pISSN: 2093-940X, eISSN: 2233-4718 Journal of Rheumatic Diseases Vol. 24, No. 5, October, 2017 https://doi.org/10.4078/jrd.2017.24.5.303 Case Report

Focal Eosinophilic Associated with Behçet's Disease

Jung Su Eun1, Jong Wan Kang1, Jin Young Kang2, Na Ri Kim1, Sang Jin Lee1, Young Mo Kang1, Man Hoon Han3, Eon Jeong Nam1 1Division of , Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, 2Division of Rheumatology, Department of Internal Medicine, Changwon Fatima Hospital, Changwon, 3Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea

Behçet’s disease (BD) is a systemic vasculitis commonly accompanied by recurrent mucosal ulceration and other systemic man- ifestations, but rarely by myositis. Focal eosinophilic myositis is the most limited idiopathic eosinophilic charac- terized by peripheral blood eosinophilia and/or eosinophilic muscle infiltration. Clinical manifestations include , mus- cle weakness, and cutaneous lesions, such as subcutaneous induration and erythema. Given that BD can mimic deep vein thrombosis or pseudotumor, muscle biopsy should be performed to enhance the accuracy of diagnosis. Microscopic examina- tion reveals extensive infiltration of eosinophils and mononuclear cells into muscle, myofiber necrosis, and regeneration. To the best of our knowledge, there have not been any published reports on MEDLINE regarding focal eosinophilic myositis asso- ciated with BD. Here, we presented a case of focal eosinophilic myositis associated with intestinal BD in a 23-year-old man who suffered from a large ulcer in the terminal ileum. (J Rheum Dis 2017;24:303-308)

Key Words. Behçet’s disease, Idiopathic eosinophilic myopathy, Focal eosinophilic myositis

INTRODUCTION ositis [1,6]. Eosinophilic infiltration into , although Behçet’s disease (BD) is a systemic vasculitis, charac- rare, has been described in a diverse group of conditions, terized by vascular injury, hyperfunction of neutrophils, including drugs such as L-tryptophan, D-penicillamine and autoimmune responses and clinically often presented and ethanol, parasitic infection, autoimmune diseases with mucous membrane ulceration, skin lesions and ocu- such as rheumatoid arthritis, myasthenia gravis and eosino- lar symptoms [1,2]. Gastrointestinal (GI) involvement in philic granulomatosis with polyangiitis, eosinophilia-myal- BD is particularly important as it is one of serious and dif- gia syndrome, and idiopathic eosinophilic myopathy ficult to treat; therefore, BD is designated ‘‘intestinal [7,8]. Although pathogenesis of eosinophilic BD,’’ if a typical oval-shaped large ulcer in the terminal is incompletely understood, it is suggested that inter- ileum or ulcerations in the GI tract are objectively docu- leukin-5 is stimulated by a precipitating factor, and the in- mented [2,3]. Musculoskeletal involvement is one of the flammatory mediators by eosinophil including cationic most frequent findings in BD, of which arthritis and ar- protein, eosinophilic major basic protein, and enzymes, thralgia are the most common findings [1,4]. Myositis is increase in the target tissues and blood [8]. Idiopathic eo- rare manifestation in BD and is usually mild, short-last- sinophilic myopathy is a rare, clinically and pathologically ing, and more localized than generalized form [5]. Histologic heterogeneous disease, characterized by the presence of examination reveals a predominant neutrophil infiltra- peripheral and/or muscle eosinophilia [8]. Clinical mani- tion associated with focal necrosis and perivasculitis, sug- festations include myalgia, , edematous gesting vasculitis participates in the pathogenesis of my- changes of extremities, arthralgia/arthritis, and skin

Received：March 21, 2017, Revised：April 12, 2017, Accepted：April 19, 2017 Corresponding to：Eon Jeong Nam, Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital, 130 Dongdeok-ro, Jung-gu, Daegu 41944, Korea. E-mail：[email protected]

Copyright ⓒ 2017 by The Korean College of Rheumatology. All rights reserved. This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

303 Jung Su Eun et al. lesions. Cutaneous manifestations include deep subcuta- covered by normal skin at the back of right upper arm and neous induration, erythema, urticarial or angioedema- several subcutaneous induration with tenderness of the tous plaques, and erythematous papular lesions, in which left flank and the right lower leg. In manual muscle test, deep subcutaneous induration is the most common find- there was no evidence of muscle weakness of both upper ing [9,10]. Biopsy of cutaneous lesions demonstrates and lower extremities. Pathergy test was positive. scanty-to-moderate perivascular mononuclear infiltrates Laboratory examination revealed a white blood cell with a considerable variability in the number of admixed count of 9,890/μL (eosinophil count 380/μL, 3.8%), er- eosinophils, ranging from lymphocytic vasculitis devoid ythrocyte sedimentation rate of 40 mm/h (normal, 0∼ of eosinophils to eosinophilic cellulitis-like lesions [9]. 10), C-reactive protein of 2.13 mg/dL (0∼0.5), creatine Most, if not all, of the patients represent peripheral or tis- phosphokinase of 33 μL (39∼308), lactate dehydrogen- sue eosinophilia, and elevated muscle enzymes [10]. ase of 392 μL (0∼250), myoglobin of 18 ng/mL (14∼ Although connective tissue disorders may be related 106), and aldolase of 15.4 μL (0∼7.6). Results of im- with eosinophilic myopathy [8] and the localized form of munological analyses were as follows: immunoglobulin myopathy can be presented as the musculoskeletal mani- (Ig) G 1,643 mg/dL (700∼1,600), IgA 237 mg/dL (70∼ festation of BD [4,5], there are no published case reports 400), IgM 154 mg/dL (94∼230), C3 132.3 mg/dL (90∼ that the localized form of myopathy in patients with BD 180), C4 34.9 mg/dL (10∼40), antinuclear antibody neg- was identified as focal eosinophilic myositis when sear- ative, rheumatoid factor negative, and anti-neutrophil cy- ched on MEDLINE. Herein, we present a case of focal eo- toplasmic antibody negative. sinophilic myositis associated with intestinal BD in a Chest X-ray, electrocardiogram, and echocardiogram 23-year-old man who suffered from a large ulcer in the findings were all nonspecific. The patient complained of terminal ileum. persistent abdominal pain and underwent abdominal computed tomography (CT) and colonoscopy. Abdominal CASE REPORT CT showed a wall thickening at the terminal ileum (Figure 1A), and colonoscopy revealed a huge, round A 23-year old man who had a history of recurrent oral ul- well-demarcated ulcer with central yellowish at cerations and pseudofolliculitis was admitted to our hos- the terminal ileum (Figure 1B). The mucosal biopsies of pital with abdominal pain and a mass in the right upper intestinal lesions showed chronic without arm. Six months ago, he began to have recurrent right . Magnetic resonance image (MRI) study of the lower abdominal pain, several subcutaneous nodules, right upper arm demonstrated a focal mass lesion meas- and, at the same time, a persistent painful firm mass ap- uring 3.0 cm (length)×2.0 cm (width) in the right triceps peared on the right upper arm. He had no past history of muscle with a heterogeneous hyper-intense signal on drug medication or allergic diseases. The abdominal ex- T2-weighted image (Figure 2A). On a gadolinium en- amination revealed tenderness in right lower quadrant. hancement T1-weighted image of MRI, the lesions ap- There were about a 3 cm-sized firm, nonmovable mass peared to be a well-defined rim of contrast enhancement

Figure 1. (A) Abdominal con- trast-enhanced computed to- mography shows a wall thick- ening and mucosal enhancement at the terminal ileum (arrows), suggesting terminal ileitis. (B) Colonoscopy reveals a large well-demarcated ulcerative le- sion with central yellowish exu- date at the terminal ileum.

304 J Rheum Dis Vol. 24, No. 5, October, 2017 Focal Eosinophilic Myositis Associated with Behçet's Disease

Figure 2. Magnetic resonance imaging of right upper arm. (A) An axial T2-weighted image de- monstrates diffuse and irregular hyperintensity signal around a focal mass lesion in triceps muscle. (B) An axial gadolini- um-enhanced T1-weighted im- age shows a focal mass lesion consisting of a well-defined rim of contrast enhancement (arrows) and a hypointense central area suspected of necrosis (arrow- head).

Figure 3. Histopathologic analysis of muscle. (A) Normal muscle structure (arrowheads) is observed sparsely, and the remainder is replaced by inflammatory cells and necrotic tissues (arrows) (H&E stain, ×40). (B) At higher magnification of the necrotic tissue (A, white arrow), the necrosis is surrounded by abundant inflammatory cells and eosinophils (H&E stain, ×400). (C, D) Infiltrations of eosinophils (C) and CD3+ T lymphocytes (D) are prominent in tissue (C: H&E stain, ×400; D: CD3 immunohistochemical stain, ×400). and a hypointense central area (Figure 2B). Muscle biop- atrophic and were replaced by inflammatory cell infiltra- sy, performed to determine the exact pathologic findings tion with predominant eosinophils, and focal central ne- of triceps muscle, showed that myofibers became severe crosis without perivasculitis, which were consistent with www.jrd.or.kr 305 Jung Su Eun et al.

Figure 4. Follow-up magnetic resonance imaging (MRI) of right upper arm. (A) On axial T2-weighted image, the signal intensity and extent of the in- volved muscle have been dis- tinctly decreased compared to the initial MRI findings. (B) An axial gadolinium-enhanced T1- weighted image reveals reduced size of focal mass lesion (arrows) and disappearance of internal necrosis, which was evident in previous MRI. focal eosinophilic myositis (Figure 3). lesions in intestinal BD are single or a few large ulcers in The patient was diagnosed as focal eosinophilic myositis the ileocecal area, which may be round or oval-shaped, associated with intestinal BD based on terminal ileal ul- deep ulcers with discrete and elevated margin [3]. Our cer, recurrent oral ulcers, skin manifestation, and positive patient, who fulfilled the ISG criteria for BD, complained pathergy test. High dose prednisone at a daily dose of 1 of abdominal pain and was diagnosed as intestinal BD mg/kg was administrated due to intestinal BD and focal based on a large, deep ulcer with mucosal swelling in the eosinophilic myositis, and azathioprine was added for the terminal ileum on the colonoscopy and abdominal CT. treatment of intestinal BD. After two weeks’ treatment, Idiopathic eosinophilic myopathy is classified into three the size of mass lesion in the triceps muscle and several subtypes including focal eosinophilic myositis, eosino- subcutaneous indurations were dramatically decreased. philic , and eosinophilic perimyositis, in In a follow-up MRI taken two weeks later, the size of mass which focal eosinophilic myositis is the most limited in the triceps muscle decreased considerably to 1.5 cm form and has several distinguishable features [8,12]. (length)×0.5 cm (width), although there was a slightly Focal eosinophilic myositis usually does not present with hypersignal intensity on T2-weighted image around the other internal organ involvement or systemic manifes- triceps muscle (Figure 4). tations except skin lesions and may resolve spontaneously. Muscular involvements are usually focal and circum- DISCUSSION scribed to the lower legs and thus often mistaken for deep vein thrombosis or pseudotumor [8], although involve- This is an extremely rare case of focal eosinophilic my- ment of other muscles such as deltoid [13] and sterno- ositis associated with intestinal BD concurrently. BD is a cleidomastoid muscles [14] was also reported. The most chronic, relapsing, and debilitating systemic vasculitis of frequent skin lesions are subcutaneous induration and er- unknown etiology, which affects both arteries and veins ythema [9]. Even though MRI is the primary imaging mo- of all sizes, thus causing a diverse spectrum of organ in- dality for evaluating soft tissue masses of the muscu- volvement from head to foot that can emerge at any point loskeletal system, its findings of focal eosinophilic my- in time [1,2]. Because BD does not have any pathogno- ositis are nonspecific, in which high signal intensity is monic symptoms or laboratory findings, a diagnosis of found in the muscle tissue on T2-weighted images [10,15]. BD is made using clinical criteria established by the Muscle biopsy is considered to be important for diag- International Study Group (ISG) criteria for BD, which nosis, revealing extensive infiltration of eosinophils in use five items including recurrent oral and genital ulcer- the perimysial and endomysial tissues and within muscle ations, ocular lesions, skin manifestations and positive fibers, associated with necrosis [7,8,12,14]. Focal ag- pathergy test [1]. Although GI involvement is not in- gregates of lymphocytes and plasma cells and degener- cluded in ISG criteria for BD, it shows the highest preva- ative changes of muscle fibers are also observed. However, lence rates in the Far-Eastern countries, such as Korea there is no perivascular infiltration [12]. Our patient, pre- and Japan [2,11]. Typical endoscopic findings of intestinal sented with a soft tissue mass with tenderness on the tri-

306 J Rheum Dis Vol. 24, No. 5, October, 2017 Focal Eosinophilic Myositis Associated with Behçet's Disease ceps muscle and several subcutaneous indurative lesions, Focal eosinophilic myositis rapidly responds to cortico- did not have blood eosinophilia, elevated muscle en- steroid therapy, although many cases run a benign course zymes, or the history of drug and allergic diseases. Muscle and improve spontaneously within weeks of presentation. biopsy showed massive muscular infiltration of eosino- Some cases of focal eosinophilic myositis treated surgi- phils and mononuclear cells, severe fibrous change, and cally have been reported [14]. Relapses are common and focal necrosis, which was consistent with pathologic find- may occur several years after the initial episode [7,13]. ings of focal eosinophilic myositis. In this case, skin biop- Our patient was treated with high dose glucocorticoid sy was not performed. and azathioprine because he had both the intestinal ulcer- Recently, a Spanish group [8] proposed a set of diag- ative lesion and focal eosinophilic myositis. After two nostic criteria in which clinical, pathological and radio- weeks’ treatment, muscle tenderness was resolved and logical findings were taken into consideration. Major cri- size of mass decreased distinctively, which was also dem- teria of the proposed criteria are as follows: 1) pain and onstrated by MRI of right upper arm. swelling of calf (other muscles can be affected) and 2) deep mononuclear cell infiltration (eosinophilic or not), SUMMARY with muscle fiber invasion and necrosis on muscle biopsy. Minor criteria are as follows: 1) elevated serum levels of We report a case of focal eosinophilic myositis in a pa- creatine kinase and aldolase, 2) MRI or electromyo- tient with intestinal BD, which showed a good response graphic evidence of focal myositis, 3) absence of systemic to glucocorticoid therapy. Because there have been no illness and 4) eosinophilia (＞0.5×109/L). Diagnosis re- published reports about BD accompanied by idiopathic quires presence of two major criteria or one major crite- eosinophilic myositis, it is not known whether these two rion and all three minor criteria, and deep vein thrombo- diseases are correlated or not. Further studies are needed sis, cellulitis, and parasitic infections must be excluded. to elucidate the relation between BD and eosinophilic Our patient was diagnosed with the focal eosinophilic myopathy. myositis based on focal painful myopathy on the upper extremity, pathologic findings including deep muscular CONFLICT OF INTEREST infiltration of mononuclear cells and eosinophils with muscle fiber invasion and necrosis, and evidence of my- No potential conflict of interest relevant to this article ositis on MRI. was reported Distinguishing between focal eosinophilic myositis and localized myopathy of BD in this case was a tough prob- REFERENCES lem because our patient was diagnosed with BD and there are no published reports about focal eosinophilic my- 1. Sakane T, Takeno M, Suzuki N, Inaba G. Behçet's disease. N ositis associated with BD when searched on MEDLINE. Engl J Med 1999;341:1284-91. We made the diagnosis of focal eosinophilic myositis in 2. Skef W, Hamilton MJ, Arayssi T. Gastrointestinal Behçet's this case for the following reasons. First, our patient sat- disease: a review. World J Gastroenterol 2015;21:3801-12. 3. Zou J, Shen Y, Ji DN, Zheng SB, Guan JL. Endoscopic find- isfied new proposed diagnostic criteria for focal eosino- ings of gastrointestinal involvement in Chinese patients philic myositis. Second, main infiltrative cells in muscu- with Behcet's disease. World J Gastroenterol 2014;20: lar lesions were eosinophils and mononuclear cells, not 17171-8. 4. Bicer A. Musculoskeletal findings in Behcet's disease. neutrophils, which was consistent with pathologic find- Patholog Res Int 2012;2012:653806. ings of focal eosinophilic myositis. Third, we did not find 5. Akansel G, Akgoz Y, Ciftci E, Arslan A, Demirci A. MRI any perivasculitic or vasculitic findings on the muscular findings of myositis in Behçet disease. Skeletal Radiol pathology, although there was a possibility that we could 2004;33:426-8. 6. Sarui H, Maruyama T, Ito I, Yamakita N, Takeda N, Nose M, not detect these lesions because of intense infiltration of et al. Necrotising myositis in Behçet's disease: characteristic inflammatory cells and tissue necrosis. Last, in addition features on magnetic resonance imaging and a review of the to myositis, our patient had several subcutaneous in- literature. Ann Rheum Dis 2002;61:751-2. durative lesions, which were one of cutaneous symptoms 7. Pickering MC, Walport MJ. Eosinophilic myopathic synd- romes. Curr Opin Rheumatol 1998;10:504-10. of idiopathic eosinophilic myositis rather than cutaneous 8. Selva-O'Callaghan A, Trallero-Araguás E, Grau JM. Eosino- manifestations of BD. philic myositis: an updated review. Autoimmun Rev 2014;

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