**4. Recurrent pericarditis**

Recurrent pericarditis is a syndrome defined by the reemergence of pericarditis after the treatment of the initial inflammatory event [31, 46–48]. A minimum 4–6 week symptom-free interval post anti-inflammatory treatment is required to differentiate recurrent pericarditis from incessant pericarditis.

#### **4.1 Etiology**

*Inflammatory Heart Diseases*

**3.4 Treatment**

workup of acute pericarditis unless the presumed etiology is a systemic inflamma-

The ECG may be perhaps the most useful diagnostic modality when considering acute pericarditis. The ECG progresses through a distinctive, four stage pattern although the evolution can be variable with up to 40% of patients showing atypical changes [30–32]. Stage 1 is characterized by widespread ST elevation with reciprocal ST depression in leads aVR and V1 as well as PR segment elevation in lead aVR accompanied by PR segment depression in the remaining limb leads and V5–6. Within 1 week of onset, normalization of ST and PR segments on the ECG comprises Stage 2. Stage 3 of the ECG is marked by diffuse T-wave inversions, while Stage 4 consists of normalization of the ECG. However, not all forms of pericarditis result in the characteristic ECG pattern as the pericardium itself is an inert tissue and only inflammatory changes involving the epicardium or myocardium would be reflected in acute pericarditis [36]. In fact, one review found that of 100 patients studied, only seven arrhythmias were identified all resulting from underlying heart disease [37], while a separate study comparing acute pericarditis to myopericarditis

tory or autoimmune disease with characteristic cardiac findings.

found arrhythmias more frequently associated with myopericarditis [38].

the absence of confounding factors such as acute kidney or liver injury.

European Society of Cardiology (ESC) guidelines [2].

Medical treatment of acute pericarditis utilizes one or a combination of two out of three different medications: NSAIDs, colchicine, and glucocorticoids. Treatment duration is usually guided by the resolution of symptoms and etiology of disease in

A combination of NSAIDs and colchicine is the mainstay of therapy for acute viral or idiopathic pericarditis. NSAIDs alone have been shown through multiple studies to effectively treat up to 80% of pericarditis cases [20, 32, 39]. No one particular NSAIDs has been shown to be more effective than another except in the case of post-myocardial infarction pericarditis for which aspirin is recommended and other NSAIDs should be avoided in order to prevent the disruption of myocardial scar formation [40]. Patients taking NSAIDs for pericarditis should concurrently take a proton-pump inhibitor for ulcer prophylaxis in the absence of any direct contraindication to do so. Treatment can be tapered once the patient is symptom-free for at least 24 hours (typically 1–2 weeks). Alternatively, one study recommends following weekly CRP levels along with symptom resolution and beginning tapering, once the patient is symptom-free for 24 hours and CRP levels have returned to normal [41]. In 2005, the Colchicine for Acute Pericarditis (COPE) trial suggested colchicine as an effective adjunct for treating acute pericarditis when combined with NSAIDs therapy for patients with non-bacterial, non-malignancy-related pericardial disease [39]. The addition of colchicine was further shown to reduce symptom burden and decrease the rate of recurrent pericarditis by a subsequent, randomized-control trial (RCT) [42], a finding, which was later supported by a meta-analysis in 2014, that demonstrated a reduced risk of recurrence at 18 months in patients undergoing treatment for acute pericarditis [43]. The management of acute pericarditis with a combination of NSAIDs and colchicine is also currently supported by the 2015

For patients with contraindications to NSAIDs therapy (kidney failure, GI bleeding, pregnancy, etc.), glucocorticoids may be used in combination with colchicine for the initial treatment of acute pericarditis. Treatment duration is then guided by symptom resolution and the normalization of CRP levels with tapering usually started 2–4 weeks thereafter. Glucocorticoids have also been utilized in patients with pericarditis refractory to NSAIDs and colchicine though one study shows a

trend toward higher rate of recurrent pericarditis with steroid use [44].

**18**

Acute pericarditis has been found to have recurrence rates as high as 30% in patients treated without colchicine [32, 39, 47, 49]. Some cases of recurrent pericarditis appear to reflect localized inflammation given the detection of certain cytokines (interleukin (IL)-6, IL-8, and interferon gamma) in the pericardial fluid and their absence in the serum [50]; however, most cases are considered to be of autoimmune etiology [2, 51].

#### **4.2 Clinical presentation**

Chest pain appears to be the most common recurring symptom; however, the clinical diagnosis of recurrent pericarditis requires the presence of at least one of the following in addition to pleuritic chest pain: fever, pericardial rub, ECG changes, pericardial effusion, elevated WBC, ESR, CRP, or evidence of active pericardial inflammation on imaging [15]. Patients with previously treated pericarditis may experience multiple recurrences over the course of months to years following the initial event [52–54].

#### **4.3 Diagnostics**

The selection of the initial treatment regimen can directly impact the potential for the recurrence of acute pericarditis and may serve as an independent predictor of risk. For instance, a prior response to NSAIDs therapy is associated with the reduced risk of recurrence [32], whereas treatment with glucocorticoids is associated with increased recurrence [55]. It is difficult to rely upon ECG changes for the diagnosis for recurrent pericarditis as they are non-specific in the majority of cases. Chest X-ray and TTE also have limited utility as both will appear to be normal without a significant pericardial effusion. CT and CMRI imaging have proven to be of benefit in elucidating the diagnosis of recurrent pericarditis as contrast-enhanced CT can detect active pericardial inflammation while CMRI may reveal the evidence of edema via pericardial gadolinium enhancement [2, 35].

#### **4.4 Treatment**

Recurrent viral or idiopathic pericarditis is typically managed with an outpatient medical regimen [2, 52, 54] initially consisting of an NSAIDs and colchicine [15] as glucocorticoids are known to increase the risk of recurrence despite multiple recurrences of pericarditis [56]. Glucocorticoid therapy is, therefore, reserved for patients who are either unable to tolerate NSAIDs or have failed NSAIDs therapy in the past [2].

It is important to ensure an adequate trial of NSAIDs was given prior to labeling a patient as refractory. Common agents such as Aspirin and Ibuprofen should be attempted first followed by Indomethacin for treatment resistant cases. Medication should be administered in three doses over 24 hours to ensure consistent therapeutic levels, and dosage should be titrated up as needed to achieve symptom control until the daily maximum is reached or symptoms have subsided [10, 32, 39, 52, 54, 57].

Patients with recurrent pericarditis are often times designated as refractory to colchicine therapy after having received inappropriate dosing or rapid tapers [43]. In addition, colchicine should be given twice a day in order to reduce the risk of poor compliance due to gastrointestinal discomfort [10, 57, 58].

In cases of recurrent pericarditis refractory to treatment with NSAIDs, colchicine, and glucocorticoids, patients found to have the evidence of systemic inflammation may benefit from anti-interleukin-1 therapy. A recent trial in 2016 demonstrated a significant reduction of recurrence (90–18%) in patients with pericarditis resistant to colchicine and dependent on corticosteroids with the addition of anakinra, an IL-1B antagonist [59]. Although promising, this study's results were limited by a small sample size and inconsistent colchicine dosing across trial participants warranting further investigation.
