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

Toshifumi Hibi, Shunsei Hirohata, Hirotoshi Kikuchi, Ukihide Tateishi, Noriko Sato, Kunihiko Ozaki, Kazuoki Kondo, Yoshiaki Ishigatsubo, Toshifumi Hibi, Shunsei Hirohata, Hirotoshi Kikuchi, Ukihide Tateishi, Noriko Sato, Kunihiko Ozaki, Kazuoki Kondo, Yoshiaki Ishigatsubo

Abstract

Behçet disease (BD) is a multisystem disease associated with a poor prognosis in cases of gastrointestinal, neurological, or vascular involvement. We conducted a multicenter, prospective, open-label, single-arm phase 3 study to determine the efficacy, safety, and pharmacokinetics of infliximab (IFX) in BD patients with these serious complications who had displayed poor response or intolerance to conventional therapy.IFX at 5 mg/kg was administered to 18 patients (11 intestinal BD, 3 neurological BD [NBD], and 4 vascular BD [VBD]) at weeks 0, 2, and 6 and every 8 weeks thereafter until week 46. In patients who showed inadequate responses to IFX after week 30, the dose was increased to 10 mg/kg. We then calculated the percentage of complete responders according to the predefined criteria depending on the symptoms and results of examinations (ileocolonoscopy, brain magnetic resonance imaging, computed tomography angiography, positron emission tomography, cerebrospinal fluid, or serum inflammatory markers), exploring the percentage of complete responders at week 30 (primary endpoint).The percentage of complete responders was 61% (11/18) at both weeks 14 and 30 and remained the same until week 54. Intestinal BD patients showed improvement in clinical symptoms along with decrease in C-reactive protein (CRP) levels after week 2. Consistently, scarring or healing of the principal ulcers was found in more than 80% of these patients after week 14. NBD patients showed improvement in clinical symptoms, imaging findings, and cerebrospinal fluid examinations. VBD patients showed improvement in clinical symptoms after week 2 with reductions in CRP levels and erythrocyte sedimentation rate. Imaging findings showed reversal of inflammatory changes in 3 of the 4 VBD patients. Irrespective of the type of BD, all patients achieved improvement in quality of life, leading to the dose reduction or withdrawal of steroids. IFX dose was increased to 10 mg/kg in 3 intestinal BD patients, resulting in the improvement of clinical symptoms, CRP levels, and visual analogue scale score. Safety and pharmacokinetics profiles were comparable to those in patients with rheumatoid arthritis or Crohn disease. These findings support IFX as a new therapeutic option for patients with intestinal BD, NBD, or VBD.

Figures

Figure 1
Figure 1
Patient disposition and flow chart of the study. ANB = acute neurological Behçet disease, BD = Behçet disease, CPNB = chronic progressive neurological Behçet disease, IC = informed consent, IFX = infliximab, NBD = neurological Behçet disease, VBD = vascular Behçet disease.
Figure 2
Figure 2
Efficacy of infliximab on intestinal Behçet disease. (A) Percentage with improved or cured clinical symptoms, (B) changes in size of major ulcers for each patient, and (C) changes in serum C-reactive protein (CRP) levels for each patient.
Figure 3
Figure 3
Efficacy of infliximab on neurological Behçet disease. (A) CSF cell count, CSF IL-6 concentration, and FLAIR MRI images in patient 1 (ANB); (B) CSF cell count, CSF IL-6 concentration, and FLAIR MRI images in patient 2 (ANB); and (C) CSF IL-6 concentration and T1-weighted MRI images in patient 3 (CPNB). ANB = acute neurological Behçet disease, CPNB = chronic progressive neurological Behçet disease, CSF = cerebrospinal fluid, IL-6 = interleukin-6, MRI = magnetic resonance imaging.
Figure 4
Figure 4
Efficacy of infliximab on vascular Behçet disease. (A) Change in clinical symptoms, (B) PET/CT images of thrombophlebitis of the lower legs in a representative patient, (C) changes in serum CRP level for each patient, and (D) changes in serum ESR for each patient. CRP = C-reactive protein, CT = computed tomography, ESR = erythrocyte sedimentation rate, PET = positron emission tomography.
Figure 5
Figure 5
Effects of infliximab on quality of life in patients with intestinal, neurological, and vascular Behçet disease. (A) Patient VAS score, (B) SF-36 score (physical health summary score). Data are shown as the means ± standard deviation. SF-36 = Short Form-36, VAS = visual analogue scale.
Figure 6
Figure 6
Efficacy of infliximab on major symptoms of Behçet disease (BD) and global assessment of overall disease activities by physicians and patients. (A) Major symptoms of BD (oral aphtha, skin symptoms, and pudendal ulcer), (B) assessment of overall disease activities of BD (assessed by physicians or patients).
Figure 7
Figure 7
Changes in serum infliximab concentration. Data of patients with intestinal and vascular BD are shown as the median. ANB = acute neurological Behçet disease, BD = Behcet disease, CPNB = chronic progressive neurological Behçet disease, IFX = infliximab, VBD = vascular BD.

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