy for recurrent pericarditis may be beneficial and warrants further study. CMR ¼ cardiac magnetic resonance; CT ¼ computed tomography; LV ¼ left ventricle; NSAID ¼ nonsteroidal anti-inflammatory drug; RV ¼ right ventricle.

FORM AND FUNCTION IN MULTIMODALITY IMAGING

echocardiography is often inferior when compared

OF THE PERICARDIUM. In a CMR evaluation for

with CT and CMR, although hemodynamic assess-

pericardial disease, morphological characteristics are

ment with echocardiography is excellent (8).

complemented by insight into the hemodynamic

In pericardial disease, the noninvasive hemody-

consequences of pericardial constraint. In contrast,

namic evaluation relates to the diagnoses of pericar-

cardiac computed tomography (CT) generally pro-

dial tamponade and constriction. Echocardiography

vides only anatomic information. For example, CT

is essential in the rapid assessment of a patient with

may occasionally aid in the percutaneous approach to

suspected pericardial tamponade, and CMR has no

pericardiocentesis and may also help with surgical

role in these patients. In the stable patient with sus-

planning prior to pericardiectomy (37). Moreover, CT

pected constrictive pathophysiology, echocardiogra-

is particularly well-suited to define the extent of

phy and CMR data may be complementary, although

pericardial calcification (Figure 1E), but generally

redundant data collection should be avoided. Echo-

provides limited and indirect hemodynamic infor-

cardiographic features of constriction include respir-

mation

ophasic septal shift, annulus reversus or paradoxus

(38).

delineation

Alternatively, of

pericardial

complete

anatomic

abnormalities

with

on tissue Doppler imaging, significant respiratory

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Complicated Pericarditis

T A B L E 2 Practical Considerations in the Current Use of CMR to Evaluate Pericarditis

Strengths

Limitations

Pericardial thickness

Assessment

T1- or T2-weighted fast-spin echo images (36)

Method

 Extent of pericardial thickness appreciated  Often abnormal in patients with constrictive pericarditis

 In-plane spatial resolution limits assessment of normal or mildly thickened pericardium (46)  Some patients with constrictive pericarditis may have normal pericardial thickness

Pericardial edema

T2 short-tau inversion-recovery fast-spin echo images (36)

 Likely a specific finding for active pericarditis

 Difficult to distinguish from pericardial effusion (48)

Pericardial inflammation

Late gadolinium enhancement (36,51)

 Increased pericardial enhancement reflects increased vascularity (53)  Potential use of “ruling in” or “ruling out” pericarditis in equivocal cases (49,56)

 Correlation with different stages of pericarditis still being defined

Ventricular interdependence

Cine imaging with short-axis images at the basal level with patients instructed to breathe deeply (36)

 Relative septal excursion may be a specific finding for constrictive pericarditis (45,46)

 Patient respiratory effort can influence diagnostic yield

CMR ¼ cardiac magnetic resonance.

variation in tricuspid and mitral inflow, preserved

excursion may be evident in a patient without

global longitudinal strain, a dilated inferior vena

constrictive pericarditis, thus decreasing specificity

cava, and prominent diastolic expiratory flow reversal

(Online Video 4). To assess anatomy, the CMR evaluation usually

in hepatic veins (39–43). If a patient has all of these findings, CMR may be

begins by assessing pericardial thickness, often with

helpful to assess for ongoing pericardial inflamma-

black blood preparation turbo spin-echo sequences

tion, but the diagnosis of constrictive pericarditis is

that include a breath-hold (Figures 2A, 2D, and 2G)

secure. Yet, few patients demonstrate all of these

(46). On CMR, normal pericardial thickness is <4 mm

features, and the best multiparametric assessment to

(36). However, anatomic studies suggest that the

diagnose constrictive pericarditis with echocardiog-

normal parietal pericardium is thinner, approxi-

raphy is unclear (44). Therefore, CMR is likely best

mately #1 mm or less (Figure 3) (47). CMR may thus

reserved for patients with suggestive, but inconclu-

overestimate pericardial thickness, possibly due to

sive evidence of constrictive pericarditis on echocar-

motion or chemical shift artifacts at the fat-fluid interface (48). Importantly, given the normal dimen-

diography (Central Illustration). The imaging features of constrictive pericarditis,

sion of parietal pericardium, the in-plane spatial

whether assessed by echocardiography or CMR,

resolution of CMR is limited (49). Therefore, normal

reflect the consequences of pericardial constraint.

pericardium can be difficult to delineate on CMR and

Specifically, this constraint renders the cardiac

often appears “pencil-thin.” In addition, given these

chambers noncompliant, results in prominent respi-

limitations, reporting a pericardial thickness of 3 mm

ratory variation in flow, and accentuates early dia-

as normal and a thickness of 4 mm as abnormal is

stolic filling. With CMR, this physiology is reflected in

clearly fraught with error. Nonetheless, markedly

ventricular coupling during real-time cine imaging

thickened pericardium is usually evident on CMR,

with free breathing (Figure 1D, Online Video 1)

and has been described in patients with constrictive

(45,46). During early inspiration in patients with

pericarditis (Figure 2G) (46,50). Although the extent

constrictive pericarditis, the septum shifts toward the

of pericardial thickness is better appreciated on CMR

left ventricle (Online Video 2). An increased relative

compared with echocardiography, the imprecision of

septal excursion has been shown as a specific finding

this measurement should be emphasized, especially

for constrictive pericarditis (Table 2) (45,46). In

in

practice, though, this technique may be limited if the

increased pericardial thickness (Table 2).

patients

with

seemingly

normal

or

slightly

patient’s breathing does not generate negative intra-

Another potential advantage of CMR is the ability

thoracic pressure that falls within an acceptable

to assess pericardial edema (Figures 2B, 2E, and 2H).

range. For example, if a patient can take only shallow

On T 2-weighted short-tau inverted recovery (STIR)

breaths, the change in intrathoracic pressure is less-

fast spin-echo sequences, pericardial edema will

ened, and the sensitivity of septal excursion is

appear bright (Figure 2E) (48). Occasionally, these

decreased

with

edema-weighted images are helpful, but their clinical

septal

effect is often limited for 2 reasons (Table 2). First,

a

(Online

particularly

Video

vigorous

3).

Conversely,

inspiration,

mild

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Complicated Pericarditis

F I G U R E 2 Cardiovascular Magnetic Resonance of the Pericardium

In a patient with a normal pericardium (A to C), the pericardium is often difficult to delineate, even on a breath-hold double inversion-recovery, dark-blood, short-axis image (A). With an edema-weighted, short-tau inversion recovery, fast spin-echo image, a hyperintense signal is seen only in the area of a trivial pericardial effusion at the inferior margin over the anterior right ventricle (B, white arrowhead). With a phasesensitive inversion-recovery technique and no fat suppression, there is no delayed pericardial enhancement (C). In this patient with active pericarditis (D to F), abnormal pericardial thickness is not seen (D), but there is diffuse hyperintense signal on edema-weighted imaging (E, white arrow), and near circumferential delayed enhancement of the pericardium (F, yellow arrow). Finally, in this patient with chronic constrictive pericarditis (G to I), the pericardium is abnormally thickened (G, yellow diamond). There is no hyperintense signal on edemaweighted imaging (H), and in this image with a fat suppression preparation, there is no delayed pericardial enhancement (I).

patients with dramatically increased pericardial sig-

effusion, the interpretation of superimposed peri-

nals on T 2-STIR images typically have severe peri-

cardial edema is difficult because both will appear

carditis on the basis of history, examination, and

bright on T 2 -STIR images. Cine steady-state free pre-

inflammatory markers. Therefore, this finding does

cision images typically define the extent of a peri-

not usually inform the diagnosis, and, at present, the

cardial effusion, and short-axis comparisons of these

effect on patient management and prognosis is un-

cine images with short-axis T 2-STIR images may help

clear. Second, in a patient who also has a pericardial

to distinguish pericardial effusion from pericardial

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F I G U R E 3 Normal Pericardial Histology

(A) The parietal pericardium is normally <1 mm in thickness. The parietal pericardium is lined with a layer of mesothelial cells, forming the serosal pericardium depicted on the top portion of the section. The fibrous pericardium forms the tough pericardial sac and consists of dense collagen bundles (yellow) with interspersed elastic fibers (black). A variable amount of adipose tissue is present outside of the fibrous pericardium facing the mediastinum. The layer of mesothelial cells at the bottom portion of the section represents the serosal surface of the mediastinum facing the pleural cavity (original magnification 100, Movat pentachrome stain). (B) The visceral pericardium, also called the epicardium, consists of a layer of mesothelial cells, which rests on a basement membrane supported by thin fibrous tissue (yellow) with elastic fibers (black). In some areas of the heart, the myocardium is seen immediately beneath the epicardium. The mesothelial cells have a fuzzy border due to well-developed surface microvilli (original magnification 600, Movat pentachrome stain). (C) In most other areas of the heart, there is a subepicardial layer of adipose tissue separating the epicardium from the myocardium. This intervening layer of adipose tissue contains blood vessels, lymphatic vessels, and nerves (original magnification 400, Movat pentachrome stain).

edema. In practice, however, a comment on pericar-

CMR with increased delayed enhancement of the

dial edema in a patient with a pericardial effusion is

pericardium and epicardial fat. However, the kinetics

difficult to report with confidence.

of gadolinium egress from the pericardium are un-

In addition, late gadolinium enhancement can

clear. Therefore, the optimal timing for imaging,

inform the presence and severity of pericardial

especially in different stages of pericarditis, is not

inflammation (Figures 1C, 2C, 2F, and 2I) (51). Typi-

defined (Table 2). These uncertainties highlight the

cally, this protocol is similar to imaging for myocar-

nascent state of pericardial CMR and the need for

dial scar. Consequently, when there is a concern of

further research. Despite these limitations, early work

myocardial involvement and echocardiography is

has correlated pericardial histopathology with CMR.

inconclusive, CMR may define the extent of associated myocarditis (Figure 1A). With severe pericarditis,

DELAYED ENHANCEMENT OF THE PERICARDIUM AND

the inflammation can also extend into the surround-

THE PATHOLOGICAL STAGES OF PERICARDITIS. The

ing epicardial fat. This epicarditis may be seen on

pericardium

responds

to

injury

with

increased

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Complicated Pericarditis

F I G U R E 4 Gross Pathology of Pericarditis

(A) The classic appearance of acute fibrinous pericarditis is shown, with fibrin deposits projecting into the pericardial space as they line both the parietal and visceral pericardium. In the early stage, there is no adhesion between the 2 layers of the pericardium. (B) Organization of the fibrinous exudate can lead to diffuse obliteration of the pericardial space or focal adhesions by a fibrotic repair process. The fibrinous exudate shown here has a more variegated appearance with pale and dark areas as the repair process ensues. (C) Healed pericarditis results in thin adhesions, appearing as depressed gray translucent soft tissue between the parietal pericardium and epicardial fat.

vascularity, a predominant infiltration of neutrophils,

scenario, pericardial delayed enhancement will be

formation of granulation tissue, and deposition

minimal (Figure 2I).

of fibrin. Grossly, in early pericarditis, the fibrin

This

putative

correlation

between

pericardial

deposits line the parietal and visceral pericardium,

vascularity and delayed enhancement is on the basis

but there is no adhesion between the 2 layers. Orga-

of small studies of patients with CMR and pericardial

nization of the fibrinous exudate can lead to focal

histology

adhesions that become more confluent as the peri-

cardiectomy, patients with more active pericarditis,

(51,53).

In

patients

who

had

peri-

carditis heals (Figure 4). On histopathology, acute

termed “organizing pericarditis with fibroplasia,”

pericarditis is characterized by disintegration and

were more likely to have delayed enhancement. In

exfoliation of the mesothelial cells lining the peri-

particular, pericardial delayed enhancement was fibroblastic

cardium (Figure 5). As the inflammatory process

associated

continues, the fibrinous exudate organizes, and

vascularization, and granulation tissue. Conversely,

eventually, deposition of extracellular matrix leads to

patients without delayed enhancement were more

fibrosis of the pericardium (Figure 5).

likely to have organized fibrous pericarditis, charac-

Typically, given the lack of vascularity in normal

with

proliferation,

neo-

terized by pericardial fibrosis and calcification (53).

pericardium, gadolinium uptake in the pericardium

In addition to the small size, a notable limitation of

is absent or minimal. As pericarditis leads to

these studies is that histological correlation is typi-

increasing

enhance-

cally performed from samples obtained during peri-

ment of the pericardium also increases (Figures 1C

neovascularization,

delayed

cardiectomy. Because pericardiectomy is most often

and 2F). This relationship is distinct from delayed

performed for constrictive pericarditis, the validity of

enhancement of the myocardium. In myocardial

these data in other inflammatory pericardial diseases

diseases, delayed enhancement reflects the degree

is limited. Moreover, even when pericardiectomy is

of myocardial fibrosis (52). Conversely, end-stage

performed for medically refractory pain related to

pericarditis

pericardial

recurrent pericarditis, patients have typically been

fibrosis and resultant pericardial thickening, but

treated aggressively with anti-inflammatory agents,

limited vascularity and active inflammation. In this

not only to reduce their pain, but also to decrease

may

have

prominent

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Complicated Pericarditis

F I G U R E 5 Histopathology of Pericarditis

(A) An example of fibrinous pericarditis with abundant deposition of fibrinous material (*) that contains scattered inflammatory cells. The fibrous pericardium with mesothelial lining (arrowhead) is present at the lower portion of the microphotograph (original magnification 100, hematoxylin-eosin stain). (B) In acute pericarditis, there is disintegration and exfoliation of the mesothelial cells (arrowhead) lining the pericardial space. The initial inflammatory cell response to injury is predominantly composed of neutrophils (arrows). The fibrin exudate (*) is seen as eosinophilic (bright pink) meshwork separating the mesothelial cells, and is also present in the background of inflammatory cells (original magnification 400, hematoxylin-eosin stain). (C) Organization of the fibrinous exudate (*) is indicated by neovascularization and ingrowth of fibroblasts, with deposition of extracellular matrix that leads to fibrosis of the pericardium (original magnification 200, hematoxylin-eosin stain). Healing with dense fibrosis may lead to pericardial constriction. (D) Depending on the extent and duration of the insult leading to injury, the fibrin exudate can be completely resorbed. The resolution of inflammation and the tissue repair process can lead to obliteration of the pericardial space. In some instances, as in this case of post-cardiac surgery pericarditis, the resulting fibrosis is loose in nature and does not cause significant fibrous thickening of the pericardium. The extracellular matrix contains sparse collagen fibers and mild neovascularization (original magnification 100, hematoxylin-eosin stain). Grossly, this healed pericarditis results in loose fibrous adhesions, as seen in Figure 4C.

complications related to operating on an intensely

in whom the presence of active pericardial inflam-

inflamed pericardium. Consequently, in patients with

mation is uncertain. The second applies to a patient

the most severe pericardial inflammation, the rela-

with constrictive pericarditis in whom the severity of

tionship between histology and pericardial delayed

active pericarditis is unclear.

enhancement is not well defined.

In a patient with a history of pericarditis, chest pain reminiscent of a previous attack may recur, but

PATIENTS WHO BENEFIT FROM AN ASSESSMENT OF

other diagnostic characteristics may be lacking. In a

DELAYED PERICARDIAL ENHANCEMENT. With these

cohort of 275 patients with previous idiopathic acute

limitations as background, the next question centers

pericarditis, approximately 10% developed chest pain

on which patients with complicated pericarditis

without other clinical evidence of pericarditis (54).

benefit from an assessment of delayed pericardial

This presentation was more common in women, pa-

enhancement. Specifically, how will patient man-

tients treated with glucocorticoids, and patients with

agement change on the basis of the presence or

a history of multiple attacks. Eventually, a third of

absence of significant delayed pericardial enhance-

these patients fulfilled typical diagnostic criteria for

ment? Currently, CMR is most appropriate for this

pericarditis. Therefore, in a patient who has chest

indication in 2 scenarios. The first applies to a patient

pain and a history of pericarditis, delayed pericardial

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Complicated Pericarditis

enhancement may favor continued or intensified

constrictive pericarditis are neither severely inflamed

anti-inflammatory treatment. If CMR does not show

nor obviously “burnt-out.” These patients appear to

delayed pericardial enhancement, then tapering of

benefit most from CMR to further characterize their

medications may continue, and other diagnoses may

pericardial inflammation. In fact, patients may not

be considered (Central Illustration).

have elevated inflammatory markers, but will still

For patients with recurrent pericarditis, pre-

have significant delayed pericardial enhancement

liminary observational data support this CMR-guided

(49). Moreover, these patients may improve with

approach to treatment. In a single-center cohort of

anti-inflammatory therapy, and referring the patient

507 patients with recurrent pericarditis, approxi-

for pericardiectomy may be unnecessary or prema-

mately one-half had CMR (55). Overall, patients with

ture (Central Illustration). Even if the patient does not

CMR subsequently received less treatment with glu-

improve enough clinically to avoid pericardiectomy,

cocorticoids. These data suggest that clinicians are

pre-treatment with anti-inflammatory agents may

more comfortable tapering glucocorticoids when CMR

facilitate a more successful surgery for organized, as

does

opposed to fibrinous, pericarditis, although this hy-

not

show

significant

delayed

pericardial

enhancement. However, these results should be

pothesis is on the basis of anecdotal experience.

considered suggestive, given their observational and retrospective nature without adjustment for potential

SIMILARITIES AND DIFFERENCES

confounders.

IN AUTOINFLAMMATORY AND

CMR also has the potential to affect management

AUTOIMMUNE PERICARDITIS

in patients with constrictive pericarditis when the degree of active pericardial inflammation is uncertain

Despite an improved understanding of the histo-

(Central Illustration). In 2 small observational studies,

pathological progression of recurrent pericarditis,

increased pericardial

was

and early studies on the correlation of pathology with

associated with reversible constrictive pericarditis

clinical and imaging features, the underlying patho-

(49,56), and a quantitative assessment of pericardial

physiology of recurrent pericarditis remains poorly

delayed enhancement may be superior to visual

understood. In general, recurrent pericarditis results

analysis (49). In patients with constrictive patho-

from an interplay between environmental triggers

physiology

delayed enhancement

delayed

and the innate and adaptive immune systems in a

enhancement, active inflammation may be contrib-

genetically susceptible host (57). Recurrent attacks

uting to the constriction. As this inflammation

may result from an inability to clear the presumed

resolves

the

viral infection with increased viral replication, a hy-

constriction may also resolve. In patients with

pothesis supported by the increased risk of relapse in

constrictive pathophysiology and without increased

patients treated with glucocorticoids (58). Alterna-

pericardial delayed enhancement, advanced fibrosis

tively,

may cause constriction. This fibrotic state is unlikely

response via molecular mimicry, where a foreign an-

to respond to anti-inflammatory therapy.

tigen shares sequences or structural similarities with

and

with

increased

pericardial

anti-inflammatory

therapy,

infections

may

trigger

an

autoimmune

However, for patients with established constrictive

self-antigens. This similarity may result in cross-

pericarditis, CMR to assess for pericardial inflamma-

reactivity and recurrent inflammatory attacks (59).

tion is not necessary in every patient. In a patient

In addition, superantigens may be generated by mi-

with heart failure, no chest pain, and prominent

crobes or virus-infected cells, which can result in

circumferential calcification on chest x-ray or CT,

activation of T cells, irrespective of antigen speci-

CMR is unlikely to add diagnostic value. The calcifi-

ficity. Moreover, following tissue injury, cell death,

cation represents the end stage of the inflammatory

and oxidative stress, self-proteins may be recognized

process, and pericardiectomy is likely necessary for

as foreign due to mutation, altered expression, mis-

symptom relief.

folding, or post-translational modification. Finally,

The patient with constrictive pericarditis at the

epitope spreading and a tolerance break may occur

other end of the inflammatory spectrum also derives

through enhanced processing and presentation of

little benefit from CMR. Medical therapy is indicated

self-antigens, independent of specific T-cell receptor

in a patient with typical pericarditic pain and

stimulation (60).

elevated inflammatory markers. Currently, there is

Although these mechanisms emphasize an inap-

increasing interest in modulating the intensity of

propriate adaptive immune response, more recent

anti-inflammatory therapy according to the severity

investigations suggest that innate immunity and its

of pericardial inflammation on CMR, but published

effector mechanisms may be at the epicenter of

data are lacking. However, many patients with

the pathogenesis of recurrent idiopathic pericarditis.

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Complicated Pericarditis

This insight stems from similarities between recur-

TNFa -dependent signaling pathways that up-regulate

rent pericarditis and prototypical autoinflammatory

the inflammasome (61). Typically, patients develop

diseases, including familial Mediterranean fever

symptoms every 5 to 6 weeks, and symptoms last 1 to

(FMF) and tumor necrosis factor–associated periodic

3 weeks. Common symptoms include fever, migratory

syndrome (TRAPS) (61). These syndromes are char-

myalgia, rash, and serositis. In an international reg-

acterized by seemingly unprovoked attacks of multi-

istry of 138 patients with TRAPS, 7% had pericarditis

system inflammation and are triggered by innate

and 25% had chest pain (67). Of note, a family history

immunity perturbations in the absence of antigen-

of recurrent pericarditis should prompt screening, as

specific T cells or high titers of autoantibodies.

incomplete TRAPS phenotypes and low-penetrance

To better understand the pathophysiology of auto-

mutations have been described (68,69). In patients

inflammatory disease and its distinction from pre-

with TRAPS, attacks may be unprovoked or may be

dominant autoimmune disease, research has focused

precipitated by injury, minor infection, stress, exer-

on the pivotal role of the inflammasome (62).

cise, or hormonal changes (67).

PUTATIVE ROLE OF THE INFLAMMASOME AS A

Another prototypical autoinflammatory disease,

DANGER AND PATHOGEN SIGNAL SENSOR. Inflam-

FMF is caused by missense mutations in the MEFV

masomes are integral players in innate immunity and

gene, which encodes pyrin, a component of the

respond to a wide array of damage- and pathogen-

NLRP3 inflammasome (70). Pyrin mutations render

associated

the NLRP3 inflammasome constitutively active, and

molecular

patterns.

In

addition,

pathogen-associated molecular patterns are recog-

therefore allow caspase 1 to cleave pro–IL-1 b to IL-1 b

nized by endosomal and extracellular Toll-like re-

(Figure 6) (71). Despite this constitutive activation of

ceptors that can also activate inflammasomes. In

the NLRP3 inflammasome, FMF is characterized by

basic structure, the inflammasome is a cytosolic

intermittent inflammatory attacks lasting 1 to 3 days

macromolecule composed of the adaptor protein ASC,

with fever, serositis, and oligoarthritis. In a registry of

procaspase 1, and, importantly, a sensor molecule

346 pediatric patients with FMF, pericarditis occurred

(Figure

in approximately 18%, although chest pain was more

This

6).

sensor

molecule

contains

a

nucleotide-binding oligomerization domain–like re-

common (56%) (72). In addition to a similar pattern of relapse and

ceptor (NLR), and is triggered by diverse stimuli. The best-characterized inflammasome has an NLR

remission, the clinical link between FMF and idio-

pyrin domain-containing 3 (NLRP3) sensor molecule.

pathic recurrent pericarditis includes the effective-

Gain-of-function mutations in NLRP3 result in the

ness of colchicine in both diseases. Colchicine inhibits

cryopyrin-associated periodic syndromes, a group of

the activation of P2X2 and P2X7 pores, 1 of the first

autosomal-dominant

autoinflammatory

signals of NLRP3 activation. Furthermore, colchicine

Seemingly

diseases

disparate

can

also

diseases. activate

inhibits caspase 1, as well as the release of TNFa and

NLRP3, including monosodium urate crystals from

reactive oxygen species (73). Finally, evidence to

gout, cholesterol related to atherosclerosis, and many

support a predominant role of the inflammasome in

viruses (63–65). In fact, some of these viruses,

recurrent idiopathic pericarditis relates to the role of

including adenovirus, influenza A, herpesvirus, and

IL-1. As a final common pathway of inflammasome

cytomegalovirus, are associated with pericarditis.

production, IL-1 has been a pharmacological target for

Once activated, the NLRP3 inflammasome leads to the

autoinflammatory diseases. In fact, as will be dis-

release of interleukin (IL)-1 (Figure 6). IL-1 then re-

cussed, antagonism of the IL-1 receptor may have

cruits effector cells of a myeloid lineage, namely

promise in the treatment of patients with refractory

neutrophils, monocytes, and macrophages, to the site

recurrent idiopathic pericarditis.

of injury. In autoinflammatory syndromes, this skew

RECURRENT

toward IL-1 expression predominates. Conversely,

AUTOIMMUNE DISEASE. Pericarditis also occurs in

autoimmune diseases, such as systemic lupus ery-

the context of systemic autoimmune disease, often

PERICARDITIS

SECONDARY

TO

AN

thematosus (SLE), primarily have a type I interferon

during flares. In SLE, pericardial inflammation or

signature (62).

effusion can occur in as many as 20% to 50% of pa-

RECURRENT

TO

tients, with a higher prevalence of pericardial

AUTOINFLAMMATORY DISEASE. TRAPS is an auto-

involvement when autopsy is performed (18,74).

somal dominant periodic fever syndrome most

Usually, other features of SLE, such as rash, arthritis,

commonly caused by missense mutations in the re-

pleuritis, or leukopenia, accompany pericarditis.

(TNF)-a (66).

Glucocorticoids are generally effective for pericardial

These mutations lead to downstream activation of

symptoms, but more aggressive immunosuppressive

ceptor

for

PERICARDITIS

tumor

SECONDARY

necrosis factor

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2323

Complicated Pericarditis

F I G U R E 6 Activation of the Inflammasome, a Proposed Pathogenic Mechanism in Recurrent Idiopathic Pericarditis

The initial stimulus can be either microbial (PAMPs) or sterile (DAMPs). This stimulus is then recognized by innate immunity receptors found either at the cell surface (TLRs) or inside the cell (NLRs). NLRs are then integrated into the structure of the inflammasome. Variants in the genes encoding inflammasome proteins can render them constitutively active or lower the threshold upon which the macromolecular structure is assembled in response to DAMPs and PAMPs. TLR signaling also leads to NF-kB activation and IL-1b production via ROS. Once primed by signals such as ATP, the threshold may be lower for inflammasome activation, resulting in recurrent attacks. ATP ¼ adenosine triphosphate; CARD ¼ caspase activation and recruitment domain; DAMPs ¼ damage-associated molecular patterns; IL ¼ interleukin; JNK ¼ Jun amino-terminal kinase; Kþ ¼ potassium ions; NF-kB ¼ nuclear factor–kappa B; NLRP3 ¼ nucleotide-binding oligomerization domain–like receptor pyrin domain-containing 3; PAMPs ¼ pathogen-associated molecular patterns; ROS ¼ reactive oxygen species; TLR ¼ Toll-like receptors; TNF ¼ tumor necrosis factor; TNFR ¼ tumor necrosis factor receptor.

therapy may be necessary, depending on overall dis-

therapy specifically directed at pericarditis is un-

ease activity (75).

usual, and constrictive pericarditis is rare in the cur-

Rheumatoid arthritis may also frequently involve the pericardium, but is symptomatic in <10% of pa-

rent era. In

conclusion,

this

dichotomization

between

tients (76). Pericarditis is more common in severe,

autoimmune and autoinflammatory disease can be a

deforming, nodular rheumatoid arthritis with high

useful construct, but it is an oversimplification of

titers of rheumatoid factor and cyclic citrullinated

complex biological processes. In fact, both innate and

peptide antibodies. Targeted biologic therapy may

adaptive effector mechanisms act in concert, and

be necessary to control other symptoms, but such

several genetic polymorphisms of inflammasome

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Complicated Pericarditis

components are associated with susceptibility, ac-

after the patient is quiescent in terms of symptoms

tivity, and treatment responses of autoimmune dis-

and inflammatory markers (3).

eases (77,78). Nevertheless, in the approach to

More recently, when added to an NSAID, colchicine

understanding and treating the patient with pericar-

has also become an established first-line therapy for

ditis, the diathesis toward autoinflammatory or

pericarditis (81). An ancient drug, colchicine was

autoimmune disease is important. Autoinflammation

approved by the U.S. Food and Drug Administration

is likely a more important mechanism in many pa-

for the treatment of FMF and gout in 2009, although

tients with recurrent idiopathic pericarditis, whereas

colchicine had been used to treat the latter condition

autoimmunity may be paramount in patients with

for centuries (82). Thirty years ago, after noting suc-

chronic

cess in treating and preventing the polyserositis at-

pericarditis

and

systemic

autoimmune

disease.

tacks in FMF, colchicine was used to effectively treat

ESTABLISHED AND NOVEL TREATMENTS FOR PERICARDIAL INFLAMMATION

3 patients with recurrent pericarditis (83). In the intervening decades, several multicenter trials have shown that colchicine can hasten the response to medical therapy, increase the duration of

Given the predominant autoinflammatory mecha-

remission,

nisms and relapsing episodes that characterize

(11,12,20,21). Overall, in a meta-analysis including 8

recurrent idiopathic pericarditis, the mainstay of

randomized trials and 1,635 patients, colchicine

medical therapy has understandably involved anti-

decreased the relative risk of recurrent pericarditis by

inflammatory therapy, with the goal of not only controlling

symptoms

during

a

flare,

but

and

decrease

the

recurrence

risk

about 50% (84). In clinical trials, gastrointestinal

also

intolerance develops in 5% to 10% of patients, and

decreasing recurrence (11,20). This latter objective of

tolerance may be improved if colchicine is used at a

secondary prevention should be emphasized. Many

lower dose without loading. This intolerance may

patients with recurrent idiopathic pericarditis have a

limit its use, but in general, colchicine is recom-

chronic disease. They may take anti-inflammatories

mended for 3 months in patients with acute pericar-

for months or years, only to relapse randomly or

ditis and for at least 6 months in patients with

when their medications are tapered. For these pa-

recurrent pericarditis (Central Illustration) (5).

tients, an understanding of therapies with estab-

Given the rapid resolution of symptoms and peri-

lished efficacy is essential, and the potential for

cardial

disease-modifying therapies should be investigated.

commonly used to treat pericarditis. Unfortunately,

ESTABLISHED

unopposed corticosteroids increase the risk of recur-

TREATMENTS

FOR

PERICARDITIS.

effusions,

corticosteroids

were

once

Over 25 years ago, nonsteroidal anti-inflammatory

rence and prolong the course of disease (58,85). In

drugs (NSAIDs) were shown to be effective in a ran-

particular, high doses at an equivalence of 1.0 to

domized trial of patients with post-pericardiotomy

1.5 mg/kg/day of prednisone are associated with se-

syndrome (79). In a single-center, double-blind trial,

vere side effects in 25% of patients. Furthermore,

149 patients were randomized to ibuprofen or indo-

brisk tapering can lead to relapse (86). Conversely,

methacin versus placebo. The diagnosis required 2 of

when the combination of colchicine and an NSAID is

3 characteristics, including fever, anterior chest pain,

ineffective, low-dose corticosteroids may prevent

and a friction rub. The primary outcome was defined

further recurrences (87).

as resolution of 2 of these characteristics at 48 h.

Consequently, corticosteroids should be consid-

Ibuprofen and indomethacin had similar efficacy,

ered only after failure of NSAIDs and colchicine,

90% and 89%, respectively, and both were signifi-

although there are a few notable exceptions. For

cantly more effective than placebo (63%).

example, patients with a systemic autoimmune dis-

Even before this pivotal randomized trial, NSAIDs

ease may benefit from corticosteroids, especially if

had been first-line therapy for many patients with

already on a maintenance dose for another indication.

pericarditis (80), although a randomized trial of

In addition, pregnant patients and patients with renal

NSAIDs in post-viral pericarditis has never been per-

failure may need to avoid NSAIDs and colchicine.

formed. In routine clinical practice, aspirin or an

Similarly, concomitant NSAIDs are a relative contra-

NSAID, in conjunction with gastroprotection, is given

indication for patients who take anticoagulants.

for rapid control of symptoms (Central Illustration) (5).

In patients on corticosteroids, after remission with

Initially, an attack dose is recommended every 8 h to

resolution of symptoms and normalization of CRP is

alleviate symptoms, and usually continues until CRP

attained, the dose must be slowly tapered. Often,

has normalized (7,33). This approach allows for indi-

pericarditis recurs at doses of prednisone <15 mg/day.

vidualized therapy, and tapering typically begins

If tolerable, the dose of NSAID or colchicine should be

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Complicated Pericarditis

increased, rather than increasing the corticosteroid (88). In difficult situations, this approach may not be

T A B L E 3 Emerging Therapies for Steroid-Dependent and

Colchicine-Refractory Pericarditis

possible, and steroid-sparing regimens should be Therapy

considered (Central Illustration).

Initial Dosing

Started at 1 mg/kg/day, then gradually increased to 2 to 3 mg/kg/day

At least 6 months

Human immunoglobulins

400 to 500 mg/kg/day iv daily for 5 days

5 days, possibly repeated course

Anakinra

1 to 2 mg/kg/day up to 100 mg/day in adults

At least 6 months

Pericardiectomy

Not applicable

Not applicable

NOVEL TREATMENTS FOR REFRACTORY PERICARDITIS.

In this subset of patients with pericarditis that is refractory to standard medical therapy, novel treatments are needed not only to control symptoms, but also to avoid the long-term side effects of glucocor-

Duration

Azathioprine

ticoids. Unfortunately, the evidence to support other anti-inflammatory therapies in recalcitrant pericar-

iv ¼ intravenous.

ditis consists primarily of case series and expert opinion (88). Among the emerging treatments, 3 promising

options

include

azathioprine,

human

central

role

of

IL-1

in

perpetuating

an

auto-

intravenous immunoglobulin (IVIG), and anakinra

inflammatory state, anakinra may have a role in the

(Table 3).

treatment

of

recurrent

idiopathic

pericarditis.

Although commonly used to treat organ transplant

Currently, anakinra is administered as a daily sub-

recipients and patients with autoimmune disease, the

cutaneous injection at 1 to 2 mg/kg/day, up to 100 mg,

largest study of azathioprine in recurrent pericarditis

for at least several months, although the optimal

is a single-center retrospective report of 46 patients

duration is unknown. With this regimen, efficacy has

(89). At a dose of 1.5 to 2.5 mg/kg/day and a mean

been demonstrated in children and adults, although

duration of treatment of over 1 year, azathioprine was

the number of treated patients is small (92–94). With

associated with stable remission following steroid

anakinra, symptoms typically improve rapidly, but

discontinuation in more than 50% of patients.

unfortunately, recurrence is common after the drug is

Azathioprine was reasonably well-tolerated, with

discontinued. Given the concern that patients may

transient hepatocellular dysfunction in 10%, leuko-

need to be on a subcutaneous immunomodulatory

penia in 7%, and transient gastrointestinal symptoms

drug for the long-term, coupled with the high cost

in 5% of patients. Overall, azathioprine is a poten-

and

tially inexpensive and efficacious therapy in patients

currently reserved for patients with the most debili-

who do not respond to conventional treatments. In

tating and refractory pericarditis, especially if they

particular, azathioprine may facilitate a gradual

are corticosteroid-dependent and colchicine-resistant

tapering of corticosteroids.

limited

published

experience,

anakinra

is

(Central Illustration). Even though these patients

In select cases, IVIG may be an effective treatment

represent a small percentage of the overall cohort of

for refractory pericarditis. In patients with a history of

patients with pericarditis, they experience severe

multiple recurrences, especially in the setting of an

morbidity related to their pericarditis, and clinical

underlying autoimmune disease, IVIG can act rapidly

trials are needed to define the optimal disease-

to improve symptoms during an acute attack (90).

modifying treatment.

Typically, patients receive infusions of 400 to 500

Finally, after medical therapy has failed, peri-

mg/kg/day for 5 days, and if necessary, this regimen

cardiectomy is rarely considered for refractory pain

can be repeated after 1 month (91). However, despite

related to recurrent pericarditis (Central Illustration).

broader use with a good safety profile in rheumato-

To attenuate the pain, as much pericardium as can be

logical diseases, IVIG therapy has been reported in

accessed should be removed. Therefore, radical per-

only 30 patients with recurrent pericarditis (90).

icardiectomy with resection extending beyond the

Given this limited experience, coupled with a high

phrenic nerves is often performed. In a single-center

cost, IVIG is currently best reserved for pericarditis

retrospective study, 58 patients had pericardiectomy

patients who have an indication on the basis of an

after failed medical therapy (95). There were no

underlying autoimmune disease.

perioperative deaths, and after a mean follow-up of

Among biological agents, anakinra is increasingly

5 years, the surgical group had a decreased relapse

used to treat patients with pericarditis that is re-

rate compared with medically treated patients. Again,

fractory to NSAIDs, colchicine, and corticosteroids.

like the other observational studies mentioned,

An IL-1 receptor antagonist, anakinra is currently

uncontrolled confounding could explain this associ-

approved by the U.S. Food and Drug Administration

ation. Nonetheless, these preliminary data argue that

for the treatment of rheumatoid arthritis. Given the

pericardiectomy could be considered as a potential

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treatment in prospective trials of patients with re-

pericarditis, the inflammasome may be an important

fractory recurrent pericarditis.

target for future therapies. This emerging focus on

CONCLUSIONS AND FUTURE DIRECTIONS If treated with appropriate anti-inflammatory therapy, the majority of patients with acute pericarditis will have a benign course. About 15% of patients will have myocardial involvement and 1% to 2% will have pericardial tamponade, but following acute management, these patients have a course that is indistinct from patients without these complications (20,30,31). After acute pericarditis, complicated pericarditis will develop in 15% to 30% of patients, and risks for recurrence include early use of corticosteroids, a lack of response to NSAIDs, and a high CRP (33). Most of these patients will also achieve sustained remission, but unfortunately, some patients will develop multiple debilitating recurrences. These patients have a chronic disease with substantial morbidity related not only to intractable symptoms, but also to side effects from medications, specifically long-term corticosteroid use. In patients with complicated pericarditis, a better understanding of the causes and pathological progression of pericardial inflammation is needed. After success was observed in FMF, colchicine was given to patients with recurrent idiopathic pericarditis (83),

the inflammasome has also highlighted an important distinction in patients with complicated pericardial disease: those with a tendency toward inappropriate autoinflammation versus those with predominant autoimmune disease. Finally, although still in its infancy given the limitations noted, CMR has the potential to provide insight into the progression of pericarditis by imaging pericardial thickness, edema, and inflammation.

Currently,

the

assessment

of

pericardial

inflammation with delayed enhancement imaging is essentially binary. A patient either does or does not have significant pericardial delayed enhancement. The patient with an inflamed pericardium warrants anti-inflammatory therapy or, in the setting of constrictive pericarditis, deferral of pericardiectomy to observe the response to intensified medical therapy. In the future, CMR may help to further stage pericarditis and guide both the intensity and duration of treatment. Thus, in conjunction with clinical data, CMR could identify the patients who are at risk for recalcitrant and protracted pericarditis. These patients are most in need of novel therapies and could be the focus of multicenter trials and registries.

and clinical trials have subsequently shown a consistent relative risk reduction of w50% (84). This

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

clinical success has led to a focus on the inflamma-

Allan L. Klein, Center for the Diagnosis and Treat-

some, a site of action for colchicine. In addition, given

ment of Pericardial Diseases, Heart and Vascular

its central role in periodic febrile syndromes that

Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk

have phenotypic similarities to recurrent idiopathic

J1, Cleveland, Ohio 44195. E-mail: [email protected].

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KEY WORDS autoimmune diseases, cardiovascular magnetic resonance imaging, colchicine, inflammasome, inflammation, pericardiectomy

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