Abstract
Introduction
Behçet’s disease (BD) with intestinal, neurological (NBD), and vascular (VBD) manifestations often leads to poor outcomes. Infliximab is approved for the treatment of intestinal BD, NBD, and VBD in Japan; however, evidence regarding its safety and effectiveness in these patients is limited. We conducted a 2-year post-marketing surveillance to evaluate the safety and effectiveness of infliximab in patients with intestinal BD, NBD, and VBD in Japan.
Methods
This 2-year, multicenter, prospective, observational study included all patients with intestinal BD, NBD, or VBD, who had experienced an insufficient response to conventional therapies (e.g., glucocorticoids and immunosuppressants/immunomodulators), and initiated infliximab for the first time at participating medical institutions. The safety endpoints included adverse events and adverse drug reactions (ADRs), and the effectiveness endpoints included global improvement, and for patients with acute NBD, acute attacks.
Results
Between October 2015 and August 2018, 255 patients (171 intestinal BD, 49 NBD, and 51 VBD; including 16 with two disease types) were enrolled from 133 medical centers and treated with infliximab. Adverse events, ADRs, and serious ADRs occurred in 100 (39.2%), 72 (28.2%), and 38 (14.9%) patients, respectively; incidences were generally similar across intestinal BD, NBD, and VBD groups. No new safety concerns were identified. At the final evaluation, 68.8% of patients with intestinal BD showed improvement, most patients with chronic progressive NBD and VBD had not worsened (100% and 91.7%, respectively), and 93.3% of patients with acute NBD had no new acute attacks during the observation period.
Conclusion
These results confirmed the safety and effectiveness of infliximab in clinical practice in 255 patients with intestinal BD, NBD, and VBD. There were no new safety concerns.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12325-024-02993-9.
Keywords: Anti-TNFα monoclonal antibody, Infliximab, Intestinal Behçet’s disease, Neurological Behçet’s disease, Post-marketing surveillance, Real-world evidence, Vascular Behçet’s disease
Key Summary Points
| Why carry out this study? |
| Behçet’s disease (BD) with intestinal tract symptoms (intestinal BD), nervous system symptoms (neurological BD [NBD]), and vascular symptoms (vascular BD [VBD]) are not common but serious, resulting in poor clinical outcomes. |
| Infliximab is approved for the treatment of intestinal BD, NBD, and VBD in Japan; however, evidence regarding its safety and effectiveness in these patients is limited. |
| This 2-year post-marketing surveillance evaluated the safety and effectiveness of infliximab in patients with intestinal BD, NBD, and VBD in Japan. |
| What was learned from the study? |
| The safety and effectiveness of infliximab were confirmed in clinical practice in 255 patients with intestinal BD, NBD, and VBD. |
| Our findings in real-world clinical practice for the use of infliximab in patients with intestinal BD, NBD, and VBD supported the previous evidence for efficacy without additional concerns to the known safety profile and suggest that infliximab is a beneficial treatment option for patients with intestinal BD, NBD, and VBD who have had an inadequate response to conventional therapies. |
Introduction
Behçet’s disease (BD) is a multisystemic inflammatory disease with an unknown cause [1, 2]. The disease is rare and has a distinct geographical distribution, with Turkey having the highest prevalence of 370/10,000 and Japan having a prevalence of 13.5/10,000 [3]. The disease is characterized by recurrent oral aphthous ulcers, genital ulcers, ocular lesions, and dermatological, cardiovascular, gastrointestinal, and neurological manifestations.
BD with intestinal tract symptoms (intestinal BD), nervous system symptoms (neurological BD [NBD]), and vascular symptoms (vascular BD [VBD]) are not common, and different populations have varied clinical manifestation patterns. Intestinal BD is found in one-third of patients with BD in Japan and South Korea, whereas it is rare in Mediterranean countries. NBD and VBD account for 5% and up to 40% of BD cases, respectively [3]. Patients with these types of BD often have poor outcomes [4, 5]. The most common gastrointestinal symptoms of intestinal BD are abdominal pain, diarrhea, and bleeding [6]. Deep ulcers are responsible for the most common intestinal complications, including severe bleeding and intestinal perforation. These complications can necessitate emergency abdominal surgery and bowel resection [6]. Patients with NBD can be divided into those who present with parenchymal lesions and those with non-parenchymal lesions. NBD with parenchymal lesions is further classified into an acute form (ANBD) and a chronic progressive form (CPNBD) by the differences in clinical courses and response to glucocorticoid (GC) treatment [7]. Manifestations of ANBD include headache, meningitis or meningoencephalitis, hemiplegia, and cranial nerve palsies. Patients with CPNBD can also experience neuropsychological symptoms, including personality changes [7]. VBD affects any blood vessel size and can occur in both arterial and venous systems. Venous thrombosis in unusual locations, such as the inferior and superior vena cava, and pulmonary and non-pulmonary artery involvement are characteristic of VBD [8].
Although the etiology of BD remains unclear, inflammatory cytokines such as tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) are involved in the pathogenesis of BD [9, 10]. TNFα production is increased in the intestinal lesions of patients with intestinal BD [11] and the blood cells of patients with VBD [12]. IL-6 concentrations are increased in the cerebrospinal fluid (CSF) of patients with NBD [13]. Therefore, inhibiting TNFα and IL-6 production is thought to be beneficial for patients with these types of BD.
Infliximab (Remicade®, Janssen Biotech, Inc., Horsham, PA, USA; hereafter referred to as IFX) is an anti-TNFα monoclonal antibody that has revolutionized the treatment of several inflammatory diseases, such as rheumatoid arthritis and Crohn’s disease. Moreover, IFX therapy is reported to decrease not only TNFα but also IL-6 [14, 15]. IFX was also approved for the treatment of BD-associated refractory retinitis/uveitis in 2007 [16], followed by approval for the treatment of intestinal BD, NBD, and VBD in 2015 in Japan according to the results of a phase III clinical trial for patients with an insufficient response or intolerance to conventional therapy (e.g., GC and immunosuppressants/immunomodulators) [17]. However, the trial had a small number of patients (intestinal BD, n = 11; NBD, n = 3; and VBD, n = 4). A recent clinical trial of IFX in Korean patients with intestinal BD [18] also had a small sample size (n = 33) and a short evaluation period. There have been several observational studies of IFX treatment in patients with intestinal BD [19–22], NBD [23, 24], and VBD [25–27], but most of these were retrospective studies and did not include large numbers of patients. Thus, evidence from prospective large-scale studies on the safety and effectiveness of IFX in these three disease types with uncommon and poor outcomes is needed.
To address this, we conducted a 2-year post-marketing surveillance (PMS) and assessed the safety and effectiveness of IFX in 255 patients with intestinal BD, NBD, and VBD in real-world clinical practice in Japan. We hypothesized that the PMS would support the safety and effectiveness results reported in previous clinical trials and observational studies.
Methods
Study Design and Population
This multicenter, prospective, observational PMS study included patients with intestinal BD, NBD, and VBD who had an insufficient response to conventional therapies and were treated with IFX for the first time. No exclusion criteria were applied. All medical institutions in Japan that administered IFX for BD were requested to participate, and the head of each medical institution that agreed to participate signed an agreement. Patients were enrolled through a central registry system.
Patients received IFX according to the Japanese product label [28]. IFX 5 mg/kg was administered as an intravenous infusion at weeks 0, 2, and 6, and at 8-week intervals thereafter. Patients who had an inadequate response or loss of response (LOR) following week 6 were allowed a dose escalation to 10 mg/kg. The maximum observation period was 2 years, as detailed in the Supplementary Methods.
This study was conducted according to the Japanese Good Post-Marketing Surveillance Practices (GPSP, Pharmaceuticals and Medical Devices Agency, 2004). As per the GPSP, pre-registration as a clinical trial, informed consent, and study protocol approval by the institutional review board (IRB) were not required for a PMS study. Therefore, no IRB was held for this study. The study protocol was approved through pre-consultation with the Pharmaceuticals and Medical Devices Agency, in accordance with the GPSP. Data were made unidentifiable to individual patients, ensuring patient confidentiality and transparency regarding data privacy.
Study Outcomes
Patient demographics and background data were collected, as described in the Supplementary Methods. The safety outcomes were the incidence of adverse drug reactions (ADRs). The definition of ADRs is described in the Supplementary Methods and ADRs of interest are shown in Table S1.
Global improvement was evaluated on the basis of the investigator’s judgment by comparing the overall symptoms of intestinal BD, CPNBD, and VBD with symptoms present prior to IFX administration. Three categories of changes in symptoms were defined as follows: “improvement” (no symptoms or improvement in symptoms), “unchanged” (no change in symptoms), and “worsening” (new or worsened symptoms). Symptom changes that could not be appropriately categorized were classified as “undetermined.” For patients with intestinal BD, the percentage of patients with an improvement in symptoms was calculated by excluding patients with undetermined, unknown, and undescribed symptoms, and for patients with CPNBD or VBD, the percentage of patients without worsening symptoms was calculated.
For patients with intestinal BD, the largest diameter of the main intestinal ulcer measured by endoscopy, blood C-reactive protein (CRP) levels, and GC use were assessed. For patients with ANBD, presence (mild or severe) or absence of acute attacks (headache, fever, and focal neurologic symptoms) was assessed. A brain MRI scan was used to assess changes in high-signal areas for patients with ANBD and brainstem atrophy for patients with CPNBD. The cell count and concentration of IL-6 in CSF was also assessed. For patients with VBD, vascular imaging using a positron emission tomography/computerized tomography scan, blood CRP and D-dimer levels, and GC use were evaluated. Assessment criteria of the largest diameter of the main intestinal ulcer, brain MRI, and vascular imaging are described in the Supplementary Methods.
Global improvement, acute attacks, and blood CRP levels were evaluated prior to IFX administration and at 2, 6, 14, 26, 52, 78, and 104 weeks after initiating IFX treatment. Patients receiving IFX dose escalations were assessed for global improvement immediately prior to dose escalation and at 8, 16, 26, 52, 78, and 104 weeks after dose escalation, and effectiveness after dose escalation was evaluated in disease types for which at least 10 patients with dose escalation were reported. All other effectiveness measurements were assessed before IFX administration and 26, 52, 78, and 104 weeks after initiating IFX treatment.
Sample Size and Statistical Analyses
No formal sample size was mandated as all eligible patients from participating institutions were enrolled. The safety analysis set comprised all eligible patients who received IFX treatment and had ADR data for evaluation, excluding registration violations, duplicates, and off-label usage. The effectiveness analysis set was composed of patients from the safety analysis set who had effectiveness data available for analysis. In addition, because it has been reported that ANBD and CPNBD are different in response to treatment [29], to adequately assess the effectiveness of ANBD and CPNBD, patients who had both ANBD and CPNBD were excluded post hoc.
Data at each timepoint and on the final evaluation date were tabulated. For patients who discontinued treatment, the final evaluation date was the date after the last administration and the date closest to the last administration date; for patients who continued treatment, the final evaluation date was the last date of treatment. Statistical analyses, conducted using SAS version 9.1.3 and above (SAS Institute Inc., Cary, NC, USA), are detailed in the Supplementary Methods.
Results
Patients
A total of 255 patients (intestinal BD, n = 171; NBD, n = 49; VBD, n = 51; including seven patients with both intestinal BD and NBD, six patients with both intestinal BD and VBD, and three patients with both NBD and VBD) from 133 medical centers in Japan were enrolled and treated with IFX between October 29, 2015 and August 31, 2018 (Fig. S1). The safety analysis set included 255 patients. Some patients had multiple BD manifestations: both intestinal BD and NBD (n = 7), both intestinal BD and VBD (n = 6), and both NBD and VBD (n = 3). Among the 49 patients with NBD, 19 patients had ANBD and 32 had CPNBD, and two patients had both. There were 51 patients with VBD; 32 of these had arterial involvement and 28 had venous involvement, and nine patients had both arterial and venous involvement. The effectiveness analysis set included 250 patients, excluding three patients with intestinal BD in whom effectiveness was not evaluated and two patients with both ANBD and CPNBD.
In the safety analysis set, approximately half (50.6%) of the patients were female (intestinal BD, 55.6%; NBD, 49.0%; and VBD, 33.3%) (Table 1). The mean age (46.8 years) and mean intestinal BD, NBD, or VBD duration (4.5 years) in the overall safety analysis set were similar across all BD types. The major symptoms of BD were recurrent oral aphthous ulcers in 96.9% of patients (intestinal BD, 98.2%; NBD, 93.9%; and VBD, 96.1%); skin symptoms in 79.2% (intestinal BD, 78.9%; NBD, 71.4%; and VBD, 86.3%); ocular symptoms in 25.5% (intestinal BD, 17.0%; NBD, 46.9%; and VBD, 29.4%); and genital ulcer in 64.3% (intestinal BD, 65.5%; NBD, 55.1%; and VBD, 66.7%). Concomitant treatment and combination therapy used at least once during the observation period are shown in Table 2. Patient baseline characteristics, and concomitant treatment and combination therapy in the effectiveness analysis set are shown in Table S2.
Table 1.
Patient baseline characteristics (safety analysis set)
| Characteristic | All N = 255a |
Intestinal BD n = 171 |
NBD | VBD n = 51 |
||
|---|---|---|---|---|---|---|
| Total n = 49 |
ANBD n = 19b |
CPNBD n = 32b |
||||
| Sex, female | 129 (50.6) | 95 (55.6) | 24 (49.0) | 11 (57.9) | 15 (46.9) | 17 (33.3) |
| Age, years | 46.8 ± 16.4 [10–86] | 48.0 ± 17.3 [10–86] | 43.8 ± 12.5 [15–71] | 37.3 ± 10.6 [15–56] | 47.0 ± 12.1 [22–71] | 45.0 ± 16.1 [16–79] |
| Disease durationc, years | 4.5 ± 5.8 [0–32] | 4.6 ± 5.8 [0–32] | 4.1 ± 5.0 [0–19] | 2.3 ± 4.6 [0–19] | 5.0 ± 5.0 [0–15] | 4.7 ± 7.0 [0–31] |
| Body mass indexd, kg/m2 | 21.72 ± 3.95 [11.9–31.8] | 21.52 ± 4.01 [11.9–31.8] | 22.57 ± 4.04 [16.7–31.8] | 22.64 ± 4.41 [16.7–31.6] | 22.34 ± 3.79 [16.9–31.8] | 22.14 ± 3.90 [15.9–31.6] |
| History of tuberculosis infection | 3 (1.2) | 2 (1.2) | 0 | 0 | 0 | 1 (2.0) |
| Tuberculosis prophylaxis | 22 (8.6) | 12 (7.0) | 6 (12.2) | 2 (10.5) | 4 (12.5) | 5 (9.8) |
| ADR history | 38 (14.9) | 28 (16.4) | 5 (10.2) | 1 (5.3) | 4 (12.5) | 8 (15.7) |
| Allergy history | 24 (9.4) | 15 (8.8) | 3 (6.1) | 2 (10.5) | 1 (3.1) | 8 (15.7) |
| Malignancy history | 6 (2.4) | 4 (2.3) | 1 (2.0) | 0 | 1 (3.1) | 1 (2.0) |
| Respiratory disease history | 10 (3.9) | 7 (4.1) | 2 (4.1) | 1 (5.3) | 1 (3.1) | 2 (3.9) |
| Major BD symptoms | ||||||
| Recurrent oral aphthous ulcers | 247 (96.9) | 168 (98.2) | 46 (93.9) | 18 (94.7) | 30 (93.8) | 49 (96.1) |
| Skin symptoms | 202 (79.2) | 135 (78.9) | 35 (71.4) | 16 (84.2) | 21 (65.6) | 44 (86.3) |
| Ocular symptoms | 65 (25.5) | 29 (17.0) | 23 (46.9) | 5 (26.3) | 18 (56.3) | 15 (29.4) |
| Genital ulcer | 164 (64.3) | 112 (65.5) | 27 (55.1) | 14 (73.7) | 15 (46.9) | 34 (66.7) |
| Minor BD symptoms | ||||||
| Arthritise | 135 (52.9) | 106 (62.0) | 16 (32.7) | 7 (36.8) | 9 (28.1) | 19 (37.3) |
| Epididymal inflammation | 8 (3.1) | 3 (1.8) | 2 (4.1) | 1 (5.3) | 1 (3.1) | 5 (9.8) |
| Gastrointestinal lesions/ileocecal ulcers | 179 (70.2) | 171 (100.0) | 11 (22.4) | 2 (10.5) | 9 (28.1) | 10 (19.6) |
| Vascular lesions | 56 (22.0) | 10 (5.8) | 4 (8.2) | 3 (15.8) | 1 (3.1) | 51 (100.0) |
| CNS lesions | 50 (19.6) | 8 (4.7) | 49 (100.0) | 19 (100.0) | 32 (100.0) | 4 (7.8) |
| History of adalimumab use | 49 (19.2) | 49 (28.7) | 1 (2.0) | 0 | 1 (3.1) | 1 (2.0) |
| Prior BD treatment within the previous 26 weeks | 242 (94.9) | 162 (94.7) | 49 (100.0) | 19 (100.0) | 32 (100.0) | 47 (92.2) |
| Immunosuppressants or immunomodulators | 124 (48.6) | 78 (45.6) | 32 (65.3) | 10 (52.6) | 23 (71.9) | 26 (51.0) |
| Glucocorticoids | 183 (71.8) | 114 (66.7) | 41 (83.7) | 17 (89.5) | 26 (81.3) | 40 (78.4) |
| Other medications | 184 (72.2) | 131 (76.6) | 27 (55.1) | 13 (68.4) | 15 (46.9) | 38 (74.5) |
| Comorbidities | 156 (61.2) | 99 (57.9) | 35 (71.4) | 12 (63.2) | 24 (75.0) | 34 (66.7) |
| Respiratory disease | 5 (2.0) | 2 (1.2) | 1 (2.0) | 0 | 1 (3.1) | 3 (5.9) |
| Hepatic dysfunction | 10 (3.9) | 6 (3.5) | 5 (10.2) | 2 (10.5) | 3 (9.4) | 0 |
| Cardiac disorders | 16 (6.3) | 6 (3.5) | 1 (2.0) | 1 (5.3) | 0 | 10 (19.6) |
| Renal impairment | 4 (1.6) | 2 (1.2) | 0 | 0 | 0 | 2 (3.9) |
| Diabetes mellitus | 23 (9.0) | 14 (8.2) | 5 (10.2) | 1 (5.3) | 4 (12.5) | 4 (7.8) |
| Other | 139 (54.5) | 90 (52.6) | 30 (61.2) | 11 (57.9) | 20 (62.5) | 29 (56.9) |
Data are shown as n (%) or mean ± SD [range]
ADR adverse drug reaction, ANBD acute neurological Behçet’s disease, BD Behçet’s disease, CNS central nervous system, CPNBD chronic progressive neurological Behçet’s disease, NBD neurological Behçet’s disease, VBD vascular Behçet’s disease
aIncluding seven patients with both intestinal BD and NBD, six patients with both intestinal BD and VBD, and three patients with both NBD and VBD
bIncluding two patients with both ANBD and CPNBD
cN = 236 in all patients, n = 159 in patients with intestinal BD, n = 48 in patients with total NBD, n = 19 in patients with ANBD, n = 31 in patients with CPNBD, and n = 44 in patients with VBD
dN = 243 in all patients, n = 163 in patients with intestinal BD, n = 48 in patients with total NBD, n = 19 in patients with ANBD, n = 31 in patients with CPNBD, and n = 47 in patients with VBD
eWithout deformity or stiffness
Table 2.
Concomitant treatment and combination therapy used at least once during the observation period
| Characteristic | All N = 255a |
Intestinal BD n = 171 |
NBD | VBD n = 51 |
||
|---|---|---|---|---|---|---|
| Total n = 49 |
ANBD n = 19b |
CPNBD n = 32b |
||||
| Concomitant treatment | 251 (98.4) | 167 (97.7) | 49 (100.0) | 19 (100.0) | 32 (100.0) | 51 (100.0) |
| Glucocorticoids | 184 (72.2) | 115 (67.3) | 36 (73.5) | 16 (84.2) | 22 (68.8) | 44 (86.3) |
| Colchicine | 149 (58.4) | 97 (56.7) | 29 (59.2) | 11 (57.9) | 19 (59.4) | 34 (66.7) |
| 5-Aminosalicylic acid | 97 (38.0) | 93 (54.4) | 8 (16.3) | 2 (10.5) | 6 (18.8) | 4 (7.8) |
| Methotrexate | 75 (29.4) | 37 (21.6) | 35 (71.4) | 11 (57.9) | 26 (81.3) | 15 (29.4) |
| Azathioprine or mercaptopurine | 56 (22.0) | 47 (27.5) | 2 (4.1) | 1 (5.3) | 1 (3.1) | 8 (15.7) |
| Cyclosporine | 12 (4.7) | 10 (5.8) | 0 | 0 | 0 | 2 (3.9) |
| Tacrolimus | 8 (3.1) | 5 (2.9) | 0 | 0 | 0 | 3 (5.9) |
| Metronidazole | 3 (1.2) | 2 (1.2) | 0 | 0 | 0 | 1 (2.0) |
| Cyclophosphamide | 1 (0.4) | 0 | 0 | 0 | 0 | 1 (2.0) |
| Other immunosuppressants or immunomodulators | 2 (0.8) | 1 (0.6) | 1 (2.0) | 1 (5.3) | 0 | 0 |
| Antiplatelet agents | 32 (12.5) | 14 (8.2) | 7 (14.3) | 5 (26.3) | 2 (6.3) | 16 (31.4) |
| Anticoagulants | 40 (15.7) | 16 (9.4) | 6 (12.2) | 3 (15.8) | 3 (9.4) | 23 (45.1) |
| Antimycobacterial drugs | 26 (10.2) | 13 (7.6) | 8 (16.3) | 2 (10.5) | 6 (18.8) | 6 (11.8) |
| Other drugs | 217 (85.1) | 143 (83.6) | 44 (89.8) | 17 (89.5) | 29 (90.6) | 46 (90.2) |
| Combination therapy | 38 (14.9) | 35 (20.5) | 0 | 0 | 0 | 6 (11.8) |
| Surgical treatment | 20 (7.8) | 18 (10.5) | 0 | 0 | 0 | 3 (5.9) |
| Endovascular treatment | 1 (0.4) | 1 (0.6) | 0 | 0 | 0 | 0 |
| Total parenteral nutrition | 12 (4.7) | 12 (7.0) | 0 | 0 | 0 | 2 (3.9) |
| Enteral nutrition | 11 (4.3) | 11 (6.4) | 0 | 0 | 0 | 0 |
| Other | 3 (1.2) | 2 (1.2) | 0 | 0 | 0 | 1 (2.0) |
Data are shown as n or n (%)
ANBD acute neurological Behçet’s disease, BD Behçet’s disease, CPNBD chronic progressive neurological Behçet’s disease, NBD neurological Behçet’s disease, VBD vascular Behçet’s disease
aIncluding seven patients with both intestinal BD and NBD, six patients with both intestinal BD and VBD, and three patients with both NBD and VBD
bIncluding two patients with both ANBD and CPNBD
The mean number of IFX infusions ± standard deviation (SD) was 12.1 ± 5.1. The IFX dose was increased to 10 mg/kg in 80 patients (intestinal BD, n = 61; NBD, n = 16; VBD, n = 10; including four patients with both intestinal BD and NBD, two patients with both intestinal BD and VBD, and one patient with both NBD and VBD): the dose was increased in 78 (97.5%) patients because of inadequate response and two (2.5%) for reasons unknown or not described. The mean ± SD observation duration was 635.1 ± 209.1 days. A total of 93 patients (36.5%) discontinued IFX treatment: 32 (34.4%, including three patients who discontinued because of adverse events [AEs] that occurred after dose escalation) because of AEs, 22 (23.7%, including 12 patients who discontinued after dose escalation of IFX) because of inadequate response, and four (4.3%) because of symptom improvement. The remaining patients (35/93; 37.6%) discontinued for other reasons (mainly because the patients transferred to a different hospital). The overall treatment persistence rate (95% confidence interval [CI]) was 74.4% (68.6–79.3%; persistence rate [95% CI] for patients with intestinal BD, 71.8% [64.4–77.9%]; ANBD, 73.7% [47.9–88.1%]; CPNBD, 84.4% [66.5–93.2%]; and VBD, 70.6% [56.0–81.1%]) at 52 weeks and 63.3% (57.1–68.9%; persistence rate [95% CI] for patients with intestinal BD, 62.4% [54.6–69.2%]; ANBD, 57.9% [33.2–76.3%]; CPNBD, 74.7% [55.7–86.5%]; and VBD, 56.7% [42.0–69.0%]) at 104 weeks (Fig. S2).
Safety Outcomes
The incidences of AEs, serious AEs, ADRs, and serious ADRs in the safety analysis set were 39.2% (100/255), 22.4% (57/255), 28.2% (72/255), and 14.9% (38/255), respectively. The most common ADRs were infusion-related reactions (11/255; 4.3%), followed by herpes zoster (6/255; 2.4%), nasopharyngitis and pneumonia (both 5/255; 2.0%), and upper respiratory tract infection, cough, interstitial lung disease, and pyrexia (each 3/255; 1.2%) (Table S3). The serious ADRs included pneumonia (5/255; 2.0%), and herpes zoster and interstitial lung disease (both 3/255; 1.2%). ADRs of interest are shown in Table 3. Serious infections occurred in 9.4% (24/255) of patients. Tuberculosis appeared in 0.8% (2/255) of patients, both of whom had CPNBD and were screened for latent tuberculosis before initiating IFX treatment. Pneumocystis pneumonia and cytomegalovirus infection occurred in 0.8% (2/255) and 0.4% (1/255) of patients, all of whom had intestinal BD. Interstitial pneumonia developed in 1.6% (4/255) of patients (intestinal BD, n = 2; VBD, n = 2). Malignant tumors were found in 1.2% of patients with intestinal BD (3/255), including one case each of gastric cancer, pancreatic cancer, and malignant neoplasm of the lung. There were 13 infusion reactions (IRs) (5.1%), all 13 patients had intestinal BD (including one patient with both intestinal BD and ANBD). The incidence of IRs was 4.1% (2/49) in patients with prior adalimumab treatment and 9.0% (11/122) in those without prior adalimumab treatment. Serious thrombocytopenia occurred in one patient with CPNBD.
Table 3.
Adverse drug reactions of interest
| Any (grade/severity) | Serious | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| All N = 255a |
Intestinal BD n = 171 |
NBD | VBD n = 51 |
All N = 255a |
Intestinal BD n = 171 |
NBD | VBD n = 51 |
|||||
| Total n = 49 |
ANBD n = 19b |
CPNBD n = 32b |
Total n = 49 |
ANBD n = 19b |
CPNBD n = 32b |
|||||||
| Patients with ADRs | 72 (28.2) | 51 (29.8) | 14 (28.6) | 5 (26.3) | 9 (28.1) | 12 (23.5) | 38 (14.9) | 24 (14.0) | 9 (18.4) | 2 (10.5) | 7 (21.9) | 8 (15.7) |
| ADRs of interest | ||||||||||||
| Serious infectionsc | N/A | N/A | N/A | N/A | N/A | N/A | 24 (9.4) | 13 (7.6) | 7 (14.3) | 1 (5.3) | 6 (18.8) | 6 (11.8) |
| Tuberculosis | 2 (0.8) | 0 | 2 (4.1) | 0 | 2 (6.3) | 0 | 2 (0.8) | 0 | 2 (4.1) | 0 | 2 (6.3) | 0 |
| Pneumocystis pneumonia | 2 (0.8) | 2 (1.2) | 0 | 0 | 0 | 0 | 2 (0.8) | 2 (1.2) | 0 | 0 | 0 | 0 |
| Cytomegalovirus infections | 1 (0.4) | 1 (0.6) | 0 | 0 | 0 | 0 | 1 (0.4) | 1 (0.6) | 0 | 0 | 0 | 0 |
| Interstitial pneumonia | 4 (1.6) | 2 (1.2) | 0 | 0 | 0 | 2 (3.9) | 4 (1.6) | 2 (1.2) | 0 | 0 | 0 | 2 (3.9) |
| Malignant tumorsd | 3 (1.2) | 3 (1.8) | 0 | 0 | 0 | 0 | 3 (1.2) | 3 (1.8) | 0 | 0 | 0 | 0 |
| Infusion reactionse | 13 (5.1) | 13 (7.6) | 1 (2.0) | 1 (5.3) | 0 | 0 | 3 (1.2) | 3 (1.8) | 0 | 0 | 0 | 0 |
| Demyelinating disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Cardiac failure | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Lupus-like syndromes associated with positive anti-dsDNA antibodies | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Cytopeniaf | 1 (0.4) | 0 | 1 (2.0) | 0 | 1 (3.1) | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Data are shown as n or n (%)
ADR adverse drug reaction, ANBD acute neurological Behçet’s disease, BD Behçet’s disease, CPNBD chronic progressive neurological Behçet’s disease, dsDNA double-stranded deoxyribonucleic acid, N/A not applicable, NBD neurological Behçet’s disease, VBD vascular Behçet’s disease
aIncluding seven patients with both intestinal BD and NBD, six patients with both intestinal BD and VBD, and three patients with both NBD and VBD
bIncluding two patients with both ANBD and CPNBD
cAll serious infections are listed under “Infections and infestations” in Table S3
dIncluding gastric cancer (n = 1), pancreatic cancer (n = 1), and malignant neoplasm of the lung (n = 1)
eIncluding infusion-related reaction (n = 10, including 2 serious cases), anaphylactic reaction (n = 1, serious case), nausea (n = 1), esophageal candidiasis (n = 1), pyrexia (n = 1)
fIncluding platelet count decreased (n = 1)
The incidences of ADRs and serious ADRs after dose escalation were 17.5% (14/80) and 7.5% (6/80), respectively (Table S4). Serious ADRs were cellulitis, herpes zoster, viral infection, post procedural infection, pneumocystis pneumonia, and infusion-related reactions.
Thirteen patients had AEs with a fatal outcome, and a causal relationship with IFX could not be excluded in five patients (six events), including events of infection (CPNBD), mucormycosis and renal infarction (intestinal BD), pancreatic cancer (intestinal BD), perforation of the small intestine (intestinal BD), and death due to an unreported cause (CPNBD).
Analysis of safety issues revealed that, among the collected background factors, the occurrence of ADRs was related to patients with a history of ADRs with other drugs and the presence or absence of comorbidities (Table 4). By system organ class, patients with a history of ADRs had a higher incidence of infections and infestations than those with no history of ADRs (26.3% [10/38] vs 13.1% [28/214]; risk ratio 2.01). Patients with comorbidities were more likely to develop infections and infestations (21.2% [33/156] vs 6.1% [6/99]; risk ratio 3.49), respiratory, thoracic, and mediastinal disorders (4.5% [7/156] vs 2.0% [2/99], risk ratio 2.22), and injury, poisoning, and procedural complications (5.8% [9/156] vs 2.0% [2/99], risk ratio 2.86). The incidence of infections and infestations were also associated with a history of ADRs and comorbidities in patients with intestinal BD and NBD (Tables S5 and S6). Moreover, we found that total parenteral nutrition in patients with intestinal BD (Table S5) and anticoagulants in patients with VBD (Table S7) were associated with the incidence of infections and infestations.
Table 4.
Adverse drug reactions by patient background
| Patients | Patients with ADRs | 95% CI | P valueb | Risk ratio [95% CI] | |
|---|---|---|---|---|---|
| All patients | 255a | 72 (28.2) | 22.80–34.19 | ||
| Sex | |||||
| Male | 126 (49.4) | 37 (29.4) | 21.59–38.14 | 0.781 | Reference |
| Female | 129 (50.6) | 35 (27.1) | 19.68–35.66 | 0.92 [0.62–1.37] | |
| Age, years | |||||
| < 65 | 212 (83.1) | 57 (26.9) | 21.04–33.39 | 0.353 | Reference |
| ≥ 65 | 43 (16.9) | 15 (34.9) | 21.01–50.93 | 1.30 [0.82–2.07] | |
| Disease duration, years | |||||
| < 3 | 135 (52.9) | 44 (32.6) | 24.78–41.19 | 0.567 | Reference |
| 3 to < 5 | 22 (8.6) | 6 (27.3) | 10.73–50.22 | 0.84 [0.41–1.73] | |
| 5 to < 10 | 37 (14.5) | 9 (24.3) | 11.77–41.20 | 0.75 [0.40–1.38] | |
| 10 to < 15 | 26 (10.2) | 5 (19.2) | 6.55–39.35 | 0.59 [0.26–1.35] | |
| ≥ 15 | 16 (6.3) | 6 (37.5) | 15.20–64.57 | 1.15 [0.58–2.27] | |
| Body mass index, kg/m2 | |||||
| < 25 | 193 (75.7) | 53 (27.5) | 21.30–34.33 | NC | Reference |
| 25 to < 30 | 41 (16.1) | 13 (31.7) | 18.08–48.09 | 1.15 [0.70–1.91] | |
| ≥ 30 | 9 (3.5) | 4 (44.4) | 13.70–78.80 | 1.62 [0.75–3.48] | |
| Lesion types | |||||
| Intestinal | |||||
| None | 84 (32.9) | 21 (25.0) | 16.19–35.64 | 0.462 | Reference |
| Yes | 171 (67.1) | 51 (29.8) | 23.08–37.28 | 1.19 [0.77–1.84] | |
| Neurological, all types | |||||
| None | 206 (80.8) | 58 (28.2) | 22.13–34.83 | 1.000 | Reference |
| Yes | 49 (19.2) | 14 (28.6) | 16.58–43.26 | 1.01 [0.62–1.66] | |
| Vascular | |||||
| None | 204 (80.0) | 60 (29.4) | 23.26–36.18 | 0.488 | Reference |
| Yes | 51 (20.0) | 12 (23.5) | 12.79–37.49 | 0.80 [0.47–1.37] | |
| ADR history | |||||
| None | 214 (83.9) | 54 (25.2) | 19.56–31.61 | 0.019 | Reference |
| Yes | 38 (14.9) | 17 (44.7) | 28.62–61.70 | 1.77 [1.16–2.70] | |
| Allergy history | |||||
| None | 225 (88.2) | 62 (27.6) | 21.83–33.89 | 0.815 | Reference |
| Yes | 24 (9.4) | 7 (29.2) | 12.62–51.09 | 1.06 [0.55–2.04] | |
| Malignancy history | |||||
| None | 249 (97.6) | 71 (28.5) | 22.99–34.56 | NC | Reference |
| Yes | 6 (2.4) | 1 (16.7) | 0.42–64.12 | 0.58 [0.10–3.54] | |
| Respiratory disease history | |||||
| None | 245 (96.1) | 67 (27.3) | 21.87–33.39 | 0.151 | Reference |
| Yes | 10 (3.9) | 5 (50.0) | 18.71–81.29 | 1.83 [0.95–3.51] | |
| Comorbidities | |||||
| None | 99 (38.8) | 17 (17.2) | 10.33–26.06 | 0.002 | Reference |
| Yes | 156 (61.2) | 55 (35.3) | 27.79–43.30 | 2.05 [1.27–3.32] | |
| Respiratory disease | |||||
| None | 250 (98.0) | 70 (28.0) | 22.53–34.01 | NC | Reference |
| Yes | 5 (2.0) | 2 (40.0) | 5.27–85.34 | 1.43 [0.48–4.26] | |
| Hepatic dysfunction | |||||
| None | 245 (96.1) | 69 (28.2) | 22.62–34.24 | NC | Reference |
| Yes | 10 (3.9) | 3 (30.0) | 6.67–65.25 | 1.07 [0.40–2.80] | |
| Cardiac disorders | |||||
| None | 239 (93.7) | 67 (28.0) | 22.43–34.19 | 0.778 | Reference |
| Yes | 16 (6.3) | 5 (31.3) | 11.02–58.66 | 1.11 [0.52–2.37] | |
| Renal impairment | |||||
| None | 251 (98.4) | 71 (28.3) | 22.80–34.29 | NC | Reference |
| Yes | 4 (1.6) | 1 (25.0) | 0.63–80.59 | 0.88 [0.16–4.88] | |
| Diabetes mellitus | |||||
| None | 232 (91.0) | 66 (28.4) | 22.74–34.72 | 1.000 | Reference |
| Yes | 23 (9.0) | 6 (26.1) | 10.23–48.41 | 0.92 [0.45–1.88] | |
Data are shown as n or n (%). Factors with a difference in ADRs were defined as those with a statistically significant difference (P < 0.05) or ratios of < 0.50 or > 2.00 in ≥ 5 patients among the factor categories (excluding unknown or not described)
ADR adverse drug reaction, CI confidence interval, NC not calculated
aIncluding seven patients with both intestinal Behçet’s disease and neurological Behçet’s disease, six patients with both intestinal Behçet’s disease and vascular Behçet’s disease, and three patients with both neurological Behçet’s disease and vascular Behçet’s disease
bP values calculated using Fisher’s exact test (for categorical factors with two levels) or chi-square test (for categorical factors with three or more levels) for categories with ≥ 5 patients per group, except where otherwise stated
Effectiveness Outcomes: Patients with Intestinal Behçet’s Disease
Figure 1a shows the effect of IFX on global improvement in patients with intestinal BD. The percentage of patients with improvement was 73.2% (112/153) at 2 weeks, then ranged from 70.2% (99/141) at 14 weeks to 77.8% (91/117) at 78 weeks. The median final evaluation (interquartile range [IQR]) was at 100.1 (97.0–102.1) weeks. At the final evaluation, the percentage of improvement was 68.8% (95/138). Among the patients who had no symptoms at 14 weeks and had a global improvement assessment at any time thereafter, symptom-free status was maintained in 79.0% (49/62) at 52 weeks, 73.2% (41/56) at 104 weeks, and 74.1% (43/58) at the final evaluation. Fifty-nine patients with intestinal BD received a dose escalation of IFX. The percentage of patients with symptom improvement (including no symptoms), no change, and worsening immediately prior to the dose escalation was 39.7% (23/58, including 13.8% [8/58] with no symptoms), 25.9% (15/58), and 34.5% (20/58), respectively. At 8 weeks after the dose escalation, the percentages of patients with symptom improvement, no change, and worsening were 61.1% (33/54, including 31.5% [17/54 patients] with no symptoms), 24.1% (13/54), and 14.8% (8/54), respectively. Symptom improvement was maintained at the final evaluation (median final evaluation [IQR], 71.4 [37.0–86.1] weeks after the dose escalation) in 55.8% (29/52, including 34.6% [18/52 patients] with no symptoms); patients with no change and worsening were 32.7% (17/52) and 11.5% (6/52), respectively. As summarized in Table S8, symptom improvement was negatively associated with age, prior adalimumab treatment, concomitant use of colchicine, and concomitant use of cyclosporine.
Fig. 1.
Effectiveness outcomes following infliximab treatment in patients with intestinal Behçet’s disease. a The number of patients categorized as improved (no symptoms), improved (with symptoms), unchanged, and worsened (multicolored bar graph, left axis), and the percentage of patients with symptom improvement (line graph, right axis) from the start of treatment in the global improvement. The median (IQR) final evaluation was at 100.1 (97.0–102.1) weeks. b Length of the largest diameter of the main intestinal ulcer at baseline and the final evaluation (median [IQR], 58.1 [33.3–81.3] weeks) and c CRP levels at baseline and the final evaluation (median [IQR], 100.7 [97.0–102.3] weeks). Box and whisker plots show median values, upper and lower quartiles (box edges), and error bars. Circles outside the error bars represent outliers. d Changes in GC dose for each patient. The median (IQR) final evaluation was at 99.1 (44.7–102.1) weeks. CRP C-reactive protein, GC glucocorticoid, IQR interquartile range
Among the 74 patients who had an endoscopy at the final evaluation, 47.3% (35/74) had resolved, 29.7% (22/74) had a reduction, 12.2% (9/74) were unchanged, and 8.1% (6/74) had worsened. The percentage of improvement (combined disappearance and reduction of the ulcer) was 77.0%. The median largest diameter of the main intestinal ulcer at baseline and at the final evaluation (median final evaluation [IQR], 58.1 [33.3–81.3] weeks) (n = 47) was 20.0 mm and 0.0 mm, respectively (Fig. 1b). The median CRP level (n = 130) was 0.800 mg/dL at baseline and 0.130 mg/dL at the final evaluation (median final evaluation [IQR], 100.7 [97.0–102.3] weeks) (Fig. 1c).
Among 85 patients who had received GC prior to IFX administration, 24 patients were free from GC use and 40 patients had a reduced GC dose during the observation period (Fig. 1d). Among 83 patients who had not received GC prior to IFX administration, 73 patients maintained GC-free status after IFX administration.
Effectiveness Outcomes: Patients with Neurological Behçet’s Disease
Acute attacks were evaluated in 15 of 17 patients with ANBD; one patient experienced a severe acute attack at 26 weeks and 14 patients (93.3%) had no new attacks during the observation period (Table 5). Among patients with ANBD who received brain MRI scans after IFX treatment, only one patient (who experienced a severe acute attack at 26 weeks) had worsening of the high-signal intensity at 26 weeks (Fig. S3a) and started receiving concomitant azathioprine. The median cell count in CSF of patients with ANBD (n = 6) was 15.0 cells/µL at baseline and 1.0 cells/µL at the final evaluation (median final evaluation [IQR], 29.5 [3.1–42.7] weeks) (Fig. 2a). The median IL-6 concentration in CSF at baseline (n = 5) was 22.8 and 2.4 pg/mL at the final evaluation (median final evaluation [IQR], 40.0 [3.1–42.7] weeks) (Fig. 2b). Of the 17 patients with ANBD in the effectiveness analysis set, seven patients received dose escalations.
Table 5.
Acute attacks following infliximab treatment in patients with acute neurological Behçet’s disease
| n = 15a | |
|---|---|
| Observation duration, days, median (IQR) | 680.0 (319.0–715.0) |
| Patients without new acute attacks, n (%) | 14 (93.3) |
| No acute attacks during the observation period, n | 12 |
| Remission, n | 1b |
| Stable, n | 1 |
| Patients with new acute attacks (relapse), n (%) | 1c (6.7) |
ANBD acute neurological Behçet’s disease, BD Behçet’s disease, IFX infliximab, IQR interquartile range, NBD neurological Behçet’s disease, VBD vascular Behçet’s disease
aIncluding two patients with both ANBD and intestinal BD, and three patients with both ANBD and VBD
bA mild acute attack was observed at 2 weeks after the start of IFX treatment, and no acute attacks were observed thereafter at 6 weeks or later
cA severe acute attack was observed at weeks 26
Fig. 2.
Effectiveness outcomes following infliximab treatment in patients with neurological Behçet’s disease. a Cell count and b IL-6 level in cerebrospinal fluid in patients with ANBD at baseline and the final evaluation (median [IQR], 29.5 [3.1–42.7] weeks in cell counts and 40.0 [3.1–42.7] weeks in IL-6 levels). Box and whisker plots show median values, upper and lower quartiles (box edges), and error bars. c The number of patients with CPNBD categorized as improved (no symptoms), improved (with symptoms), unchanged, and worsened (multicolored bar graph, left axis), and the percentage of patients with no worsening symptoms (line graph, right axis) from the start of treatment in the global improvement. The median (IQR) final evaluation was at 99.6 (95.7–102.4) weeks. d Cell count and e IL-6 level in cerebrospinal fluid in patients with CPNBD at baseline and the final evaluation (median [IQR], 52.1 [4.4–91.0] weeks in cell counts and 73.2 [6.1–94.1] weeks in IL-6 levels, respectively). Box and whisker plots show median values, upper and lower quartiles (box edges), and error bars. Circles outside the error bars represent outliers. ANBD acute neurological Behçet’s disease, CPNBD chronic progressive neurological Behçet’s disease, IL-6 interleukin-6, IQR interquartile range
In terms of global improvement, no patients with CPNBD were categorized as worsened at 2 weeks (n = 27) (Fig. 2c). The percentage of patients without progression ranged from 89.3% (25/28) at 26 weeks to 100% at 78 weeks (22/22) and 104 weeks (21/21). At the final evaluation (median final evaluation [IQR], 99.6 [95.7–102.4] weeks), no patients were categorized as worsened (n = 26). As no patients with CPNBD worsened in a global improvement assessment at the final evaluation, it was not possible to conduct an analysis of factors associated with effectiveness outcomes.
The percentages of patients with worsened and unchanged brainstem atrophy at the final evaluation were 5.3% (1/19) and 94.7% (18/19), respectively (Fig. S3b). The one patient with worsened brainstem atrophy was categorized as “unchanged” in a global improvement assessment at the last assessment. Worsening of brainstem atrophy was also reported in one patient excluded from the analysis because the patient had both ANBD and CPNBD. The median cell count in CSF of patients with CPNBD (n = 12) was 8.0 cells/µL at baseline and 2.5 cells/µL at the final evaluation (median final evaluation [IQR], 52.1 [4.4–91.0] weeks) (Fig. 2d). The median IL-6 concentration in CSF at baseline (n = 10) was 46.7 and 4.9 pg/mL at the final evaluation (median final evaluation [IQR], 73.2 [6.1–94.1] weeks) (Fig. 2e). Of 30 patients with CPNBD in the effectiveness analysis set, nine patients received dose escalations.
Effectiveness Outcomes: Patients with Vascular Behçet’s Disease
In the global improvement assessment, the percentage of patients with VBD who had not worsened from the period prior to receiving IFX was 97.8% (44/45) at 2 weeks, ranging from 94.9% (37/39) at 14 weeks to 100.0% (42/42) at 26 weeks (Fig. 3a). The percentage of patients who had not worsened at the final evaluation (median final evaluation [IQR], 98.1 [85.3–102.2] weeks) was 91.7% (33/36). In 10 of 51 patients (six with arterial disease and seven with venous disease, including three patients with both types of disease), IFX dose was escalated. The percentages of patients with symptom improvement (including no symptoms), no change, and worsening prior to the dose escalation were 60.0% (6/10, including 40.0% [4/10 patients] with no symptoms), 20.0% (2/10), and 20.0% (2/10), respectively. The percentages with symptom improvement (including no symptoms), no change, and worsening at 8 weeks after dose escalation were 75.0% (6/8, including 62.5% [5/8 patients] with no symptoms), 25.0% (2/8), and 0% (0/8), respectively, and at the final evaluation (median final evaluation [IQR], 30.3 [16.7–69.0] weeks) were 57.1% (4/7, all no symptoms), 28.6% (2/7), and 14.3% (1/7), respectively. As shown in Table S9, no factors associated with no worsening were identified.
Fig. 3.
Effectiveness outcomes following infliximab treatment in patients with vascular Behçet’s disease. a The number of patients categorized as improved (no symptoms), improved (with symptoms), unchanged, and worsened (multicolored bar graph, left axis), and the percentage of patients with no worsening symptoms (line graph, right axis) from the start of treatment in the global improvement. The median (IQR) final evaluation was at 98.1 (85.3–102.2) weeks. b CRP levels and c D-dimer levels at baseline and the final evaluation (median [IQR], 98.1 [90.1–102.2] weeks in CRP levels and 80.4 [62.3–99.9] weeks in D-dimer levels, respectively). Box and whisker plots show median values, upper and lower quartiles (box edges), and error bars. Circles outside the error bars represent outliers. d Changes in GC dose for each patient. The median (IQR) final evaluation was at 95.4 (44.1–102.1) weeks. CRP C-reactive protein, GC glucocorticoid, IQR interquartile range
Vascular imaging modalities demonstrated no worsening lesions after IFX treatment at any of the timepoints in all patients. At the final evaluation (median final evaluation [IQR], 46.0 [23.1–90.6] weeks), 50.0% (5/10) improved, while 50.0% (5/10) were unchanged. Median CRP level (n = 36) was 0.275 mg/dL at baseline and 0.135 mg/dL at the final evaluation (median final evaluation [IQR], 98.1 [90.1–102.2] weeks) (Fig. 3b). The median D-dimer level (n = 12) was 0.850 µg/mL at baseline and 0.500 µg/mL at the final evaluation (median final evaluation [IQR], 80.4 [62.3–99.9] weeks) (Fig. 3c). Of 36 patients receiving GC at baseline, GC was discontinued in 8 patients and the GC dose was reduced in 26 patients during the observation period (Fig. 3d). Among 15 patients who had not received GC prior to IFX administration, 13 maintained GC-free status after IFX administration.
Discussion
This 2-year PMS study showed that IFX was well tolerated and effective for intestinal BD, NBD, and VBD in a real-world clinical setting. The overall incidences of ADRs and serious ADRs were 28.2% and 14.9%, respectively; incidences were generally similar across intestinal BD, NBD, and VBD groups. At the final evaluation, the percentage of patients with intestinal BD who improved overall was 68.8%, and the percentage of patients with CPNBD and VBD who did not have worsened outcomes was 100% and 91.7%, respectively. Moreover, 93.3% of patients with ANBD had no new acute attacks during the observation period.
In comparison with the Japanese phase III trial [17], the current study showed lower incidence of ADRs (28.2% vs 67%) but higher incidence of serious ADRs (14.9% vs 11%). Regarding the ADRs of interest, serious infections (including tuberculosis, pneumocystis pneumonia, and cytomegalovirus infection), interstitial pneumonia, malignancies, IRs, and cytopenia were observed in patients treated with IFX in the current study, whereas only IRs and cytopenia were observed in the phase III trial [17]. These differences may be explained by the smaller number of patients (n = 18) and the shorter duration (54 weeks) of the phase III trial. Another observational study of patients with severe and/or resistant BD reported incidences of AEs and serious AEs (28% and 13%, respectively) comparable to those in the current study [30]. The Korean clinical trial [18] and a systematic review [31] also reported a similar incidence of ADRs in patients with intestinal BD (16.1% and 22% [pooled estimate of the proportion of overall ADRs], respectively). In the current study, dose escalation of IFX did not appear to influence either the incidence of ADRs or the types of ADRs. However, as this was an observational study, this finding may be explained by a potential selection bias and should be interpreted carefully.
Five patients had ADRs that had a fatal outcome (infection [CPNBD], mucormycosis and renal infarction [intestinal BD], pancreatic cancer [intestinal BD], perforation of the small intestine [intestinal BD], and death due to an unreported cause [CPNBD]). As these fatal events lacked a clear pattern and were heterogenous, they did not raise any new safety concerns.
In this PMS, a past history of ADRs and presence of comorbidities were identified as background factors associated with incidence of ADRs, especially infections and infestations. Furthermore, total parenteral nutrition in patients with intestinal BD and concomitant use of anticoagulants in patients with VBD were associated with a high incidence of infections and infestations. A past history of ADRs, presence of comorbidities and concomitant medications are known to be risk factors for ADRs [32, 33], which is consistent with the findings from this study. Intestinal, neurological, and vascular involvement in BD is indicative of severe forms of BD with an unfavorable prognosis [4, 5]. Furthermore, when compared with the 2-year PMS of IFX for patients with refractory uveoretinitis in BD, the current study showed a trend toward a higher incidence of herpes zoster (2.4% vs 0.91%), tuberculosis (0.8% vs 0.30%), and serious infections (9.4% vs 3.66%) [34]. Therefore, patients with intestinal BD, NBD, and VBD who are treated with IFX should be carefully screened and monitored according to the guidance on the label [28], especially patients with comorbidities and those receiving other medications.
Despite the use of a different definition of overall improvement for intestinal lesions in the Japanese phase III study (including resolution of clinical symptoms and healed or scarred ulcers), the overall percentage of symptom improvement was similar between the phase III study and our reported findings (64% and 68.8%, respectively) [17]. Additionally, other measurements of IFX effectiveness, including a reduction in the largest diameter of the main intestinal ulcers and discontinuation or dose reduction of GC, were observed in both the phase III study and the current study. Although also using varied definitions of improvement, other interventional [18] and observational studies [21, 22], as well as a systematic review [31], have reported similar findings.
In this study, some patients did not maintain a status of “no symptoms” at 14 weeks or later, and some patients underwent IFX dose increases because of inadequate response or LOR. Thus, as in previous reports in other diseases [35, 36], LOR during IFX therapy was observed. The percentage of patients with symptom improvement (including no symptoms) increased after dose escalation (from 39.7% [no symptoms, 13.8%] to 55.8% [34.6%]), similar to the percentage of patients with LOR to IFX treatment for Crohn’s disease showing improvement after dose escalation (approximately 60%) [37]. These results suggest that dose escalation is effective in patients with intestinal BD and an inadequate response or LOR, as observed in patients with other diseases [37, 38], and supporting the results of a phase III study in a small number of patients with intestinal BD [17].
We identified that older age, prior treatment with adalimumab, and concomitant use of either colchicine or cyclosporine were negatively associated with effectiveness outcomes in patients with intestinal BD. A previous study in patients with other forms of BD found that older age was associated with more severe BD [39], though this association may have other explanations. Regarding the influence of adalimumab treatment on outcomes, our findings are similar to a report that showed previous anti-TNFα therapy is a risk factor for treatment failure with another anti-TNFα therapy [40]. Additionally, the development of anti-drug antibodies is associated with anti-TNFα therapy treatment failure as well as IRs [41], and immunogenicity to adalimumab is related to subsequent immunogenicity to IFX [42]. As immunogenicity was not assessed in this study, we could not determine the impact of prior adalimumab treatment on immunogenicity. However, the current study also showed that IFX was effective in 46.3% (19/41) of patients with a history of adalimumab treatment and did not increase the percentage of IRs (4.1% [2/49] in patients with prior adalimumab treatment and 9.0% [11/122] in those without prior adalimumab treatment), although the number of the patients was small. Furthermore, severe intestinal BD is associated with IFX treatment failure [20]. Therefore, the difference in response to IFX observed in this study may be explained by the severity of BD; however, as disease severity was not evaluated in this PMS, this was outside of the scope of our analysis and could not be determined.
Regarding patients with NBD, the Japanese phase III study identified improvement through clinical symptoms, imaging findings, CSF cell counts, and IL-6 levels, and percentage of patients achieving improvement was reported to be 33–50% [17]. A retrospective study of patients with parenchymal NBD (n = 19) reported a remission rate of 58% with IFX treatment [24]. A systematic review in patients with NBD reported that 93.7% of patients responded to IFX [43]. As the current study was an observational study, effectiveness could not be defined by imaging findings and CSF results; therefore, improvement was defined as patients with no new acute attacks for those with ANBD (93.3%), and as patients with no worsening symptoms according to the investigator’s overall judgment of symptoms for those with CPNBD (final evaluation, 100%). The discrepancy with previous studies likely reflects differences in patient population and outcome definitions. However, only one (6.7%) patient with ANBD who had a new acute attack was reported in our study, and in the patients with CPNBD, no worsening of brainstem atrophy was observed in 94.7%; furthermore, CSF IL-6 levels decreased at the final evaluation. These results support previous evidence for the efficacy of IFX for the treatment of NBD [13, 17]. The dose escalation effect of IFX in patients with NBD could not be determined because of the small number of patients with increasing doses having available effectiveness data (ANBD, n = 7; CPNBD, n = 9).
For patients with VBD, the Japanese phase III trial reported a response rate of 100% (n = 4), which was defined as unchanged or improved clinical symptoms or imaging findings and a decrease in CRP levels [17]. As our current study was an observational study, we were not able to define effectiveness with imaging and inflammatory marker measurements, although the percentage of patients without symptom exacerbations at the final evaluation was 91.7%, which is similar to the phase III trial [17]. We also observed that vascular imaging modalities improved or had not worsened and D-dimer levels decreased at the final evaluation. The previous retrospective studies reported that 63–94% of patients with VBD and treated with IFX achieved remission [26, 27], although the effectiveness definitions differed from this study. Overall, the findings from our current study support previous evidence for the efficacy of IFX for the treatment of VBD. However, the present study did not clearly show that dose escalation of IFX was beneficial for patients with VBD, as the global improvement assessments showed worsening in these patients even after dose escalation.
Regarding study limitations, this was a single-arm study with no control; therefore, safety and effectiveness of IFX relative to other treatments could not be determined. Additionally, potential long-term side effects, such as malignancy, may occur beyond this study’s 2-year period. As this was an observational study under routine clinical practice, available data were limited, which may have led to selection bias. In particular, there were missing data for many of the effectiveness outcomes (including endoscopic outcomes, imaging results, and inflammatory markers). There were also missing data because of treatment discontinuations. In addition, the diagnosis of BD and evaluation of effectiveness were determined according to the investigator’s judgment, and no central review by specialists was performed. Because intestinal BD, NBD, and VBD are rare diseases, the diagnosis of BD and the evaluation of effectiveness were performed by investigators at approximately 130 medical centers. Therefore, the effectiveness findings from this study should be carefully interpreted. Future studies investigating the long-term clinical outcomes (particularly safety) of IFX are required. Additionally, a prospective study evaluating the diagnosis of BD and IFX effectiveness on the basis of central review by specialists is considered necessary.
Conclusion
This study confirmed the safety and effectiveness of IFX in real-world clinical practice in 255 patients with intestinal BD, NBD, and VBD. There were no new safety concerns. Although there were some limitations, these results support and reinforce previous evidence. Our findings suggest that IFX is a beneficial treatment option for patients with intestinal BD, NBD, and VBD who have had an inadequate response to conventional therapies.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors deeply appreciate the contributions of the physicians from the participating medical institutions and the patients who participated in this study.
Medical Writing, Editorial, and Other Assistance
The authors thank Hannah Read, PhD, of Edanz (http://www.edanz.com) for providing medical writing support, which was funded by Mitsubishi Tanabe Pharma Corporation, in accordance with Good Publication Practice 2022 guidelines (https://www.ismpp.org/gpp-2022).
Author Contributions
Conceptualization, Toshifumi Hibi, Shunsei Hirohata, Yoshiaki Ishigatsubo, Mayumi Tashiro, Yutaka Susuta; Investigation, Mayumi Tashiro, Yutaka Susuta; Methodology, Toshifumi Hibi, Shunsei Hirohata, Yoshiaki Ishigatsubo, Mayumi Tashiro; Data curation, Mayumi Tashiro, Yutaka Susuta; Formal analysis, Yutaka Susuta; Project administration, Mayumi Tashiro, Yutaka Susuta; Resources, Mayumi Tashiro, Yutaka Susuta; Software, Yutaka Susuta; Validation, Mayumi Tashiro, Yutaka Susuta; Interpretation of data, all authors; Visualization, all authors; Writing – original draft, Toshifumi Hibi, Shunsei Hirohata, Yoshiaki Ishigatsubo, Tadakazu Hisamatsu, Hirotoshi Kikuchi, Mitsuhiro Takeno, Noriko Sato; Writing – review & editing, Toshifumi Hibi, Shunsei Hirohata, Tadakazu Hisamatsu, Hirotoshi Kikuchi, Mitsuhiro Takeno, Noriko Sato, Naomi Mizuno, Mayumi Tashiro, Yutaka Susuta, Yoshiaki Ishigatsubo.
Funding
The study, the journal’s Rapid Service Fee, and Open Access Fee were funded by Mitsubishi Tanabe Pharma Corporation.
Data Availability
The datasets generated and/or analyzed during the current study are not publicly available due to that the data were collected for re-examination in Japan and are confidential, but are available from the corresponding author on reasonable request.
Declarations
Conflict of Interest
The study was funded by Mitsubishi Tanabe Pharma Corporation. T. Hibi., S.H., T. Hisamatsu, H.K., M. Takeno, and Y.I. have received consulting fees from Mitsubishi Tanabe Pharma Corporation. N.S., N.M., M. Tashiro, and Y.S. are employees of Mitsubishi Tanabe Pharma Corporation.
Ethical Approval
This study was conducted according to the Japanese Good Post-Marketing Surveillance Practices (GPSP, Pharmaceuticals and Medical Devices Agency, 2004). As per the GPSP, pre-registration as a clinical trial, informed consent, and study protocol approval by the institutional review board were not required for a PMS study. Therefore, no IRB was held for this study. The study protocol was approved through pre-consultation with the Pharmaceuticals and Medical Devices Agency, in accordance with the GPSP. Data were made unidentifiable to individual patients, ensuring patient confidentiality and transparency regarding data privacy.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due to that the data were collected for re-examination in Japan and are confidential, but are available from the corresponding author on reasonable request.