Premature coronary disease, in-stent restenosis and vascular complications in a young man with Behçet syndrome

Abstract

A young man with a history of early-onset coronary disease presented with an ST-elevation myocardial infarction at the age of 38. He subsequently had recurrent in-stent restenosis requiring repeating interventions and ultimately bypass surgery. After 4 years, he presents with systemic symptoms, new skin lesions and a femoral artery pseudoaneurysm. He is diagnosed with Behçet syndrome, a rare systemic vasculitis characterised by the triad of oral aphthous ulcers, genital ulcers and ocular involvement. Behçet is not associated with premature coronary disease but can have a variety of cardiac complications. Additionally, pathergy, an exaggerated inflammatory response to local injury, is characteristic. We hypothesise that in retrospect, subclinical inflammation and a vascular pathergy likely predisposed him to his cardiac and vascular complications. Here, we review risk factors and presentation of premature coronary artery disease and review the literature on the cardiovascular complications of Behçet syndrome.

Background

Symptomatic coronary artery disease (CAD) in patients less than 40–45 years of age is uncommon, but still represents approximately 4%–10% of patients presenting with myocardial infarction (MI).¹ Many patients have typical cardiovascular risk factors, though younger patients more frequently have a family history of CAD and are more commonly smokers, while diabetes and hypertension are less common.² Hyperlipidaemia has similar prevalence in young versus old patients. Younger patients are more likely to present with acute coronary syndrome as oppose to progressive angina,³ and have a higher incidence of single vessel-coronary disease with a predilection for involvement of the left anterior descending (LAD) artery. In patients both with and without these risk factors, it is important to consider other systemic diseases that could be leading to coronary disease in a young patient.

Case presentation

A 38-year-old Southeast Asian man presented to the hospital with 2 months of subjective fevers, fatigue, malaise, weight loss, skin lesions and genital ulcers. He had a history that was significant for an ST-elevation MI 4 years ago with a drug-eluting stent placed to the LAD (figure 1). After 1 year, he had presented with a non-ST-elevation MI and was found to have significant in-stent restenosis (ISR) of the LAD-requiring intravascular-guided restenting to assure good stent apposition. This was complicated by a radial artery dissection and compartment syndrome. After 1 year, repeat catheterisation with a femoral approach showed recurrent ISR of his LAD (figure 2). He then underwent single-vessel bypass surgery. He had subsequently remained asymptomatic from a coronary perspective. Throughout this time, he had no other systemic symptoms.

Figure 1.

Timeline of clinical course. CABG, coronary artery bypass graft; DES, drug-eluting stent; ISR, in-stent restenosis; LAD, left anterior descending; NSTEMI, non-ST-elevation myocardial infarction; PCP, primary care physician.

Figure 2.

Cardiac catheterisation showing in-stent restenosis of his LAD. LAD, left anterior descending.

On his examination during this admission, which was over 2 years since his last instrumentation, he was found to be afebrile with normal vital signs. He had a left groin palpable pulse and bruit, ulcerations of his buccal mucosa, genital ulcerations without scarring, erythematous papules on his upper extremities in antecubital spaces at prior intravenous sites, a hyperpigmented sternotomy scar and tenderness to palpation along several metatarsophalangeal joints bilaterally (figure 3). His cardiovascular examination was unremarkable.

Figure 3.

Physical examination findings. (A) Genital ulcer, (B) oral ulcer and (C) skin pathergy in his antecubital fossa at site of prior peripheral intravenous.

His medical history was notable for coronary disease as described above, familial combined hyperlipidaemia, elevated lipoprotein(a), hypothyroidism and eczema. He had no history of smoking or drug use. His family history was notable for coronary disease in his father in his 30s.

Investigations

His admission labs were notable for an elevated erythrocyte sedimentation rate of 46 and C-reactive protein level of 44; other labs including white blood cell count and troponin were within normal limits. His ECG showed normal sinus rhythm with new anterior T-wave inversions. CT of his abdomen/pelvis showed two left common femoral artery pseudoaneurysms measuring 8 and 11 mm. Transthoracic echocardiogram showed normal left ventricular size and function, with an echo-bright area of his septum suggestive of scar or fibrosis. Cardiac MRI also revealed areas of non-ischemic late gadolinium enhancement in the lateral left ventricular wall and right ventricular wall that were suggestive of systemic disease.

Treatment

Vascular surgery was consulted, and a joint decision was made to defer repair of his pseudoaneurysms pending further work-up of a suspected infectious versus inflammatory condition. Rheumatology and dermatology were consulted. Pathergy testing was performed which was positive. He was diagnosed with Behçet syndrome. He was started on prednisone and had normalisation in his inflammatory markers.

Outcome and follow-up

His systemic symptoms markedly improved, though while attempting to wean off steroids, he had recurrent episodes of superficial vein thromboses, necessitating anticoagulation. He has also had flares of oral ulcers. Prednisone was increased to 40 mg daily and azathioprine was started as a steroid-sparing agent. This was switched to adalimumab due to transaminitis. At time of this publication, he was stable on prednisone 10 mg daily and adalimumab 40 mg weekly. Further attempts to wean prednisone have resulted in recurrent skin lesions, ulcers and arthralgias. He is also combatting weight gain and mood irritability due to prednisone. Given ongoing disease activity, he has remained on prophylactic anticoagulation with apixaban 2.5 mg two times per day. Over 1 year after his diagnosis, he has not had recurrent angina or other cardiac complaints.

Discussion

We present an unusual case of premature CAD and vascular complications in a young man who was subsequently diagnosed with Behçet syndrome. His clinical manifestations are summarised in box 1. Behçet syndrome is a rare systemic vasculitis that typically affects young adults age 20–40.⁴ Most cases are sporadic, though having a first degree relative with Behçet syndrome does increase risk of the disease. It is more common along the ancient ‘Silk Road’ from Asia to the Mediterranean, with the highest prevalence in Turkey. Behçet syndrome is a unique vasculitis in that it can affect small, medium and large vessels. It classically is characterised by the triad of oral aphthous ulcers, genital ulcers and ocular involvement, though it can have neurologic, arthritic, renal, pulmonary, vascular and cardiac involvement as well. Skin pathergy, which is a profound inflammatory response to local injury, is characteristic.⁵

Box 1. Clinical manifestations of Behcet's in this patient.

• Pathergy at site of prior intravenouses

• Arterial pseudoaneurysm and dissection

• Mucosal ulcers.

• Genital ulcers

• Skin lesions

• Superficial thrombophlebitis

Vascular involvement occurs in an estimated 14.3%⁶ of patients and can include venous disease and thrombosis, as well as arterial occlusions or aneurysm formation—both spontaneous or after instrumentation.^{7 8} The most common vascular manifestations are superficial vein thrombosis (53.3%), followed by deep vein thrombosis (29.8%) and less commonly arterial lesions (3.6%).⁶ It remains unclear whether venous disease in these patients is best treated with immunosuppression alone or immunosuppression plus systemic anticoagulation.⁹ Arterial aneurysms can occur both in the coronary arteries as well as pulmonary artery, and are morbid complications.¹⁰

Cardiac involvement is estimated to occur in 7%–46% of patients.⁴ The underlying process of cardiac and vascular involvement is a T-cell-mediated autoimmune reaction leading to neutrophilic infiltration and vascular destruction.⁴ This can result in aneurysm formation, endothelial dysfunction and thrombosis. Additional cardiac manifestations can include pericarditis, endocarditis, intracardiac thrombosis, MI, endomyocardial fibrosis, conduction disease, cardiomyopathy and subclinical systolic or diastolic dysfunction.¹⁰

Involvement of the coronary arteries themselves is a rare but significant complication. In a recent case–control study of 476 patients with Behçet syndrome, only 4% had coronary involvement.¹¹ Coronary stenoses were the most common lesions (68%), followed by aneurysms (47%) and occlusions (16%). The LAD was involved 68% of the time. Patients presented most commonly with angina (42%) or an acute MI (42%). The presence of pathergy, extracardiac vasculitis and elevated inflammatory markers were more common in patients with coronary involvement than those without, though in a multivariate analysis only the presence of pathergy predicted coronary involvement. The data are unclear as to whether Behçet syndrome itself results in accelerated atherosclerosis, as is seen in other autoimmune diseases such as systemic lupus erythematous. There are data both for¹² and against¹³ increased subclinical atherosclerosis in this population. However, CAD does appear to occur at a younger age in Behçet syndrome, which would suggest an accelerated course of atherosclerosis may be occuring.¹⁴ Given the rarity of the disease, there is extremely limited data on the risk of ISR or bypass graft patency. In the study discussed above,¹¹ 2 of 19 patients with coronary involvement had progression of their disease during a median follow-up of 15 months. Further research is needed to determine whether Behçet syndrome is an independent risk factor for CAD and to characterise outcomes after revascularisation.

Our patient did have typical coronary disease risk factors (family history of CAD in his father though no known history of Behçet syndrome, hyperlipidaemia), which could have contributed to his early-onset CAD. Ophthalmological evaluation did not reveal atherosclerosis of his retinal arteries. However, it is peculiar that he had recurrent ISR of his LAD stent in a short time frame. We hypothesise that there was a disproportionate inflammatory response to the vessel injury during stent placement that led to premature restenosis, that is, a ‘vascular pathergy’ response. Additionally, he had multiple vascular complications from his cardiac catheterisations including a radial artery dissection and pseudoaneurysm. All of this occurred prior to any systemic symptoms and his diagnosis of Behçet syndrome, but it seems quite plausible that a subclinical inflammatory state existed in the years prior to his diagnosis that predisposed him to these vascular complications. Our patient was also noted to have areas of endomyocardial fibrosis, which is known to occur in Behçet syndrome,¹⁰ and was unlikely to be from ischemia. Fortunately, at this point his overall cardiac function remains preserved.

Overall, there exists a paucity of data on the management and clinical outcomes of coronary disease in these patients. Classic risk factor modification in addition to immunosuppression for Behçet syndrome is the typical approach.

Learning points.

• Behçet syndrome is a systemic vasculitis, which can rarely have involvement of the coronary arteries.

• Behçet syndrome can manifest with non-specific systemic symptoms and a range of laboratory, imaging and histologic features.

• Behçet syndrome follows a distinct pattern of vasculitic involvement and classically presents with the triad of oral aphthous ulcers, genital ulcers and ocular involvement.