|CASE BASED REVIEW
|Ahead of print publication
Fever, uveitis, and myocarditis as the initial presentation of Behcet's Disease: A case report and review of the literature
Vishal Mangal1, Yogendra Mishra1, Amar Tej Atal1, Divya Kochhar2, Durga Madhab Tripathy3, Manish Manrai1
1 Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Ophthalmology, Armed Forces Medical College, Pune, Maharashtra, India
3 Department of Dermatology, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Submission||20-Nov-2020|
|Date of Acceptance||12-Feb-2021|
Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
Behcet's disease (BD) is an inflammatory disease characterized by recurrent aphthous ulcers, genital ulcers, and eye involvement. The involvement of the vascular system, heart, lungs, gastrointestinal tract, and the brain is less common, and BD myocarditis is very rare, with only a few cases reported in the literature. The prevalence of BD is variable globally, with Turkey having the highest prevalence, with 370 cases/100,000 population. Out of the 17 criteria proposed for the diagnosis of BD, the most commonly used criteria are the International Study Group (ISG) on BD criteria and the “International Criteria of BD” (ICBD) criteria. We present a case of a 40-year-old female who presented with fever of unknown origin, oral ulcers, odynophagia, and a rash over the face, extremities, and trunk. She developed acute-onset bilateral painful red eyes in the hospital with marked diminution of vision and persistent tachycardia. On evaluation, she was diagnosed to have bilateral intermediate uveitis based on the clinical finding of conjunctival congestion, and 1+ cells in the anterior chamber of both eyes, dispersion of iris pigments on the anterior surface of lens bilaterally, and Grade 1 vitreous haze on slit-lamp examination. The patient had persistent tachycardia for which an electrocardiogram was done, which revealed nonspecific ST-changes. Echocardiography was done, which showed a left ventricular ejection fraction of 40%, with global hypokinesia, suggestive of myocarditis. Our patient fulfilled the ICBD criteria, and she tested positive for human leukocyte antigen B51. She also had persistent transaminitis, and on evaluation, she was found to have occult hepatitis B infection with possible reactivation. The final diagnosis of BD with myocarditis and occult hepatitis B infection was established. She was managed with oral glucocorticoids, colchicine, azathioprine, and entecavir with a favorable outcome. BD causing myocarditis is an infrequent presentation, and we could find only 15 cases reported in the literature since 1947 when Dr. Hulusi Behcet first described the disease.
Keywords: Behcet's disease, case report, fever of unknown origin, myocarditis
|How to cite this URL:|
Mangal V, Mishra Y, Atal AT, Kochhar D, Tripathy DM, Manrai M. Fever, uveitis, and myocarditis as the initial presentation of Behcet's Disease: A case report and review of the literature. Indian J Rheumatol [Epub ahead of print] [cited 2021 Jun 18]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=313582
| Introduction|| |
Behcet's disease (BD) is an inflammatory disease characterized by the triad of recurrent aphthous ulcers, genital ulcers, and eye involvement. It has also been described as a variable vessel vasculitis by the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. The prevalence of BD is variable globally, with Turkey having the highest prevalence, with 370 cases/100,000 population. It usually presents in the third to fourth decade of life, and it is unusual for the disease to occur during adolescence or after 40 years of age. Until 1991, to the best of our knowledge, only 19 cases were reported from India. Subsequently, till 2013, we could find only four studies from India, one from the rheumatology and dermatology department, and two from the ophthalmology department.,,, In India, the mean age of presentation ranges from 23 years to 33 years.,, Globally, the disease affects males predominantly; however, in India, the data are variable, with two studies showing male predominance, and one study demonstrated female preponderance. The cardiovascular system involvement in BD is seen in 7%–46% of the patients. The vascular involvement occurs in the form of superficial thrombophlebitis, deep vein thrombosis, aneurysms, Budd–Chiari syndrome, and cerebral venous sinus thrombosis. The heart involvement occurs in the form of pericarditis, myocarditis, endocarditis, intracardiac thrombus, interatrial septum aneurysm, mitral valve prolapse, and cardiomyopathy. To the best of our knowledge, no study from India has ever documented the involvement of the heart. We present a case of BD that initially presented with aphthous ulcers, fever of unknown origin (FUO), and subsequently developed bilateral uveitis and myocarditis, without any genital ulcer or arthritis.
| Case Report|| |
A 40-year-old female with no significant history presented with complaints of fever with chills, oral ulcers along with difficulty in swallowing, and conjunctival congestion of 8-day duration. On examination, she was afebrile with a pulse rate of 92 beats per minute and blood pressure of 142/86 mmHg. She had multiple aphthous ulcers over the tongue, soft palate, and postpharyngeal wall. She was initially managed with injectable empirical antibiotics. On day 15 of the illness, she developed a maculopapular rash involving the trunk, face, and extremities with surface excoriations and scaling. The rash was associated with pruritus [Figure 1]. Because of persistent odynophagia, an otorhinolaryngologist consultation was taken, and barium swallow was advised. The barium swallow revealed filling defects in the proximal part of the esophagus, likely mucosal erosions [Figure 2]. Initial laboratory evaluation was suggestive of anemia, transaminitis, and raised C-reactive protein [Table 1]. All the workup for tropical infections was negative with normal serum procalcitonin level and erythrocyte sedimentation rate of 36 mm fall in 1 h [Table 1]. She had total hepatitis B core antibody positive with hepatitis B e antigen detected suggesting a diagnosis of occult hepatitis B infection with possible reactivation. She continued to have a low-grade fever even after 3 weeks of the onset of her symptoms. The clinical diagnosis of FUO was made. She underwent contrast-enhanced computed tomography of the chest, abdomen, and pelvis, which did not reveal any obvious abnormality. The patient had persistent tachycardia for which an electrocardiogram was done, which revealed nonspecific ST-changes. Echocardiography was done, which showed a left ventricular ejection fraction of 40%, with global hypokinesia, suggestive of myocarditis. There were no vegetations, pericardial effusion, or clots. A cardiac magnetic resonance imaging was planned; however, the patient could not hold breath and had claustrophobia during the procedure, and it was abandoned. The diagnosis of systemic lupus erythematosus (SLE) was considered because of constitutional symptoms, skin involvement, oral ulcers, and myocarditis. Two weeks after admission, the patient developed a painful red eye with a diminution of vision in both eyes. An urgent ophthalmology consultation revealed distant visual acuity of 4/60 in the right eye and 2/60 in the left eye. On detailed evaluation, she had bilateral conjunctival congestion, the cornea was clear, the anterior chamber had 1+ cells in both eyes, iris pigments were dispersed on the anterior surface of the lens bilaterally, and Grade 1 vitreous haze was present [Figure 3]. She underwent optical coherence tomography of both eyes, which revealed cystoid macular edema with serous retinal detachment [Figure 4]. She was diagnosed with intermediate uveitis with anterior spillover uveitis with cystoid macular edema in both eyes and started on oral glucocorticoids at the dose of 1 mg/kg. Because of the anticipated prolonged glucocorticoid requirement, tablet entecavir 0.5 mg once a day orally was administered. Antinuclear antibody (ANA) by indirect immunofluorescence was negative. The detailed immunological workup is depicted in [Table 2]. Because of oral ulcers, skin involvement, bilateral uveitis, and myocarditis, she was evaluated for BD. She tested positive for human leukocyte antigen (HLA) B51; however, the pathergy test was negative. After the initiation of glucocorticoids, the patient had a remarkable recovery over the next 2 weeks. Her vision improved to 6/12 in the right eye and 6/24 in the left eye with pinhole. She was discharged with the final diagnosis of BD with bilateral uveitis, myocarditis, and occult hepatitis B infection. The informed written consent was obtained from the patient for publication of this article.
|Figure 1: (a) The yellow arrows show multiple confluent erythematous macules and plaques distributed over the photo-exposed surfaces of the face. The red arrowheads show scaling. The crusting of the lips is noted. (b) The trunk shows confluent hyperpigmented macules with surface excoriations with a characteristic rippled surface|
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|Figure 2: Barium swallow: The red arrow shows filling defects suggestive of mucosal erosions|
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|Figure 3: (a) Right eye, (b) Left eye showing posterior synechiae with the festooned appearance of the pupil on dilatation. Iris pigments dispersed on the anterior lens capsule in both eyes. (c) Right eye, (d) Left eye – Fundus photograph of showing Grade +1 vitreous haze due to anterior vitritis and periphlebitis in both eyes|
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|Figure 4: (a) Right eye, (b) Left eye – Initial HD: High Definition cross optical coherence tomography image showing cystoid macular edema with serous retinal detachment in both eyes. (c) Right eye, (d) Left eye – HD cross optical coherence tomography image after 1 week of treatment showing resolution of the macular edema and incomplete posterior vitreous detachment in both eyes with few retinal exudates in the left eye only (d)|
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| Discussion|| |
Dr. Hulusi Behcet was indeed not the first to identify this condition. Planner and Remenovsky had described a case similar to BD in the year 1922. In 1947, the medical world acknowledged Behcet's observations as a new disease, and Dr. Miescher proposed that the new disease be named “Morbus Behcet.” Nevertheless, Behçet credited Dr. Adamantiades' work in his original publication, and Behçet's syndrome is sometimes referred to as the “Adamantiades–Behçet syndrome.”
From 1946 to 2020, in 74 years, 17 sets of diagnostic criteria have been proposed. Out of these 17 criteria, the most commonly used criteria to diagnose BD are the Japan criteria (1972), the O'Duffy criteria (1974), the International Study Group (ISG) on BD criteria (1990/1992), the Dilsen criteria (1986), and the “International Criteria of BD” (ICBD) criteria (2006). Among the ISG and ICBD criteria, ISG has better specificity, and ICBD has better sensitivity. ICBD criteria utilize six items: oral ulcers; genital ulcers; skin involvement in the form of pseudofolliculitis or erythema nodosum; eye involvement in the form of anterior uveitis, posterior uveitis, and retinal vasculitis; vascular manifestations in the form of superficial thrombophlebitis; and deep vein thrombosis, aneurysms, and positive pathergy test. The presence of genital ulcers and eye lesions get two points each. The other four items get one point each. A patient has to get three or more points to be diagnosed/classified as having BD; however, oral ulcers are not mandatory. Our patient had oral ulcers (1 point), eye involvement (2 points), and skin involvement (1 point), all in all, a total score of four and hence diagnosed to have BD.
The most commonly used criteria do not include HLA-B51 positivity. HLA-B51 positivity is associated with a relative increase in the prevalence of genital ulcers, ocular or skin manifestations, and a 30% relative reduction in gastrointestinal tract involvement prevalence. HLA-B51 positivity is seen in 50%–72% of the BD patients. Our patient also tested positive for HLA-B51 and had bilateral uveitis and skin involvement. However, she did not have genital ulcers. This can be attributed to the fact that she presented for the first time. She needs to be followed up in the future to see if genital ulcers develop.
A positive pathergy phenomenon is defined as the formation of erythematous nodule or pustule more than 2 mm in diameter on the skin following a prick by a sterile needle. It is commonly associated with BD, Sweet's syndrome, inflammatory bowel disease, and spondyloarthropathies. We performed a pathergy test in our patient by pricking the skin (3 mm deep) over the right forearm's ventral aspect with the help of a 21G blunt hypodermic needle. It was read at 48 h and reported as negative by one of the authors. In India, the pathergy test was found positive in 14.8% of the patients in a study by Pande et al. and in 31% of the patients in a study by Singal et al. Pathergy phenomenon is part of the ICBD criteria, and a positive test is scored one point. However, it is not mandatory for BD's diagnosis, as was the case with our patient.
Our patient initially presented as a case of FUO. In their study, Mir et al. described infections as the most common cause of FUO, followed by noninfectious inflammatory diseases and malignancies. In our patient following the potentially diagnostic clues of oral ulcers, and bilateral uveitis, we considered the diagnosis of BD. Few case reports have reported FUO as the initial presentation of BD similar to our case., Patients with inflammatory bowel disease, SLE, reactive arthritis, and herpetic infections can mimic BD and shall be ruled out first. SLE can have a very similar presentation to BD and can involve all the organs involved in BD in a similar fashion. However, inflammatory thrombi are not usually seen in SLE, and the SLE-specific autoantibodies can help differentiate these two conditions. Our patient was also initially evaluated for SLE; however, it was ruled out by negative ANA.
The most common skin manifestations in BD are papulopustular lesions, erythema nodosum lesions, thrombophlebitis, and varied cutaneous and vasculitic lesions. The papulopustular lesions are clinically similar to lesions of acne vulgaris, and they are seen in patients with positive pathergy reaction and joint involvement. Our patient did not have a positive pathergy response, joint involvement, or papulopustular eruptions. Instead, she had a maculopapular rash involving the trunk, face, and extremities with surface excoriations and scaling. This has not been described previously in the literature.
The involvement of the heart per se is rare in BD. In a study by Geri et al., on cardiac manifestations in BD, pericarditis was seen in 38%, endocarditis in 26% of the patients (which can present as aortic regurgitation or mitral valve incompetence), intracardiac thrombus in 19%, myocardial infarcts in 17%, endomyocardial fibrosis in 7%, and myocardial aneurysm in 2% of the patients. To the best of our knowledge, none of the studies from India has ever reported cardiac involvement in BD.,,, Our patient has cardiac involvement in the form of myocarditis, which was evident clinically in the form of palpitations and persistent tachycardia and on echocardiography in the form of global hypokinesia. Myocarditis is an infrequent occurrence in BD, and we could find only 15 cases reported in the literature. To the best of our knowledge myocarditis, whether clinical or subclinical, as a manifestation of BD, has never been reported from India. The published literature was searched using PubMed and Google Scholar databases to search terms of BD, cardiac disease, and myocardial disease. We also scanned the reference list of the articles found on these platforms. All relevant studies were included in the review. The intracardiac thrombus cases were also included as it can be caused by endocarditis, myocarditis, or both. The summary of the literature for myocarditis in BD is given in [Table 3].,,,,,,,
BD runs a relapsing, remitting course, and the goal of treatment is to suppress the inflammation and prevent organ damage due to repeated attacks. The European League against Rheumatism (EULAR) 2018 guidelines on the management of BD recommends topical steroids for oral and genital ulcers. Due to colchicine's excellent safety profile, it should be used as first-line therapy for preventing the recurrences of mucocutaneous manifestations. Our patient was also managed with oral colchicine 0.5 mg orally once a day for oral ulcers and skin lesions. Despite colchicine, other immunomodulatory drugs such as azathioprine, thalidomide, and tumor necrosis factor (TNF) inhibitors can be used in refractory mucocutaneous disease. The newer biological such as anakinra, canakinumab, and ustekinumab has also shown efficacy in refractory mucocutaneous disease.
The patients with posterior uveitis should be managed with high-dose glucocorticoids along with azathioprine, cyclosporine, anti-TNF monoclonal antibodies, or interferon-alpha. Our patient had intermediate uveitis with anterior spillover uveitis and was managed with oral glucocorticoids at the dose of 1 mg/kg with remarkable recovery within 2 weeks. EULAR recommends that azathioprine can be used in patients with poor prognostic factors (young age, male sex, and early-onset disease) in anticipation as some of these patients with anterior uveitis may develop posterior uveitis over time, and it is challenging to predict the patients who are at high risk. Based on this recommendation, we initiated her on azathioprine 50 mg once a day. The EULAR recommendations have not described the management of cardiac disease in BD. However, the general principles of therapy remain the same. Myocarditis is extremely rare in BD, and no guidelines exist for its management. We administered colchicine and glucocorticoids for myocarditis with a favorable outcome. She underwent whole-body positron emission tomography 2 weeks after discharge, which did not show any metabolically active lesion in the heart.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sakane T, Takeno M, Suzuki N, Inaba G. Behçet's disease. N Engl J Med 1999;341:1284-91.
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al
. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1-1.
Kaklamani VG, Variopoulos G, Kaklamanis PG. Behçet's disease. Semin Arthritis Rheum 1998;27:197-217.
Pande I, Uppal SS, Kailash S, Kumar A, Malaviya AN. Behçet's disease in India: A clinical, immunological, immunogenetic and outcome study. Br J Rheumatol 1995;34:825-30.
Sachdev N, Kapali N, Singh R, Gupta V, Gupta A. Spectrum of Behçet's disease in the Indian population. Int Ophthalmol 2009;29:495-501.
Singal A, Chhabra N, Pandhi D, Rohatgi J. Behçet's disease in India: A dermatological perspective. Indian J Dermatol Venereol Leprol 2013;79:199-204. [Full text]
Rohatgi J, Singal A. Ocular manifestations of Behcet's disease in Indian patients. Indian J Ophthalmol 2003;51:309-13.
] [Full text]
Demirelli S, Degirmenci H, Inci S, Arisoy A. Cardiac manifestations in Behcet's disease. Intractable Rare Dis Res 2015;4:70-5.
Tan SY, Poole PS. Hulusi Behçet (1889-1948): Passion for dermatology. Singapore Med J 2016;57:408-9.
Zouboulis CC, Kaklamanis P. Early descriptions of Adamantiades Behçet's disease. Ann Rheum Dis 2003;62:691-2.
Davatchi F, Sadeghi Abdollahi B, Chams-Davatchi C, Shahram F, Shams H, Nadji A, et al
. The saga of diagnostic/classification criteria in Behcet's disease. Int J Rheum Dis 2015;18:594-605.
Maldini C, Lavalley MP, Cheminant M, de Menthon M, Mahr A. Relationships of HLA-B51 or B5 genotype with Behcet's disease clinical characteristics: Systematic review and meta-analyses of observational studies. Rheumatology (Oxford) 2012;51:887-900.
Sequeira FF, Daryani D. The oral and skin pathergy test. Indian J Dermatol Venereol Leprol 2011;77:526-30.
] [Full text]
Mir T, Nabi Dhobi G, Nabi Koul A, Saleh T. Clinical profile of classical Fever of Unknown Origin (FUO). Caspian J Intern Med 2014;5:35-9.
Samad T, Ahmed J, Rahim M, Musa A, Uddin K, Ahmed A, et al
. Behcets disease presenting as fever of unknown origin: A case report. BIRDEM Med J 2013;3:50-3.
Fatima J, Shukla V, Karoli R. Behçet's syndrome presenting as FUO. J Assoc Physicians India 2010;58:331-2.
Scherrer MA, Rocha VB, Garcia LC. Behçet's disease: Review with emphasis on dermatological aspects. An Bras Dermatol 2017;92:452-64.
Geri G, Wechsler B, Thi Huong DL, Isnard R, Piette JC, Amoura Z, et al
. Spectrum of cardiac lesions in Behçet disease: A series of 52 patients and review of the literature. Medicine (Baltimore) 2012;91:25-34.
Lakhanpal S, Tani K, Lie JT, Katoh K, Ishigatsubo Y, Ohokubo T. Pathologic features of Behçet's syndrome: A review of Japanese autopsy registry data. Hum Pathol 1985;16:790-5.
Higashihara M, Mori M, Takeuchi A, Ogita T, Miyamoto T, Okimoto T. Myocarditis in Behcet's disease – A case report and review of the literature. J Rheumatol 1982;9:630-3.
Kechida M, Salah S, Kahloun R, Klii R, Hammami S, Khochtali I. Cardiac and vascular complications of Behçet disease in the Tunisian context: Clinical characteristics and predictive factors. Adv Rheumatol 2018;58:32.
Hammami AS, Jellazi M, Ben-Brahim M, Daada S, Hassine M, Kechida M, et al
. Cardiac complication spectrum of Behçet disease in Tunisia: A 10-case series: Clinical and therapeutic approach. Research Square: rs-23761v1 [Preprint].2020 [26 p.]. Available from:https://doi.org/10.21203/rs.3.rs-23761/v1
. [Last accessed on 2020 Nov 19].
Maeda S, Tamura A, Zaizen H, Takahashi N. Behçet's disease complicated by giant-cell myocarditis. Intern Med 2014;53:1721.
Ghorbel IB, Belfeki N, Houman MH. Intracardiac thrombus in Behçet's disease. Reumatismo 2016;68:148-53.
Adamjee QR, Hamid OM, Bashir Y, Colaco BC. Cardiac presentation of Behcet's disease: The impact of HLA-B51 positivity in early diagnosis. Rheumatol Adv Pract 2018;2 Suppl 1:rky034.050. doi: 10.1093/rap/rky034.050.
Kechida M, Jomaa W, Maatouk M. A Case of Behçet Disease Myocarditis Documented Using Cardiac Magnetic Resonance Imaging. Can J Cardiol 2020;36:1554.e9-1554.e11. doi: 10.1016/j.cjca.2020.05.006.
Hatemi G, Christensen R, Bang D, Bodaghi B, Celik AF, Fortune F, et al
. Update of the EULAR recommendations for the management of Behçet's syndrome. Ann Rheum Dis 2018;77:808-18.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]