Cell Biochem Biophys (2014) 69:735–739 DOI 10.1007/s12013-014-9860-4
ORIGINAL PAPER
Etanercept in the Treatment of Intestinal Behcet’s Disease Dan Ma • Chao-Jun Zhang • Ru-Peng Wang Lie Wang • Hua Yang
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Published online: 13 March 2014 Ó Springer Science+Business Media New York 2014
Abstract Behcet’s disease (BD) accompanied by intestinal involvement is called intestinal BD. Although recent studies have attained positive feedback with the administration of anti-TNF-a agents in patients with BD, only a few reports on the study of etanercept in intestinal BD have been found. In this study, 35 cases of intestinal BD were treated with conventional therapy (prednisone or methotrexate) for a minimum period of 3 months (group 1). Another 19 patients who failed to respond to conventional therapy were then treated with etanercept (25 mg twice a week for 3 months). During each subsequent relapse, the patients were given the same treatment. The main outcome measures were the four criteria for diagnosis of BD (buccal ulcers, genital ulcers, ocular lesions, and skin lesions), the manifestation of intestinal involvement (abdominal symptoms, double-balloon enteroscopy), laboratory examinations of the acute phase reactants (erythrocyte sedimentation rate) and C-reactive protein, and relapses. As a result of the administered therapy, the healing rate of buccal and genital ulcers, the remission rate of ocular lesions, skin lesions, and abdominal symptoms, the healing
D. Ma C.-J. Zhang H. Yang (&) Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People’s Republic of China e-mail:
[email protected] R.-P. Wang Department of Dermatology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People’s Republic of China L. Wang Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People’s Republic of China
rate of intestinal ulcers, and the recovery rate of ESR and CRP were significantly higher in group 2 than those of group 1. The relapse rate in the etanercept therapy was reduced significantly when compared with conventional therapy group. In conclusion, etanercept treatment, in contrast to the conventional therapy, can result in better curative effect and less adverse reactions in intestinal BD. Keywords
Behcet’s disease Treatment Etanercept
Introduction Behcet’s disease (BD) is a multisystem inflammatory disorder characterized by recurrent oral and genital ulcers in association with other dermatological and ocular manifestations [1]. Intestinal BD is a specific subtype of disease, characterized by intestinal ulcers associated with gastrointestinal symptoms such as abdominal pain, bleeding, diarrhea, and nausea. Round and oval ulcers are typically localized in the ileocecum [2]. Pharmaceutical drugs such as corticosteroids and immunomodulators are commonly used in treating BD. These pharmaceuticals drugs may cause serious side effects as well as trigger allergies, often causing most patients with BD to need ileocecal resections. Even after surgical treatments, these patients are still threatened by recurrence and intestinal reperforations. Therefore, it is necessary to discover new methods for treating intestinal BD. Tumor necrosis factor alpha (TNF-a) is a multifunctional pro-inflammatory cytokine which has proven to be closely associated with BD [3–5]. Recently, blocking TNFa has been successfully used in treating patients with BD, many reports have shown that TNF-a inhibitor can effectively improve the main clinical manifestation and complications of BD [6–8]. The aim of this study was to assess
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the effects of etanercept, a TNF-a inhibitor, on patients with intestinal BD.
Materials and Methods Patients and Groups It is a retrospective comparative study based on observation to evaluate the outcomes of patients with intestinal BD treated with etanercept administration or conventional therapy. 54 patients were included in this study. All patients were diagnosed based on the Mason-Barnes criteria [9]. The criteria consist of four major symptoms (buccal ulcerations, genital ulcerations, ocular lesions, and skin lesions) and six minor symptoms (gastrointestinal lesions, thrombophlebitis, cardiovascular lesions, arthritis, neurologic lesions, and family history). These criteria are required to establish the diagnosis of BD. The lesion in the intestine of each patient was confirmed by double-balloon enteroscopy. The patients were divided into two groups. In group 1, 35 patients were treated with conventional therapy (prednisone or oral methotrexate). 19 patients were included in group 2, who have failed to respond under conventional therapy, were treated with etanercept administered subcutaneously. During each relapse, patients in both groups were given the same drugs as before. Patients who had active infections or tuberculosis were excluded from the study. The degree of abdominal pain was recorded for each patient. The healing of ulcers in ileocecum was observed with double-balloon enteroscopy. Acute phase reactants, erythrocytes sedimentation rate (ESR) and C-reactive protein (CRP), were tested and the number of relapse in patients was calculated (Table 1). Drug Administration In group 1, patients were treated with prednisone (Jinyao Pharmaceutical Co. Ltd, Tianjin, China) administered
Table 1 Comparison of clinicopathological parameters of etanercept group (group 2) with conventional therapy group (group 1) in intestinal Behcet disease Group 1 (N = 35)
Group 2 (N = 19)
either intravenously or methotrexate (Xinyi Pharmaceutical Co. Ltd, Shanghai, China) administered orally. The initial dosage of prednisone was 1 mg/kg/day, and decreased in a time-dependent manner during remissions. Methotrexate at the dose of 15 mg was administered orally once per week. Both drugs were prescribed for at least 3 more months. In group 2, etanercept (CP Guojian Pharmaceutical Co. Ltd, Shanghai, China) was administered subcutaneously at the dose of 25 mg twice a week. A relapse refers to a recurrence occurring for at least 3 months after remission. During each relapse, the therapy was reinstituted the same as before. After administrating the drugs for 3 months, all the patients were conducted to follow-up sessions for two more years. Exclusion Criteria and Clinical Parameters Before the study, all the patients were tested for tuberculosis with a purified tuberculin protein derivative (PPD) skin test. Only the patients with negative skin tests were included in the study. During the therapy, laboratory examinations of the acute phase reactants ESR and CRP were conducted. Other conventional laboratory examinations of indexes, such as complete blood count, liver function tests, renal function tests, and serum glucose were conducted. After the therapy, double-balloon enteroscopy was performed on all the patients. Statistical Analysis Software SPSS10.0 was used for statistical analysis. Data of the patients’ age and the level of CRP and ESR were analyzed using completely randomized design analysis of variance by t test. P values \0. 05 were considered statistically significant. The sex ratio of the patients, the healing rate of buccal ulcers and genital ulcers, the remission rate of ocular lesions and skin lesions, the remission rate of abdominal symptoms, the healing rate of intestinal ulcers, as well as the recovery rate of ESR and CRP were analyzed using v2 test, and the number of relapses was analyzed using t test. The significant level was set at 0.05, and all P values were two-sided.
P value
Results
Age (year)
40 ± 9.64
37 ± 8.72
P [ 0.05
Sex ratio(male to female)
1.5:1
2.2:1
P [ 0.05
Study Population The mean age of patients in group 1 was 40 years (age range 18–55 years) with male to female ratio 1.5:1, while in group 2 was 37 years (age range 20–48) with male to female ratio 2.2:1 (Table 1). There was no significant age and male to female between both groups with P values.
CRP (mg/l)
17.49 ± 5.75
18.47 ± 5.38
P [ 0.05
ESR (mm/h)
30.03 ± 5.48
30.47 ± 6.01
P [ 0.05
There was no significant age and male to female between both groups with P values (P [ 0.05). There was also no significant levels of CRP and ESR between the two groups with P values (P [ 0.05)
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There was also no significant levels of CRP and ESR between the two groups with P values. Buccal Ulcers and Genital Ulcers The criterion of healing of the two kinds of ulcers is disappearance. The healing rate of buccal ulcers was 89.47 % in etanercept-treated group (group 2), and 51.42 % in conventional-treated group (group 1), respectively. We found the same result in genital ulcers. Etanercept treatment significantly increases (P \ 0.05) the healing rate of buccal ulcers and genital ulcers when compared with conventional therapy (Table 2). Ocular Lesions There was 84.21 % of remission rate of ocular lesions in group 2 patients, and only 45.71 % in group 1 patients, indicating that etanercept therapy significantly improved (P \ 0.05) the remission rate of ocular lesions when compared with conventional therapy (Table 2). Remission Rate of Skin Lesions and Abdominal Symptoms The remission rate of skin lesions and abdominal symptoms was nearly 2-fold higher in group 2 patients than group 1 patients. These results showed that etanercept improved significantly (P \ 0.05 and P \ 0.01, respectively) the remission rate of skin lesions and abdominal symptoms when compared to conventional therapy (Table 2). Table 2 Comparison of the curative effect of etanercept with that of conventional therapy in intestinal Behcet disease Group 1 (N = 35) (%)
Group 2 (N = 19) (%)
P value
Healing rate of buccal ulcers
51.42
89.47
P \ 0.05
Healing rate of genital ulcers
51.42
89.47
P \ 0.05
Remission rate of ocular lesions
45.71
84.21
P \ 0.05
Remission rate of skin lesions
48.57
89.47
P \ 0.05
Remission rate of abdominal symptoms
57.14
94.74
P \ 0.01
Healing rate of intestinal ulcers Recovery rate of ESR
51.42 45.71
89.47 73.68
P \ 0.01 P \ 0.05
Recovery rate of CRP
48.57
78.95
P \ 0.05
The mean number of recurrences in group 1 was 4.0, generally ranging from 2 to 6 for the 2-year period. Ileocecal resection was performed on three patients due to perforation. The mean number of recurrences in group 2 was 1.2, generally ranging from 0 to 3. A statistically significant difference was found between the two groups (P \ 0.001)
Intestinal Ulcers The criterion of healing of the intestinal ulcers is disappearance confirmed by double-balloon enteroscopy. There was 89.47 % of healing rate of intestinal ulcers in etanercept-treated group, and 51.42 % in conventional-treated group, again suggested that etanercept therapy significantly (P \ 0.05) improved healing rate of intestinal ulcers when compared with conventional therapy (Table 2). Clinical Parameters The criterion of the recovery clinical parameters is on the regular range. As compared with conventional therapy, etanercept treatment also significantly improved (P \ 0.05 for both) the recovery rate of ESR and CRP (Table 2). Side Effects We found very less side effects of etanercept treatment than conventional therapy. In conventional therapy group, the main adverse events were included liver dysfunction (6 cases), abnormality of renal function (5 cases), leukopenia (3 cases), hypertension (2 cases), and hyperglycemia (2 cases). while, the adverse events only included transient low-grade fever (5 cases), and light headaches (4 cases) in etanercept-treated group.
Discussion In 1937, Hulusi Behcet, a Turkish dermatologist, described a triple symptom complex of aphthae, genital ulcer, and uveitis [2]. Subsequent studies showed that it was a multisystem syndrome which including skin lesion, arthritis, thromboplebitis, and additionally central nervous system. Almost all patients experienced relapse with an unknown etiology. The syndrome is called Behcet symptom or Behcet disease (BD). Three years later, Bechgaard first described intestinal involvement in BD and in 1964, the term ‘‘intestinal BD’’ was proposed [2]. The frequency of intestinal BD varies in different geographic areas throughout the world, but it is most commonly present in populations inhabiting areas in the east of the mediterranean basin, the middle east, and eastern Asia [10]. Abdominal pain is the most common gastrointestinal manifestation followed by gastrointestinal bleeding, diarrhea, nausea, and vomiting. The typical image of intestinal BD, which has been shown by endoscopy, are round and oval ulcers localized in the terminal ileum, ileoceal region, and cecum. Perforation is the most severe complication of intestinal BD, typically associated with high mortality rates. If perforation occurs, surgical treatment such as ileal resection would be inevitable.
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Same to the manifestation of BD in other system, the conventional therapy of BD in the intestine may include administration of corticosteroids and immunomodulators. However, these two kinds of agents may induce significant side effects, moreover, promote drug dependence. As a result of that the drugs, satisfactory result of the relapse rate of conventional therapy could hardly achieved. Even if ileocecal resection is enforced on patients with BD, chances of recurrence and reperforation will always persist. Consequently, new therapy which could both elevate curative effect and reduce adverse events is desired. TNF-a is a multifunctional pro-inflammatory cytokine involved in inflammation. Recently, it has been observed that patients with BD show high levels of TNF-a and its receptor in the serum and that the concentration of TNF-a is correlated with clinical manifestations and recurrence of the disease [3, 4]. Administering anti-TNF-a may be a new and effective method of dealing with BD, for many TNF-a inhibitors have been successfully used in patients with BD, but few reports have been found on the study of intestinal BD. Among the TNF-a inhibitors used in treating BD, the most frequently used is infliximab, a chimeric monoclonal antibody consisting of the Fc region of the human immunoglobulin IgG and the Fab antigen binding site consisting of mouse origin anti-TNF-a antibody, which can neutralize TNF-a [6–8]. Contrast to infliximab, etanercept is a dimeric humanized anti-TNF-a antibody, manufactured by recombinant DNA techniques [11, 12], which theoretically, has greater binding affinity with TNF-a than monometric receptors. Ideally, this method may bring about less side effects of autoantibodies. In addition, etanercept will be more economically friendly to patients since it will reduce cost of therapy through subcutaneous self-administration [13–15]. In 1 year etanercept treatment, it has been demonstrated that the mean numbers of oral ulcers and nodular skin lesions were less in the etanercept group compared to the placebo group at all weekly evaluations [16]. We also got similar results in our study. Our results demonstrated the healing rate of buccal ulcers and remission rate of skin lesions were significantly higher in etanercept-treated group than conventional therapy. Moreover, the administration of etanercept, a resolution of the clinical, laboratory and instrumental picture was achieved with a suspension of immunosuppressive treatments and a reduction of steroid dependency with no side effects [17]. We also showed that etanercept-treated group had least side effects and significant recovery rate of ESR and CRP than conventional therapy group. In addition, we found that the healing rate of genital ulcers, the remission rate of ocular lesions and abdominal symptoms, the healing rate of intestinal ulcers, and the number of times of relapse in the etanercept group was much higher than that of the conventional therapy
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group. In conclusion, we got better curative effect and less adverse reactions with etanercept treatment in intestinal BD as compared to the conventional therapy. Thus, etanercept might be a drug of choice in treating intestinal BD. Acknowledgments Thanks are due to Ming Liu, Ru-Peng Wang, and Lie Wang for assistance with the study and to Hua Yang for significant guidance and valuable discussion.
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