Cyclosporine-induced pericarditis: an elusive cause of chest pain in Behçet’s disease

Abstract

Behçet’s disease (BD) is a variable-vessel vasculitis which commonly presents with recurrent orogenital ulceration, skin lesions, visual disturbances and neurodeficits. Arterial involvement is seen variably in 8%–18% cases of BD, with common affliction of the carotid, pulmonary, aortic and iliofemoral arteries. Cardiac involvement in the form of myocarditis, myocardial infarction, pericarditis, cardiac dysrhythmias or valvular disease is also known in BD, although rarely. Sudden-onset chest pain in BD is a medical emergency, with acute coronary syndrome, pulmonary thromboembolism and rupture of aortic or pulmonary artery aneurysms being the commonly implicated causes. Here, we report a rare case of BD who presented with sudden-onset severe chest pain, the cause of which remained elusive despite extensive evaluation for the abovementioned causes. To the best of our knowledge, this is the first reported case of cyclosporine-induced pericarditis in BD in available literature and should be considered in patients on cyclosporine presenting with chest pain.

Background

Behçet’s disease (BD) is a variable-vessel vasculitis commonly presenting with recurrent orogenital ulceration, skin lesions, visual disturbances and neurological deficits.¹ Arterial involvement is seen in 8%–18% cases of BD, with common affliction of the carotid, pulmonary, aortic and iliofemoral arteries.² Coronary artery vasculitis with or without aneurysms is uncommon. Cardiac involvement in the form of myocarditis, myocardial infarction, pericarditis, cardiac dysrhythmias or valvular disease is also known in BD, although rarely.³ Chest pain in patients with BD is usually attributable to cardiac or major vessel involvement, with myocardial infarction, pulmonary embolism and rupture of aortic or pulmonary artery aneurysm being commonly implicated fatal causes. Here we report, for the first time, a rare case of BD who presented with severe chest pain, the cause of which remained elusive despite extensive evaluation for these causes.

Case presentation

An 18-year-old thin built North Indian boy, presented to the ophthalmology services with gradually progressive, painful diminution of vision in both eyes for last 2 years. There was no history of redness of eyes or floaters or excessive tearing. He was evaluated and found to have bilateral panuveitis with retinal vasculitis (fern-like pattern of vascular leakage on fluorescein angiography). The patient was referred to the rheumatology services for possibility of an underlying systemic aetiology. There was no history of prolonged cough or tuberculosis or contact with tuberculosis. There was no history of recurrent oral ulceration, skin rash, headache, seizures or neuropathy. There were no sinonasal,musculoskeletal, lower respiratory or urinary complaints. A history of genital ulceration was present. On examination, acneiform lesions were noticed over the back and the chest. Rest of the general physical and systemic examination was unremarkable. Human Leucocyte Antigen (HLA-B51) by PCR and pathergy tests were negative. He was classified as a case of BD (ocular predominant) as per 2014 International Criteria for Behcet’s disease and started on oral prednisolone (1 mg/kg/day) with azathioprine.⁴ He improved symptomatically but had a relapse on tapering prednisolone <20 mg/day, requiring escalation of steroid dose and addition of cyclosporine. Two weeks later, he started complaining of episodic precordial (non-radiating) chest pain, squeezing in character; initially exertional (NYHA II) but progressing to rest symptoms within 1 week. There was no associated fever or mucosal ulceration or skin rash or any worsening of ocular symptoms. His vitals were stable. General physical examination was unremarkable, except for acneiform lesions over the back (now healed). Cardiovascular and systemic examination was unremarkable.

Investigations

Hemogram, liver function and renal functions were within normal limits. Inflammatory markers were elevated (erythrocyte sedimentation rate of 42 mm in the first hour, high sensitivity C-reactive protein of 21 mg/L). ECG showed progressive ST segment elevation in multiple precordial leads with subtle PR segment depression and absence of reciprocal ST segment depression (figure 1A). Viral markers, Venereal Disease Research Laboratory test, Treponema pallidum hemagglutination, Mantoux test and chest X-ray were normal. His cardiac enzymes, N-terminal Pro-Brain natriuretic peptide and D-Dimer were also normal. 2D echocardiography showed left ventricular ejection fraction (LVEF) of 60% without any wall-motion abnormality or pericardial effusion or evidence of pulmonary hypertension or left ventricular hypertrophy. The deep S waves seen in precordial leads were consequently attributed to the slender built of the patient. Coronary angiogram and CT pulmonary angiography were within normal limits, with no evidence of aneurysm or vascular occlusion. A detailed ocular evaluation using slit lamp biomicroscopy, funduscopy and fluorescein angiography ruled out any activity in the eye.

Figure 1.

ECG at presentation (A) and after stopping cyclosporine and giving non-steroidal anti-inflammatory drugs (B).

Differential diagnosis

Sudden onset chest pain in BD is a medical emergency, warranting expeditious evaluation. Acute coronary syndrome, pulmonary thromboembolism and rupture of aortic or pulmonary artery aneurysms are potentially fatal causes of chest pain in BD. These were ruled out in the index case through appropriate investigations. Other sinister causes of chest pain in BD include coronary arteritis and pericarditis related to active disease. However, the index case was on high dose prednisolone (1 mg/kg/day), azathioprine (2 mg/kg/day) and cyclosporine at the time of onset of chest pain, with ocular and systemic disease in remission, making disease activity unlikely. The patient was noticed in-hospital to prefer a leaning forward habitus. With suggestive clinical presentation, ECG features, onset of symptoms after starting cyclosporine and a negative diagnostic evaluation for other etiologies, a diagnosis of cyclosporine-induced acute pericarditis was considered.

Treatment

Cyclosporine was withheld and a brief course of non-steroidal anti-inflammatory drugs (NSAIDs) was given.

Outcome and follow-up

The patient had a prompt response to the treatment instituted. ECG changes reverted to normal (figure 1B) and patient was discharged with no recurrence of symptoms till last follow-up visit (8 months after the index event).

Discussion

Careful observation of preferred patient habitus (leaning forward) during hospital stay, along with temporal correlation of symptom onset with starting of cyclosporine, suggestive ECG changes and treatment response to cyclosporine withdrawal and brief course of NSAIDs helped to clinch the diagnosis in our case. Cyclosporine is commonly employed in the treatment of BD, especially for ocular disease. Although it is listed as an implicated drug in drug-induced pericarditis as per the European Society of Cardiology Task Force guidelines on diagnosis and management of pericardial diseases,⁵ we could find only one reported case of cyclosporine-induced pericardial effusion in available literature, that too in a postcardiac transplantation setting.⁶ Very little is known about the underlying pathogenetic mechanism,⁵ which might be idiosyncratic as the pericarditis in the index patient developed at the low starting dose. No component of pericardial effusion was noted in our patient. Prompt reversal with discontinuation of cyclosporine therapy is reassuring. Pericarditis due to BD itself is an important diagnostic consideration that needs to be teased out in such cases, after having ruled out more common causes of acute pericarditis. The fact that pericarditis occurred while on intensive immunomodulatory therapy, in the absence of disease activity elsewhere, and did not recur even after 8 months of stopping cyclosporine and de-escalation of therapy for underlying BD, is what makes it very unlikely to be ‘per se’ due to BD in the presented case. To the best of our knowledge, this is the first reported case of cyclosporine-induced pericarditis in BD in available literature, and we would like to emphasise this as a diagnostic consideration in patients of BD (or other diagnoses) on cyclosporine therapy presenting with chest pain.

Learning points.

• Sudden-onset chest pain in a case of Behçet’s disease (BD) is a medical emergency, necessitating expeditious evaluation.

• Pulmonary thromboembolism, myocardial infarction and rupture of aortic and/or pulmonary artery aneurysm are potentially fatal causes of chest pain in BD.

• Cyclosporine-induced pericarditis should be considered as a differential, especially in the setting of a negative diagnostic evaluation for abovementioned causes.