Skip to main content
Download PDF
  • Research article
  • Open access
  • Published:

Efficacy and predictor of anti-TNFα agents in patients with intestinal Behçet's disease

BMC Gastroenterology volume 22, Article number: 149 (2022) Cite this article

Abstract

Background

Behçet’s disease (BD) is a recurrent multisystem inflammatory disease. Anti-tumor necrosis factor (TNF) α agents have been used to treat patients with intestinal BD with severe disease activity or those who are resistant to conventional treatments; however, the long-term efficacy of anti-TNFα agents in intestinal BD remains unclear. In the present study, we investigated the clinical outcomes and predictors of discontinuation of anti-TNFα agents in patients with intestinal BD.

Methods

We reviewed the medical records of patients with intestinal BD who received first-line anti-TNFα agents between January 2009 and June 2020. The primary outcome was the percentage of patients who continued anti-TNFα therapy for 48 weeks. Secondary outcomes included the percentage of patients who achieved marked improvement, complete remission, and mucosal healing, as well as predictors of discontinuation of anti-TNFα agents.

Results

A total of 29 patients were included in the study. Twenty-two (75.9%) patients continued anti-TNFα therapy for 48 weeks. The percentage of patients who achieved marked improvement, complete remission, and mucosal healing at week 48 was 48.3%, 37.9%, and 48.3%, respectively. At week 96, 11 (37.9%) patients achieved marked improvement, complete remission, and mucosal healing. A higher C-reactive protein level (CRP; ≥ 1 mg/dL) at baseline was a predictor of discontinuation of anti-TNFα agents.

Conclusions

The 48-week continuation rate of anti-TNFα agents was 75.9% in bio-naïve patients with intestinal BD. However, a higher baseline CRP level (≥ 1 mg/dL) was associated with discontinuation of anti-TNFα agents.

Peer Review reports

Background

Behçet's disease (BD) is a chronic multisystem inflammatory disorder characterized by recurrent oral and genital ulcers and ocular and skin lesions [1]. In Japan, a BD diagnosis is reached by assessing a combination of clinical manifestations [2], as there are no disease-specific symptoms or laboratory tests for diagnosis.

Patients are diagnosed with intestinal BD if gastrointestinal symptoms are present, and typical ulcerative lesions are documented by employing objective measures. In BD, typical intestinal lesions are usually characterized by discrete ulcers with a punched-out appearance, located most commonly on the ileocecal valve [3].

The incidence of gastrointestinal manifestations is reportedly 3–25% in patients with BD [1]. In addition, patients with intestinal BD present a high risk for intestinal perforation and severe intestinal bleeding [4]; therefore, disease activity should be strictly controlled. Moreover, optimal treatment strategies are yet to be established, as intestinal BD is extremely rare, and the choice of treatment modality depends on disease severity [5, 6]. Among the available treatments for intestinal BD, 5-aminosalicylic acid (5-ASA), systemic corticosteroids, and immunosuppressive agents such as thiopurines are known to be useful in clinical settings [7]. 5-ASA is used in mild cases, and the cumulative relapse rates of intestinal BD at 1 and 5 years after remission were 8.1% and 31.2%, respectively [8]. Although there have been no prospective studies demonstrating the clinical efficacy of systemic corticosteroids in intestinal BD, they are often empirically used to induce clinical remission in patients with moderate to severe disease activities. Azathioprine (AZA) and 6-mercaptopurine (6-MP) are also widely used in patients who are dependent and refractory to corticosteroids. Jung et al. have reported that the cumulative relapse rates at 1 and 5 years after remission were 5.8% and 51.7%, respectively [9]. Despite the availability of these treatments, some patients experience treatment failure or require surgery [10].

Notably, anti-tumor necrosis factor-α (anti-TNFα) agents are now expected to be promising treatment options, with accumulating evidence revealing the therapeutic efficacy of anti-TNFα agents such as infliximab (IFX) and adalimumab (ADA) [6, 11, 12]. IFX therapy has shown a complete response rate of 61% at 54 weeks post-induction [13], while that of ADA was 60% at 52 weeks post-induction [14, 15]. In Japan, IFX and ADA have recently been approved for treating patients with intestinal BD exhibiting severe disease or resistance to existing treatment. Accordingly, anti-TNFα agents are expected to gain momentum in the management of intestinal BD [6]. However, data regarding the long-term outcomes of anti-TNFα therapy remain scarce.

In the present study, we retrospectively evaluated continuation rate of anti-TNFα in intestinal BD and factors predictive of sustained response.

Methods

Patients

Among 51 patients with intestinal BD, we reviewed the medical records of all patients who received first-line anti-TNFα agents at Kobe University Hospital from January 2009 to June 2020. The diagnosis of intestinal BD was based on the Japanese diagnostic criteria for intestinal BD [6]. We excluded patients with any evidence of other gastrointestinal diseases, such as Crohn's disease (CD), intestinal tuberculosis, or ischemic colitis, during the follow-up period.

Drug administration

IFX or ADA was administered according to the standard Japanese administration protocol. IFX (5 mg/kg) was intravenously administered at weeks 0, 2, and 6, and then every 8 weeks. ADA was subcutaneously administered at 160 mg at week 0, followed by 80 mg at week 2, followed by 40 mg every other week. Concomitant therapies, such as corticosteroids and immunosuppressants, are permitted at stable dosages during anti-TNFα therapy. Upon observation of clinical improvement, corticosteroids were gradually reduced and discontinued.

Data collection and definition

We collected information regarding sex, age at disease onset, body weight, social history (smoking and alcohol drinking), type of anti-TNFα agent administered, age at initial administration of the anti-TNFα agent, disease duration before initiating the anti-TNFα agent, presence of clinical manifestations, positivity for human leukocyte antigen (HLA)-B51 or HLA-A26 (HLA types highly associated with BD), concomitant medication administered with the anti-TNFα agent, history of major abdominal surgery (e.g., colectomy), and adverse events (AEs). First, we investigated the efficacy and safety by evaluating the continuation of anti-TNFα agents. Patients who continued anti-TNFα agents according to the administration protocol were defined as the continuation group (CG). The remaining patients were considered not to have continued therapy, as they deviated from the administration protocol (increasing dose, shortening interval, switching of anti-TNFα agent, or adding other treatments). These patients were defined as the discontinuation group (DG). Next, we used the composite disease activity index to comprehensively evaluate the efficacy of the anti-TNFα agent (Fig. 1), used in Japanese clinical trial for the obtainment of pharmaceutical approval of ADA for refractory intestinal BD (clinical trial number: NCT01243671) [14]. Global gastrointestinal (GI) symptom scores (ranging from 0 to 4 at the time of each visit) were assessed before the initial administration and 48 and 96 weeks after the initial administration of anti-TNFα agents. Endoscopic findings were evaluated by comparing changes in ulcer size with the original ulcer size before initiating anti-TNFα administration; score 0 was defined as complete ulcer healing, score 1 was defined as an ulcer size ≤ 1/4 the size of the largest ulcer when compared with the original ulcer size, score 2 was defined as ulcer size between 1/2 and 1/4 the size of the largest ulcer, and a score of 3 was defined as an ulcer size ≥ 1/2 of the largest ulcer.

Fig. 1
figure 1

The composite disease activity index for global GI symptom and endoscopic assessment scores. A combination of scores is used to characterize disease activity after medical treatment

Full size image

Global drug responses were assessed by dividing the observed responses into four categories: no change/aggravated, improvement, marked improvement (MI), and complete remission (CR), using the composite disease activity index at the indicated time points, consisting of global GI symptom scores and endoscopic assessments. MI was defined as a global GI symptom score and endoscopic assessment score of ≤ 1, while CR was defined as a global GI symptom score and an endoscopic score of 0. In addition to the global drug response, mucosal healing (MH) was defined separately when the endoscopic score was 0.

Primary and secondary endpoints of our study

In the present study, the primary outcome was the continuation rate of anti-TNFα therapy at week 48. The secondary outcomes included the percentage of patients who achieved MI, CR, and MH at weeks 48 and 96, the predictors of discontinuation of anti-TNFα therapy, and all AEs through week 96.

Statistical analysis

All data are summarized and presented as mean ± standard deviation (SD) for continuous variables. Categorical data are expressed as the number of patients plus the percentage. Comparisons of groups were performed using the Student's t-test for unpaired data in a two-group comparison. The Chi-square test with Fisher's correction was used to evaluate differences in categorical data, where needed. Statistical significance was set at a p value of ≤ 0.05. The Kaplan–Meier survival method was used to estimate the cumulative probability of continuing anti-TNFα therapy. Differences between curves were tested using the log-rank test. EZR software was used for the statistical analyses.

Results

Baseline characteristics of patients (Table 1)

A total of 29 patients with intestinal BD were included in this study. The baseline patient characteristics are shown in Table 1. Among the 29 patients, 14 (48.3%) were men. The average age at initiation of anti-TNFα therapy was 42 years (range 17–74 years), and the average disease duration before anti-TNFα therapy was 6 years (range 0–41 years). Regarding the type of anti-TNFα agent, 16 (55%) patients were treated with IFX and 13 (45%) were treated with ADA. Ocular lesions, skin lesions, oral ulcers, and genital ulcers were present in 9, 12, 28, and 10 patients, respectively. In terms of HLA serological typing (A/B), 21 patients (21/29, 72.4%) were investigated for HLA serological typing (A/B). We identified 5 (5/21, 23.8%) patients positive for HLA-B51 and three (3/21, 14.3%) positive for HLA-A26. Concomitant medications administered with anti-TNFα agents included systemic corticosteroids (20/29, 69.0%), 5-ASA (11/29, 37.9%), cyclosporine A (2/29, 6.9%), methotrexate (3/29, 10.3%), AZA/6-mercaptopurine (18/29, 62.1%), and colchicine (16/29, 55.2%). Four patients (13.8%) had a history of major abdominal surgery. The mean baseline global GI score was 1.69, while the mean baseline C-reactive protein (CRP) level was 1.81 mg/dL.

Table 1 Baseline characteristics of patients
Full size table

During the observation period, AEs occurred in 14 patients (48.3%). AEs included nasopharyngitis in 7 patients (24.1%), hepatic events in 2 patients (6.9%), dizziness in 2 patients (6.9%), urinary tract infection in 1 patient (3.4%), pulmonary infection in 1 patient (3.4%), influenza in 1 patient (3.4%), and headache in 1 patient (3.4%). Among these, two serious events were observed. One patient died of lung cancer, which developed one year after the initial IFX administration. The other patient experienced ileum perforation due to exacerbation of intestinal BD.

Relation between failure of anti-TNFα agent and CRP levels (Table 2)

Next, we evaluated the continuation rate of anti-TNFα therapy. As shown in Table 2, 25 (86.2%) and 22 (75.9%) patients continued anti-TNFα therapy at weeks 8 and 48, respectively. We compared CRP levels at baseline in the CG and DG groups. At week 8, the mean CRP levels at baseline in the CG and DG were 1.16 ± 2.09 mg/dL and 5.93 ± 8.60 mg/dL, respectively (p = 0.017). At week 48, the mean CRP levels at baseline in the CG and DG were 0.84 ± 1.41 mg/dL and 4.86 ± 6.80 mg/dL, respectively (p = 0.006).

Table 2 Relationship between the continuation of anti-TNFα agent and CRP levels
Full size table

Moreover, 9 (36.0%) patients in the CG had baseline CRP levels of 1 mg/dL or higher, whereas two (50.0%) patients in the DG showed similar levels. At week 48, 6 (27.3%) patients in the CG had baseline CRP levels of 1 mg/dL or higher when compared with 5 (71.4%) patients in the DG.

Continuation rates and efficacy of anti-TNFα agents (Figs. 2, 3)

We investigated the overall clinical course of patients with intestinal BD who received first-line anti-TNFα therapy (Fig. 2). The cumulative continuation rate of anti-TNFα agents was calculated using the Kaplan–Meier curve. Kaplan–Meier curves demonstrated that the cumulative continuation rates of anti-TNFα agents at weeks 8, 48, and 96 were 86.2%, 72.0%, and 60.4%, respectively. The median duration of continuation was 63 months.

Fig. 2
figure 2

The cumulative continuation rate of anti-TNFα agents was calculated by using the Kaplan–Meier curve. A There is no significant difference between IFX users and ADA users. B A significant difference can be observed between patients with a baseline CRP level ≥ 1 mg/dL and those with a baseline CRP level < 1 mg/dL

Full size image

Furthermore, we compared the cumulative continuation rates calculated by the Kaplan–Meier curve according to the type of anti-TNFα agent (IFX or ADA) and the difference in baseline CRP levels (CRP ≥ 1 mg/dL vs. CRP less than 1 mg/dL) using the log-rank test (Fig. 2). No significant difference in cumulative continuation rates was observed between the IFX and ADA groups (p = 0.5). In contrast, baseline CRP levels of 1 mg/dL or higher were associated with discontinuation of anti-TNFα agents (p = 0.04).

Next, we investigated the response rate of anti-TNFα agents in patients with intestinal BD at the indicated time points (Fig. 3). At week 48, 14 (48.3%), 11 (37.9%), and 14 (48.3%) patients achieved MI, CR, and MH, respectively, whereas 11 (37.9%) patients achieved MI, CR, and MH at week 96.

Fig. 3
figure 3

Response rates of anti-TNFα agent (at weeks 48 and 96)

Full size image

Predictors of discontinuation of anti-TNFα agents (Table 3)

We investigated factors associated with the discontinuation of anti-TNFα agents in patients with intestinal BD. To identify predictors of discontinuation of anti-TNFα therapy, we conducted a logistic regression analysis stratified by demographic variables such as sex (male vs. female), age at disease onset (≥ 40 vs. < 40 years), disease duration before anti-TNFα agent initiation (≥ 5 vs. < 5 years), type of anti-TNFα agent administered (IFX vs. ADA), CRP level at baseline (≥ 1 vs. < 1 mg/dL), and concomitant use of systemic corticosteroids at a dose of ≥ 20 mg (yes vs. no). The results are presented in Table 3. Univariate analysis showed no significant differences between the two groups in terms of sex, age at disease onset, disease duration before anti-TNFα agent initiation, type of anti-TNFα agent administered, and concomitant use of corticosteroids (≥ 20 mg). Notably, only the baseline CRP level was significantly associated with the discontinuation of anti-TNFα agents at week 48 (p = 0.019). In addition, multivariate analysis revealed that only a baseline CRP level of 1 mg/dL or higher was statistically associated with the discontinuation of anti-TNFα therapy at week 48 (p = 0.033).

Table 3 Univariate and multivariate logistic regression analyses of predictors for discontinuation of anti-TNFα therapy at week 48
Full size table

Discussion

BD, first described in 1937 by the Turkish dermatologist Hulusi Behcet [16], is a multisystem immune-mediated inflammatory disorder characterized by recurrent oral aphthous ulcers, uveitis, skin lesions, and genital ulcers. In addition, BD may involve the intestinal tract (intestinal BD), nervous system, and vascular system, which is categorized as special-type BD in Japan. Those with special-type BD tend to have a poor prognosis, typically necessitating treatment with potent immunosuppressive agents, such as corticosteroids and immunomodulators. Intestinal BD can also result in complications such as perforations, fistulas, or massive intestinal bleeding, eventually requiring surgical treatment [4].

The pathogenesis of BD remains unclear, and some studies have implicated genetic factors, environmental factors, and subsequent immune abnormalities. Genome-wide association studies have identified several genes associated with susceptibility to BD, including IL23R-IL12RB2, IL-10 [17, 18], and STAT4 [19]. Interleukin (IL)12 induces Th1 immune responses [20], which leads to the production of Th1 cytokines such as interferon (IFN)γ, TNFα, and IL2. STAT4 is a transcription factor required for the Th1 immune response [21]. Meanwhile, IL23 plays an important role in driving aberrant Th17 immune response [22]. Additionally, Th17 cells also produce several cytokines, including IL17 and TNFα [23]. These results suggesting that TNFα plays a crucial role in the pathogenesis of BD. It has been reported that Serum levels of TNFα have been reported to be increased in patients with BD [24], and tissue samples harvested from intestinal BD lesions were found to express TNFα [25].

IFX and ADA are anti-TNFα monoclonal antibodies that have been highly effective against Th1 inflammation. IFX and ADA are reportedly effective against several diseases, including rheumatoid arthritis [26, 27], CD [28, 29], and ulcerative colitis during the active phase [30]. In patients with BD, IFX has been effective in patients with uveitis resistant to combination therapy with AZA, cyclosporine, and corticosteroids [31]. Also, Vallet et al. have reported the efficacy of anti-TNFα agents in severe and/or refractory BD [32]. Furthermore, previous studies have revealed that anti-TNFα agents are also effective for treating intestinal BD [13, 14]. Herein, our study revealed that 48% of patients achieved MI at week 48. In previous studies, the clinical response rates of anti-TNFα agents for intestinal BD varied between 40 and 60% [13, 14, 33, 34]. This was likely due to differences in evaluation criteria and eligible patients. Thus, anti-TNFα agents are effective for intestinal BD therapy, as suggested by previous reports and our study.

In the present study, the CRP level at baseline was significantly associated with the discontinuation of anti-TNFα therapy at week 48 (p = 0.019). There are few reports describing the predictors of sustained response in patients with intestinal BD treated with anti-TNFα agents. Some literatures have shown that early achievement of mucosal healing and low CRP level after administration of anti-TNFα agent might be used as predictors of long-term response [35, 36], however, those predictors will be only available after starting the treatment and confirming the well-responsiveness to it. To the best of our knowledge, current study is the first to show that CRP level over 1 mg/dL at baseline is associated with the higher discontinuation rate of anti-TNFα therapy compared with low CRP level in patients with intestinal BD.

Several studies have reported that clinical disease activity correlates with CRP levels in patients with BD. It has been reported that mean CRP levels increase with the number of involved organs [37], and that the CRP level can be correlated with the Behçet's Disease Current Activity Form (BDCAF), which depends on the accurate history of clinical features present during the month prior to the date of assessment [38]. These results indicate that CRP levels are closely associated with disease activity and response to treatment in patients with BD. CRP is an acute-phase inflammatory protein that is synthesized in the liver upon stimulation by IL6. IL6 is immediately produced by innate immune cells, such as macrophages and monocytes, in response to infections and tissue injuries [39]. Along with transforming growth factor (TGF) β, IL6 induces the differentiation of naïve T cells into Th17 cells, which produce several cytokines, including IL17 [40]. As mentioned above, IL23 plays an important role in the Th17 immune response by promoting Th17 differentiation. Moreover, IL23 is necessary to maintain IL17 production by Th17 cells [41]. IL17, together with IL6, triggers a positive-feedback loop of IL6 expression through the activation of NF-κB and STAT3 in non-immune cells [42]. These mechanisms reportedly play a role in the development of autoimmune diseases such as arthritis, with markedly high serum IL6 levels detected in these disorders [42].

It has been shown that trough levels of anti-TNFα agents reflect the efficacy in rheumatoid arthritis [43] and in CD [44]. Our results indicate that it is important to maintain a trough level of anti-TNFα agents for continued long-term anti-TNFα therapy. CRP levels before treatment are positively associated with TNFα levels [45]; therefore, higher doses of anti-TNFα agents are needed to control disease activity in patients with high CRP levels at baseline. Moreover, baseline CRP levels can be correlated with the continuation of anti-TNFα agents in patients with rheumatoid arthritis [46] and with a colectomy-free rate in patients with ulcerative colitis in the active phase [47]; for continued long-term maintenance therapy with anti-TNFα, we may need to maintain a high trough level of anti-TNFα agents by employing corticosteroids or immunosuppressive agents in patients with high CRP levels at baseline, higher dosages of anti-TNFα agents, or shorter dosing intervals in patients with escalated activity during anti-TNFα therapy.

Our study had several limitations. First, this was a single-center study, and the sample size was relatively small. Moreover, our study had a retrospective design. Finally, the disease severity evaluated using endoscopic findings before treatment was not included. However, we believe that our data will provide useful insights when clinicians encounter patients with severe intestinal BD.

Conclusions

The 48-week continuation rate of anti-TNFα agents was 75.9% in bio-naïve patients with intestinal BD. Patients with a CRP level of 1 mg/dL or less at baseline could continue anti-TNFα therapy for a prolonged duration.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

BD:

Behçet's disease

5-ASA:

5-Aminosalicylic acid

AZA:

Azathioprine

6-MP:

6-Mercaptopurine

anti-TNFα:

Anti-tumor necrosis factor-α

IFX:

Infliximab

ADA:

Adalimumab

CD:

Crohn’s disease

HLA:

Human leukocyte antigen

AEs:

Adverse events

CG:

Continuation group

DG:

Discontinuation group

GI:

Gastrointestinal

MI:

Marked improvement

CR:

Complete remission

MH:

Mucosal healing

CRP:

C-reactive protein

IL:

Interleukin

IFN:

Interferon

BDCAF:

Behçet's Disease Current Activity Form

TGF:

Transforming growth factor

References

  1. Sakane T, Takeno M, Suzuki N, Inaba G. Behçet’s disease. N Engl J Med. 1999;341:1284–91.

    Article  CAS  PubMed  Google Scholar 

  2. Suzuki Kurokawa M, Suzuki N. Behcet’s disease. Clin Exp Med. 2004;4:10–20.

    Article  CAS  PubMed  Google Scholar 

  3. Lee CR, Kim WH, Cho YS, et al. Colonoscopic findings in intestinal Behçet’s disease. Inflamm Bowel Dis. 2001;7:243–9.

    Article  CAS  PubMed  Google Scholar 

  4. Hatemi I, Esatoglu SN, Hatemi G, et al. Characteristics, treatment, and long-term outcome of gastrointestinal involvement in Behcet’s syndrome: a strobe-compliant observational study from a dedicated multidisciplinary center. Medicine. 2016;95:e3348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hatemi G, Christensen R, Bang D, et al. 2018 update of the EULAR recommendations for the management of Behçet’s syndrome. Ann Rheum Dis. 2018;77:808–18.

    PubMed  Google Scholar 

  6. Watanabe K, Tanida S, Inoue N, et al. Evidence-based diagnosis and clinical practice guidelines for intestinal Behçet’s disease 2020 edited by Intractable Diseases, the Health and Labour Sciences Research Grants. J Gastroenterol. 2020;55:679–700.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Park YE, Cheon JH. Updated treatment strategies for intestinal Behçet’s disease. Korean J Intern Med. 2018;33:1–19.

    Article  PubMed  Google Scholar 

  8. Jung YS, Hong SP, Kim TI, et al. Long-term clinical outcomes and factors predictive of relapse after 5-aminosalicylate or sulfasalazine therapy in patients with intestinal Behcet disease. J Clin Gastroenterol. 2012;46:e38-45.

    Article  CAS  PubMed  Google Scholar 

  9. Jung YS, Cheon JH, Hong SP, et al. Clinical outcomes and prognostic factors for thiopurine maintenance therapy in patients with intestinal Behcet’s disease. Inflamm Bowel Dis. 2011;18:750–7.

    Article  PubMed  Google Scholar 

  10. Jung YS, Cheon JH, Park SJ, et al. Clinical course of intestinal Behcet’s disease during the first five years. Dig Dis Sci. 2013;58:496–503.

    Article  PubMed  Google Scholar 

  11. Park Y, Cheon JH. Update on the treatment of Behcet’s disease of the small Bowel with biologic agents. Curr Gastroenterol Rep. 2020;22:24.

    Article  PubMed  Google Scholar 

  12. Park J, Cheon JH. Anti-tumor necrosis factor therapy in intestinal Behçet’s disease. Gut Liver. 2018;12:623–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hibi T, Hirohata S, Kikuchi H, et al. Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study. Medicine. 2016;95:e3863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tanida S, Inoue N, Kobayashi K, et al. Adalimumab for the treatment of Japanese patients with intestinal Behçet’s disease. Clin Gastroenterol Hepatol. 2015;13:940-948.e943.

    Article  CAS  PubMed  Google Scholar 

  15. Inoue N, Kobayashi K, Naganuma M, et al. Long-term safety and efficacy of adalimumab for intestinal Behçet’s disease in the open label study following a phase 3 clinical trial. Intest Res. 2017;15:395–401.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Behcet H. Uber rezidivierende, aphthose durch ein Virus verursachte Geschuwuere am Mund, am Auge und Genitalien. Dermatol Wochenschr. 1937;105:1152–7.

    Google Scholar 

  17. Mizuki N, Meguro A, Ota M, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet. 2010;42:703–6.

    Article  CAS  PubMed  Google Scholar 

  18. Remmers EF, Cosan F, Kirino Y, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease. Nat Genet. 2010;42:698–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hou S, Yang Z, Du L, et al. Identification of a susceptibility locus in STAT4 for Behçet’s disease in Han Chinese in a genome-wide association study. Arthritis Rheum. 2012;64:4104–13.

    Article  CAS  PubMed  Google Scholar 

  20. Hsieh CS, Macatonia SE, Tripp CS, et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993;260:547–9.

    Article  CAS  PubMed  Google Scholar 

  21. Bacon CM, Petricoin EF 3rd, Ortaldo JR, et al. Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci USA. 1995;92:7307–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–32.

    Article  CAS  PubMed  Google Scholar 

  23. Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Evereklioglu C, Er H, Türköz Y, Cekmen M. Serum levels of TNF-alpha, sIL-2R, IL-6, and IL-8 are increased and associated with elevated lipid peroxidation in patients with Behçet’s disease. Mediat Inflamm. 2002;11:87–93.

    Article  CAS  Google Scholar 

  25. Imamura Y, Kurokawa MS, Yoshikawa H, et al. Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet’s disease. Clin Exp Immunol. 2005;139:371–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999;354:1932–9.

    Article  CAS  PubMed  Google Scholar 

  27. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45.

    Article  CAS  PubMed  Google Scholar 

  28. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–9.

    Article  CAS  PubMed  Google Scholar 

  29. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006;130:323–33 (quiz 591).

    Article  CAS  PubMed  Google Scholar 

  30. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.

    Article  CAS  PubMed  Google Scholar 

  31. Tugal-Tutkun I, Mudun A, Urgancioglu M, et al. Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behçet’s disease: an open-label trial. Arthritis Rheum. 2005;52:2478–84.

    Article  CAS  PubMed  Google Scholar 

  32. Vallet H, Riviere S, Sanna A, et al. Efficacy of anti-TNF alpha in severe and/or refractory Behçet’s disease: Multicenter study of 124 patients. J Autoimmun. 2015;62:67–74.

    Article  CAS  PubMed  Google Scholar 

  33. Lee JH, Cheon JH, Jeon SW, et al. Efficacy of infliximab in intestinal Behçet’s disease: a Korean multicenter retrospective study. Inflamm Bowel Dis. 2013;19:1833–8.

    PubMed  Google Scholar 

  34. Sugimura N, Mizoshita T, Sugiyama T, et al. Real-world efficacy of adalimumab and infliximab for refractory intestinal Behçet’s disease. Dig Liver Dis. 2019;51:967–71.

    Article  CAS  PubMed  Google Scholar 

  35. Zou J, Ji DN, Cai JF, et al. Long-term outcomes and predictors of sustained response in patients with intestinal Behcet’s disease treated with infliximab. Dig Dis Sci. 2017;62:441–7.

    Article  CAS  PubMed  Google Scholar 

  36. Zou J, Ji DN, Shen Y, et al. Mucosal healing at 14 weeks predicts better outcome in low-dose infliximab treatment for Chinese patients with active intestinal Behcet’s disease. Ann Clin Lab Sci. 2017;47:171–7.

    CAS  PubMed  Google Scholar 

  37. Müftüoğlu AU, Yazici H, Yurdakul S, et al. Behçet’s disease. Relation of serum C-reactive protein and erythrocyte sedimentation rates to disease activity. Int J Dermatol. 1986;25:235–9.

    Article  PubMed  Google Scholar 

  38. Melikoglu M, Topkarci Z. Is there a relation between clinical disease activity and acute phase response in Behcet’s disease? Int J Dermatol. 2014;53:250–4.

    Article  PubMed  Google Scholar 

  39. Tanaka T, Narazaki M, Kishimoto T. Interleukin (IL-6) immunotherapy. Cold Spring Harb Perspect Biol. 2018;10:a028456.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–89.

    Article  CAS  PubMed  Google Scholar 

  41. McGeachy MJ, Chen Y, Tato CM, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009;10:314–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ogura H, Murakami M, Okuyama Y, et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity. 2008;29:628–36.

    Article  CAS  PubMed  Google Scholar 

  43. Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305:1460–8.

    Article  CAS  PubMed  Google Scholar 

  44. Hibi T, Sakuraba A, Watanabe M, et al. Retrieval of serum infliximab level by shortening the maintenance infusion interval is correlated with clinical efficacy in Crohn’s disease. Inflamm Bowel Dis. 2012;18:1480–7.

    Article  PubMed  Google Scholar 

  45. Petrovic-Rackov L, Pejnovic N. Clinical significance of IL-18, IL-15, IL-12 and TNF-alpha measurement in rheumatoid arthritis. Clin Rheumatol. 2006;25:448–52.

    Article  PubMed  Google Scholar 

  46. Takeuchi T, Miyasaka N, Tatsuki Y, et al. Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:1208–15.

    Article  CAS  PubMed  Google Scholar 

  47. Ferrante M, Vermeire S, Fidder H, et al. Long-term outcome after infliximab for refractory ulcerative colitis. J Crohns Colitis. 2008;2:219–25.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank our lab members for all the support provided and Dr. Sae Murakami for the valuable advice regarding the statistical analysis.

Funding

The authors did not receive any funding.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Haruka Miyazaki, Daisuke Watanabe, Norihiro Okamoto, Eri Tokunaga, Yuna Ku, Haruka Takenaka, Namiko Hoshi, Makoto Ooi & Yuzo Kodama

  2. Department of Gastroenterology, University of Michigan, 6520C MSRB I, SPC 5682, 1150 W Medical Center Dr, Ann Arbor, MI, 48109, USA

    Daisuke Watanabe

  3. Division of Gastroenterology, National Hospital Organization Kobe Medical Center, Kobe, Japan

    Haruka Takenaka

Authors
  1. Haruka Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daisuke Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Norihiro Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eri Tokunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuna Ku
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haruka Takenaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Namiko Hoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Makoto Ooi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuzo Kodama
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HM, DW, and MO designed the study; HM, NO, ET, YK, HT, NH, and MO collected the data; HM analyzed the data and wrote the initial draft of the manuscript; DW and MO assisted in the revision of the manuscript; MO and YK approved the final version of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Makoto Ooi.

Ethics declarations

Ethics approval and consent to participate

This study was conducted in accordance with the principles of the Declaration of Helsinki. This study was approved by the ethics committee of Kobe University Hospital (No. B200279). The requirement for written informed consent to participate in the study was replaced by an opt-out method, owing to the retrospective nature of this study.

Consent for publication

The requirement for written informed consent was replaced by an opt-out method owing to the retrospective nature of this study.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyazaki, H., Watanabe, D., Okamoto, N. et al. Efficacy and predictor of anti-TNFα agents in patients with intestinal Behçet's disease. BMC Gastroenterol 22, 149 (2022). https://doi.org/10.1186/s12876-022-02221-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12876-022-02221-0

Keywords

BMC Gastroenterology

ISSN: 1471-230X

Contact us