Recurrent Pericarditis

Recurrent pericarditis is a return of pericarditic symptoms and signs after a documented first episode of acute pericarditis and a symptom free interval of at least 4 to 6 weeks. Incessant pericarditis persists for more than 4 to 6 weeks but under 3 months without remission, and chronic pericarditis lasts over 3 months.

Without colchicine, recurrence follows 15 to 30% of first episodes, and rises to as high as 50% after the first recurrence. Most cases are idiopathic, usually presumed viral.

Other causes are autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, systemic sclerosis), autoinflammatory disease (familial Mediterranean fever, tumour necrosis factor receptor associated periodic syndrome, adult Still disease), post-cardiac injury syndromes, tuberculosis, malignancy, uraemia and radiotherapy.

In sub-Saharan Africa and other tuberculosis endemic regions, tuberculosis and HIV are leading causes of pericardial disease, and must be excluded before immunosuppression.

Pathophysiology. Most recurrent disease is autoinflammatory, driven by interleukin-1 through the NLRP3 inflammasome, and not by infection. Persistent inflammation of the pericardium causes pain, effusion and, over years, fibrosis and constriction.

A subgroup has an autoimmune mechanism with antiheart antibodies, in which steroid dependence is common. Early steroid use, high doses, a rapid taper and a short course of colchicine are linked with recurrence.

• Pleuritic chest pain that is sharp, worse supine and on inspiration, and eased by sitting forward. Fever, malaise, dyspnoea and cough.
• Pericardial friction rub (often transient). Pericardial effusion in about 60%. Tamponade is uncommon.
• ECG: widespread concave ST elevation with PR depression, evolving through T wave inversion to normalisation, but often atypical in recurrence.
• Diagnosis needs 2 of 4: pericarditic chest pain, a friction rub, widespread ST elevation or PR depression, and a new or worsening pericardial effusion. Supportive findings are raised CRP, ESR or white cell count, and evidence of pericardial inflammation on imaging.

Red flags.

• Hypotension, raised venous pressure, pulsus paradoxus or muffled heart sounds (tamponade)
• Troponin rise or reduced ejection fraction (myopericarditis)
• Fever over 38 degrees Celsius, subacute onset, or a large effusion (tuberculous, bacterial or malignant cause)
• Weight loss, night sweats, HIV infection or contact with tuberculosis
• Features of constriction (raised venous pressure with Kussmaul sign, oedema)
• Dependence on steroids, or recurrence on tapering

• ECG at each episode. CRP, ESR, full blood count, creatinine, liver function and troponin. CRP tracks activity and directs treatment duration and taper.
• Echocardiography: effusion size, tamponade, constriction (septal bounce, respiratory ventricular interdependence, annulus reversus), and ventricular function.
• Cardiac MRI: pericardial thickening, oedema on T2 imaging, and pericardial late gadolinium enhancement shows active inflammation and supports a prolonged treatment course and escalation. CT for calcification, thickness and masses.
• Chest X-ray (cardiac silhouette, pleural effusion, mediastinal mass).
• Cause workup: antinuclear antibody, rheumatoid factor, anti-CCP, complement, thyroid function, HIV, hepatitis B and C, tuberculosis tests (interferon gamma release assay or skin test, sputum and pericardial fluid Xpert MTB/RIF Ultra, adenosine deaminase, urine lipoarabinomannan in HIV), and genetic testing for periodic fever syndromes (MEFV, TNFRSF1A) when episodes began in childhood or fever is recurrent.
• Pericardiocentesis only for tamponade or suspected purulent, tuberculous or malignant effusion. Fluid for cell count, protein, glucose, LDH, culture, acid fast stain, Xpert, adenosine deaminase and cytology.

Differential diagnosis.

• Acute coronary syndrome and myocarditis
• Pulmonary embolism, pleuritis and pneumonia
• Aortic dissection
• Early repolarisation pattern
• Post-myocardial infarction and post-cardiac surgery syndromes
• Tuberculous, bacterial and malignant pericarditis
• Constrictive pericarditis
• Takotsubo syndrome
• Costochondritis and gastro oesophageal reflux
• Uraemic and radiation pericarditis

Restrict exercise until symptoms resolve and CRP and ECG normalise (athletes for at least 3 months).

Anti-inflammatory drugs (first line). Give with gastric protection (omeprazole 20 mg orally once daily, or pantoprazole 40 mg once daily when the patient also takes clopidogrel).

• Ibuprofen 600 mg orally every 8 hours (maximum 2.4 g daily), or aspirin 750 to 1,000 mg orally every 8 hours (maximum 4 g daily), or indomethacin 25 to 50 mg orally every 8 hours (maximum 150 mg daily; avoid in coronary disease).
• Continue until symptoms resolve and CRP normalises, then taper over weeks: reduce ibuprofen by 200 to 400 mg every 1 to 2 weeks, or aspirin by 250 to 500 mg every 1 to 2 weeks.
• Avoid in active peptic ulcer, creatinine clearance under 30 mL/min, and decompensated heart failure. Prefer aspirin when the patient takes antiplatelet therapy or has had a recent myocardial infarction. Monitor creatinine, blood pressure and gastrointestinal symptoms.

Colchicine (add to every episode).

• 0.5 mg orally once daily under 70 kg, or 0.5 mg twice daily at 70 kg or over, for at least 6 months in recurrent disease (many continue for 12 months), and taper at the end (reduce by 0.5 mg every other week). A loading dose is not used, because it increases gastrointestinal effects.
• At eGFR 30 to 50 mL/min/1.73 m2 give 0.5 mg once daily, and avoid under 30 mL/min/1.73 m2 except under specialist supervision. Avoid with strong CYP3A4 and P-glycoprotein inhibitors (clarithromycin, ketoconazole, ritonavir, ciclosporin, verapamil, diltiazem), and watch for myopathy with statins. Contraindicated with combined severe renal and liver impairment.
• Check full blood count, liver enzymes and creatine kinase at baseline and at 1 month, then every 3 to 6 months. Stop for severe diarrhoea, cytopenia or myopathy.

Corticosteroids (second line). Reserved for contraindication to, or failure of, anti-inflammatory drugs plus colchicine, after excluding infection and tuberculosis.

• Prednisolone 0.2 to 0.5 mg/kg orally once daily, kept until symptoms resolve and CRP normalises, then tapered slowly: over 25 mg daily, reduce by 5 to 10 mg every 1 to 2 weeks; 15 to 25 mg daily, by 2.5 mg every 2 to 4 weeks; under 15 mg daily, by 1.25 to 2.5 mg every 2 to 6 weeks. Continue colchicine throughout the taper.
• Add calcium and vitamin D, a gastroprotective drug, and monitor blood pressure, glucose and mood. High doses and rapid tapers raise recurrence.

Interleukin-1 blockade for steroid dependence or colchicine resistance with raised CRP.

• Anakinra 100 mg subcutaneously once daily (children 1 to 2 mg/kg daily, maximum 100 mg) for at least 6 to 12 months, then taper by lengthening the interval. At creatinine clearance under 30 mL/min give every other day. Check neutrophils monthly for 3 months and then every 3 months, and monitor liver enzymes, injection site reactions and infection. Screen for tuberculosis and hepatitis B first. Contraindicated in active infection and neutropenia. Avoid live vaccines.
• Rilonacept 320 mg subcutaneously as a loading dose, then 160 mg once weekly, in adults, with the same screening and monitoring.
• In resource limited settings where these are unavailable, use azathioprine 1 mg/kg orally once daily, increased to a maximum of 2 mg/kg daily (check TPMT or NUDT15 status first, with full blood count weekly for 4 weeks, then monthly; reduce to a quarter of the dose with allopurinol), or methotrexate 10 to 15 mg orally once weekly with folic acid 5 mg once weekly on a different day (avoid in pregnancy and at eGFR under 30 mL/min/1.73 m2; monitor full blood count and liver enzymes). Evidence for both is limited.
• Intravenous immunoglobulin 400 to 500 mg/kg daily for 5 days is an option in refractory cases, with weak evidence.

Specific causes.

• Tuberculous pericarditis: isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg (maximum 2 g) and ethambutol 15 mg/kg, each orally once daily for 2 months, then isoniazid and rifampicin for 4 months, with pyridoxine 25 mg once daily. Monitor liver enzymes at baseline, 2 weeks and monthly. Adjust pyrazinamide and ethambutol (three times weekly dosing) at creatinine clearance under 30 mL/min. Adjunctive steroids are decided by the specialist team, because benefit is limited and HIV status matters.
• Autoimmune and autoinflammatory disease: treat the underlying disease with the specialist team.

Pericardiocentesis for tamponade. Pericardiectomy for constriction that persists after medical therapy, and as a last resort for refractory recurrent disease.

Special groups.

• Pregnancy: ibuprofen or aspirin up to 20 weeks, with low dose aspirin only after 20 weeks. Prednisolone is acceptable at the lowest effective dose, and colchicine has limited data and is used when needed. Stop methotrexate before conception. Anakinra has limited data.
• Breastfeeding: ibuprofen and prednisolone are compatible, and colchicine has limited data.
• Kidney impairment: avoid anti-inflammatory drugs and reduce colchicine to 0.5 mg once daily at eGFR 30 to 50 mL/min/1.73 m2 and avoid it under 30 mL/min/1.73 m2.

Monitoring. CRP every 1 to 2 weeks during treatment and the taper until normal, then every 3 months. Echocardiography at 1 month and after any relapse. Full blood count, liver enzymes and creatine kinase on colchicine at 1 month and then every 3 to 6 months, creatinine and blood pressure on anti-inflammatory drugs, and neutrophils on anakinra. Taper only when symptoms have resolved and CRP is normal.

Referral and escalation. Refer to a pericardial disease clinic or cardiology for recurrence, and to rheumatology for refractory or autoinflammatory disease. Urgent for tamponade, suspected infection or malignancy, myopericarditis, or constriction.