Advertisement

Intravenous immunoglobulin in patients with bullous pemphigoid insufficient response to corticosteroids: Nationwide post-marketing surveillance in Japan

Open AccessPublished:January 11, 2023DOI:https://doi.org/10.1016/j.jdermsci.2023.01.004

      Highlights

      • We investigated the efficacy and safety of intravenous human immunoglobulin (IVIG).
      • Patients with corticosteroid-refractory bullous pemphigoid (BP) were enrolled.
      • Most patients showed improved disease severity and decreased corticosteroid dose.
      • Equivalent improvement was also noted in patients treated with DPP-4 inhibitor.
      • IVIG, including its multiple administration, is a safe option for rapid recovery.

      Abstract

      Background

      In Japan, intravenous immunoglobulin (IVIG) has been approved for corticosteroid-unresponsive bullous pemphigoid (BP); however, its usage, efficacy, and safety in clinical settings remain unclear.

      Objective

      To elucidate IVIG efficacy, we examined the improvement in disease severity based on the Bullous Pemphigoid Disease Area Index (BPDAI).

      Methods

      In this 3-year (April 2016–March 2019), prospective, post-marketing, observational surveillance study, we enrolled 379 patients (51.3 % men; mean age, 74.5 years) with corticosteroid-unresponsive BP treated with IVIG from 143 institutions in Japan (720 treatment cycles). The percentage of patients who improved by at least one severity stage or whose symptoms completely resolved based on the BPDAI score was evaluated at 15, 30, and 60–90 days.

      Results

      The improvement rates at 15, 30, and 60–90 days after initial treatment in the 328 IVIG-naïve patients were 70.7 %, 83.5 %, and 84.3 %, respectively. The BPDAI score decreased rapidly and significantly by 15 days compared with that observed during pre-treatment. Further improvement was observed at 30 and 60–90 days. The corticosteroid dose and anti-BP180 antibody titers decreased significantly post-treatment (both, p < .001). Approximately 25 % of IVIG-naïve patients underwent multiple treatment cycles. The improvement rate at 30 days after the final dose was 88 %, and the symptoms completely resolved in 44 % of patients. The incidence of adverse drug reactions per cycle was 8.34 %; the most common reaction was transient thrombocytopenia.

      Conclusion

      Most patients showed improvement in severity and decrease in corticosteroid dose and anti-BP180 antibody levels post-treatment, indicating that IVIG is useful for corticosteroid-unresponsive BP treatment.

      Abbreviations:

      ADRs (adverse drug reactions), BP (bullous pemphigoid), BPDAI (Bullous Pemphigoid Disease Area Index), CLEIA (chemiluminescent enzyme immunoassay), DPP-4i (dipeptidyl peptidase-4 inhibitor), ELISA (enzyme-linked immunosorbent assay), IVIG (intravenous immunoglobulin)

      Keywords

      1. Introduction

      Bullous pemphigoid (BP) is an autoimmune bullous disease that produces subepidermal blisters because of the involvement of autoantibodies (IgGs) against epidermal basement membrane antigens, mainly BP180 [
      • Schmidt E.
      • Zillikens D.
      Pemphigoid diseases.
      ,
      • Amber K.T.
      • Murrell D.F.
      • Schmidt E.
      • Joly P.
      • Borradori L.
      Autoimmune subepidermal bullous diseases of the skin and mucosae: clinical features, diagnosis, and management.
      ,
      • Ujiie H.
      • Iwata H.
      • Yamagami J.
      • Nakama T.
      • Aoyama Y.
      • Ikeda S.
      • et al.
      Japanese guidelines for the management of pemphigoid (including epidermolysis bullosa acquisita).
      ,
      • Feliciani C.
      • Joly P.
      • Jonkman M.F.
      • Zambruno G.
      • Zillikens D.
      • Ioannides D.
      • et al.
      Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology.
      ,
      • Venning V.A.
      • Taghipour K.
      • Mohd Mustapa M.F.
      • Highet A.S.
      • Kirtschig G.
      British Association of Dermatologists, British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012.
      ]. Clinically, it is characterized by multiple areas of edematous erythema and fluid-filled blisters with widespread pruritus. It is common in the elderly, particularly in those aged ≥ 75 years, with the number of cases increasing as the population ages.
      BP is mainly treated with oral corticosteroids, although topical corticosteroids, tetracycline, nicotinamide, and other agents may be used. BP generally responds well to treatment, and the condition of 60–90 % of patients was reportedly improved within 4 weeks of treatment with prednisolone 0.75–1.0 mg/kg/day [
      • Venning V.A.
      • Taghipour K.
      • Mohd Mustapa M.F.
      • Highet A.S.
      • Kirtschig G.
      British Association of Dermatologists, British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012.
      ]. However, some cases are refractory to corticosteroids and difficult to treat. Additionally, continuous corticosteroid therapy is often inadvisable because of advanced age or underlying diseases.
      Intravenous immunoglobulin (IVIG) preparation is a treatment option for patients with BP who do not respond to corticosteroid treatment [
      • Ahmed A.R.
      Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment.
      ,
      • Kirtschig G.
      • Middleton P.
      • Bennett C.
      • Murrell D.F.
      • Wojnarowska F.
      • Khumalo N.P.
      Interventions for bullous pemphigoid.
      ]. In Japan, the efficacy and safety of IVIG for BP were demonstrated in phase II and III placebo-controlled, randomized, multicenter, double-blind, parallel-group, comparison clinical trials [
      • Amagai M.
      • Ikeda S.
      • Hashimoto T.
      • Mizuashi M.
      • Fujisawa A.
      • Ihn H.
      • et al.
      A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.
      ], and the drug was approved for this indication in 2015 [

      Review Report, Pharm Devices Agency, 2015. 〈https://www.pmda.go.jp/files/000223353.pdf〉.

      ]. The purpose of this study was to validate the proven safety and efficacy of IVIG in a wide range of patients and demonstrate IVIG usage, including multiple administrations, in clinical practice.

      2. Materials and methods

      2.1 Design and data collection

      A 3-year prospective post-marketing surveillance study (April 2016–March 2019) was conducted in patients with BP who had insufficient response to corticosteroids (designated as: BP inadequately responsive to corticosteroids [

      Review Report, Pharm Devices Agency, 2015. 〈https://www.pmda.go.jp/files/000223353.pdf〉.

      ]) and were treated with approved IVIG preparation (kenketu glovenin-I for intravenous injection; Nihon Pharmaceutical Co., LTD, Tokyo, Japan).
      The exclusion criteria were as follows: 1) history of contraindications to IVIG; 2) patient judged as inadequate by attending physician. Based on the Japanese approved dosage, IVIG is typically administered at 400 mg/kg/day for 5 consecutive days concomitantly with oral corticosteroids. No restrictions were placed on the corticosteroid dose or treatment before and after IVIG administration or on multiple administrations of IVIG. The physicians in charge made the final treatment decisions. Data were recorded by physicians in charge via questionnaires collected after the 90-day observation period.

      2.2 Laboratory measurements and diagnostic criteria

      BP was diagnosed by dermatologists at each institution according to the diagnostic criteria [
      • Schmidt E.
      • Zillikens D.
      Pemphigoid diseases.
      ]. The pre- and post-treatment clinical courses were recorded using the Bullous Pemphigoid Disease Area Index (BPDAI) [
      • Murrell D.F.
      • Daniel B.S.
      • Joly P.
      • Borradori L.
      • Amagai M.
      • Hashimoto T.
      • et al.
      Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.
      ]. Severity was assessed per the Japanese Criteria for assessing pemphigoid severity (including acquired epidermolysis bullosa) [
      • Ujiie H.
      • Iwata H.
      • Yamagami J.
      • Nakama T.
      • Aoyama Y.
      • Ikeda S.
      • et al.
      Japanese guidelines for the management of pemphigoid (including epidermolysis bullosa acquisita).
      ], which involves scoring on (1) skin: erosion/blisters (mild:< 15 points; moderate: 15–34 points; severe:> 34 points), (2) skin: urticaria/erythema (mild:< 20 points; moderate: 20–34 points; severe:> 34 points), and (3) mucosa: erosion/blisters (mild:< 10 points; moderate: 10–24 points; severe:> 24 points). The highest severity level in three components was evaluated as severity at the time. Evaluation was performed at four points (baseline, day 15, day 30, and days 60–90) and used for the analysis. IgG antibodies to the BP180 non-collagenous 16a domain were measured using chemiluminescent enzyme immunoassay (CLEIA) or enzyme-linked immunosorbent assay (ELISA) [
      • Kobayashi M.
      • Amagai M.
      • Kuroda-Kinoshita K.
      • Hashimoto T.
      • Shirakata Y.
      • Hashimoto K.
      • et al.
      BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid.
      ,
      • Sakuma-Oyama Y.
      • Powell A.M.
      • Oyama N.
      • Albert S.
      • Bhogal B.S.
      • Black M.M.
      Evaluation of a BP180-NC16a enzyme-linked immunosorbent assay in the initial diagnosis of bullous pemphigoid.
      ]. For corticosteroids used during the 90-day period, the drug name, administration route, duration, and dose were recorded. Doses were converted to prednisolone doses for analysis. Regarding adverse drug reactions (ADRs), the symptoms, severity, relevant laboratory test values, and any causal relationship with the drug were recorded.

      2.3 Ethics approval, patient consent, study permissions, and consent to publish

      This study was conducted in accordance with the principles of the Declaration of Helsinki, Good Vigilance Practice, and Good Post-marketing Study Practice of the Japanese Ministerial Ordinance. The requirements for informed consent and approval from an ethics committee were waived by the Ordinance, and data were collected anonymously; however, when an individual institutional review board decided it was necessary, informed consent was obtained using a pre-established method by that institution.

      2.4 Statistical analyses

      Descriptive statistics are used to summarize patient characteristics presented as frequency tables and percentages. Fisher's exact test was used to compare frequencies between two groups, and the chi-square test was used for three or more groups. The Kolmogorov–Smirnov test was used to evaluate data normality. An unpaired t-test or the Wilcoxon rank-sum test was used to compare continuous variables between the groups as appropriate according to variable distribution. Changes in the BPDAI scores, corticosteroid doses, and anti-BP180 antibody titers are presented in time-series graphs. Time-series data were compared using a paired t-test or the Wilcoxon signed-rank test. Values of p < .05 were considered statistically significant, and all tests were two-tailed. Values are expressed as percentages (counts), means (95 % confidence intervals [CIs]), or medians (25th, 75th percentile), as appropriate. We used SAS version 22.1 (SAS Institute Inc, Cary, NC) or R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria) for the analyzes.

      2.5 Evaluation of improvement in severity based on the BPDAI

      The improvement rate was calculated based on the number of patients where severity was improved by at least one grade according to the BPDAI or whose BPDAI score was 0 points for all lesions (e.g., changes from severe to moderate or mild and from moderate to mild were judged as improvement; in cases of patients with mild condition at baseline, the change of the total BPDAI score into 0 points was judged as improvement). The number of improved cases was divided into the analysis set. Assessments were performed at three time points after IVIG therapy initiation: day 15, day 30, and the closest to day 90 on days 60–90. Patients with a BPDAI score of 0 points at baseline were excluded. Additionally, changes in the BPDAI score from before administration to days 15, 30, and 60–90 were evaluated according to severity.

      2.6 Evaluation of safety

      Safety was evaluated in terms of ADR incidence per IVIG cycle. The incidence rate of each symptom of ADRs was also calculated.

      3. Results

      3.1 Study flowchart

      Data were collected from 379 patients with BP who were unresponsive to corticosteroid treatment across 143 institutions (720 cycles in total; Fig. 1). A safety evaluation was conducted in 378 cases (719 cycles). Efficacy was evaluated using clinical assessments based on the BPDAI in 308 cases (572 cycles, 262 initial cycles), changes in corticosteroid dose in 375 cases (711 cycles, 325 initial cycles), and changes in anti-BP180 antibody titer in 249 cases (497 cycles, 207 initial cycles).
      Fig. 1
      Fig. 1Study flowchart. Of the 379 patients, safety was evaluated in 378 cases for a total of 719 cycles. Of these, 328 were administered IVIG for the first time (IVIG-naïve cases). In addition, the evaluation based on the BPDAI score was conducted in 308 cases (IVIG-naïve cases: 262) and 572 total cycles, the corticosteroid dose was evaluated in 375 cases (IVIG-naïve cases: 325) and 711 total cycles, and the evaluation of anti-BP180 antibody titer was conducted in 249 cases (IVIG-naïve cases: 207) and 497 total cycles. In addition, for IVIG-naïve cases, changes in the BPDAI score, corticosteroid dose, and anti-BP180 antibody titer were evaluated at the initial administration and after multiple administrations. IVIG, intravenous immunoglobulin; BPDAI, Bullous Pemphigoid Disease Area Index.

      3.2 Patient demographics

      Table 1 shows the baseline characteristics of 378 patients. IVIG was administered for the first time in 328 (86.8 %) patients (IVIG-naïve patients).
      Table 1Baseline characteristics of the patients.
      ItemBPDAI mean (95 % CI)n (%)
      Sexmalen = 170

      46.1 (40.2–52.0)
      194 (51.3 %)
      femalen = 154

      43.4 (36.9–49.8)
      184 (48.7 %)
      Age≤ 14-0 (0.0 %)
      15–64n = 55

      40.1 (28.7–51.5)
      64 (16.9 %)
      ≥ 65n = 269

      45.8 (41.1–50.5)
      314 (83.1 %)
      Disease duration before IVIG use

      in this study
      < 1n = 244

      48.2 (43.1–53.3)
      285 (75.6 %)
      (years)≥ 1 < 2n = 35

      35.3 (23.2–47.5)
      42 (11.1 %)
      ≥ 2n = 44

      33.3 (22.3–44.4)
      50 (13.3 %)
      Disease severity based on the BPDAIn = 324

      44.8 (40.5–49.1)
      Mild *n = 120

      8.59 (7.24–9.95)
      120 (37.0 %)
      Moderate *n = 101

      41.4 (39.0–43.7)
      101 (31.2 %)
      Severe *n = 103

      90.3 (83.8–96.9)
      103 (31.8 %)
      Skin erosions/blisters (BPDAI)n = 324

      23.9 (21.4–26.4) **
      Mild

      (≤ 14)
      138 (42.6 %)
      Moderate

      (15–34)
      96 (29.6 %)
      Severe

      (≥ 35)
      90 (27.8 %)
      Skin urticaria/erythema (BPDAI)n = 324

      19.6 (17.4–21.8) **
      Mild

      (≤ 19)
      182 (56.2 %)
      Moderate

      (20–34)
      84 (25.9 %)
      Severe

      (≥ 35)
      58 (17.9 %)
      Mucosa: erosions/blisters (BPDAI)Alln = 324

      1.33 (0.92–1.74) **
      Mild

      (≤ 9)
      306 (94.4 %)
      Moderate

      (10–24)
      18 (5.6 %)
      Severe

      (≥ 25)
      0 (0.0 %)
      History of IVIGNon = 280

      48.1 (43.4–52.8)
      328 (87.5 %)
      Yesn = 41

      23.1 (13.7–32.5)
      47 (12.5 %)
      Reason of IVIG useInsufficient reduction or improvement in skin lesionsn = 144

      61.5 (54.9–68.0) #1
      172 (45.5 %)
      Insufficient suppression of new erosion/blister, urticaria/erytheman = 211

      53.9 (48.7–59.2) #2
      248 (65.6 %)
      Insufficient improvement in mucosa lesionsn = 31

      80.1 (63.1–97.2) #3
      40 (10.6 %)
      To spare corticosteroidn = 141

      36.9 (30.1–43.6) #4
      152 (40.2 %)
      To reduce antibody titern = 135

      41.7 (34.4–48.9) #5
      158 (41.8 %)
      Othersn = 25

      29.7 (18.6–40.9) #6
      28 (7.4 %)
      Underlying disease343 (90.7 %)
      Diabetes mellitus190 (50.3 %)
      History of use of DPP-4 inhibitor100 (26.5 %)
      Hyperlipidemia90 (23.8 %)
      Hypertension188 (49.7 %)
      Osteoporosis51 (13.5 %)
      Infection46 (12.2 %)
      Digestive diseases/symptoms40 (10.6 %)
      Eye disease44 (11.6 %)
      Neurological disease85 (22.5 %)
      Neoplasm23 (6.1 %)
      Liver disease16 (4.2 %)
      Renal disease28 (7.4 %)
      Total378 (100.0 %)
      Abbreviations: IVIG, intravenous immunoglobulin; BPDAI, Bullous Pemphigoid Disease Area Index; DPP-4, dipeptidyl peptidase-4.
      * The highest severity level of three component were evaluated as severity.
      ** Score of one component of skin erosions/blisters, skin urticaria/erythema, Mucosa: erosions/blisters, respectively.
      # Total BPDAI at day 30 after the initial IVIG administration.
      #1 n = 133, 14.9 (10.4–19.4); #2 n = 198, 13.2 (10.0–16.4); #3 n = 27, 35.1 (16.7–49.6);
      #4 n = 120, 7.39 (4.31–10.5); #5 n = 126, 9.82 (6.36–13.3); #6 n = 26, 8.15 (3.73–12.6).
      There was no difference in sex distribution (51.3 % men), and most patients (83.1 %) were aged ≥ 65 years [mean (standard deviation): 74.5 (12.4) years]. Furthermore, 75.6 % of patients had disease duration< 1 year from symptom onset to drug administration. The underlying disease was present in 90.7 % of patients, particularly diabetes (50.3 %), and 26.5 % had a history of dipeptidyl peptidase-4 inhibitor (DPP-4i) use. Other common underlying diseases included hypertension (49.7 %), hyperlipidemia (23.8 %), and neurological diseases (22.5 %).
      BPDAI-based severity during IVIG administration was mild in 37 %, moderate in 31.2 %, and severe in 31.8 % of cases, with no significant bias. The common reason for IVIG administration was “insufficient suppression of new erosion/blister or urticaria/erythema” (65.6 %), “insufficient reduction or improvement in skin lesions” (45.5 %), “to reduce antibody titer” (41.8 %), and “to spare corticosteroid dose” (40.2 %).

      3.3 IVIG administration

      IVIG was administered over 5 days in 99 % of cases, and the mean daily dose was within 400 mg/kg/day± 10 % in 65 % [mean (2 SD): 405 (92.3)] of patients, according to the approved dosage.
      Of the 328 IVIG-naïve patients, 84 underwent multiple administrations (re-administration or repeated administrations). The total number of cycles was two in 45 cases, three in 16 cases, four in three cases, and five or more in 20 cases. The interval between cycles was approximately 1 month in most cases [median (25th, 75th percentiles): 34 days (28, 42)].

      3.4 Other treatments

      Supplementary eTable 1 shows pre-treatment or concomitant treatment with IVIG. Systemic corticosteroids (oral or intravenous) and pulse therapy were respectively administered in 96.3 % and 19.8 % of patients as pre-treatment and in 99.5 % and 11.9 % as concomitant treatment. Topical corticosteroids were administered in 18 % and 75.9 %. Among non-steroidal drugs, nicotinamide and minocycline were widely used as pre- and concomitant treatments in more than 20 % of patients. Immunosuppressants were used in 18 % and 28.6 % of cases as pre- and concomitant treatments, respectively.

      3.5 Disease improvement following IVIG treatment

      3.5.1 Improvement in severity after initial IVIG administration

      Of the 378 cases, it was possible to evaluate efficacy after the initial administration in 262 IVIG-naïve cases, and efficacy for these cases was further evaluated on days 15, 30, and 90. Initial administration was defined as the first time IVIG was administered. The improvement rates were 70.7 %, 83.5 %, and 84.3 % on days 15, 30, and 90, respectively (Table 2). The remission rates (BPDAI score: 0 points) on days 15, 30, and 90 were 20 %, 38.5 %, and 54.1 %, respectively. Supplementary eTable 2 shows the improvement rates on day 30 compared to the baseline characteristics.
      Table 2Improvement or remission rate after the first IVIG.
      nImprovement rateaRemission rateb
      Day 1522570.7 % (159/225)20.0 % (45/225)
      Day 3023183.5 % (193/231)38.5 % (89/231)
      Days 60–90c18584.3 % (156/185)54.1 % (100/185)
      Abbreviation: IVIG, intravenous immunoglobulin.
      a. Proportion of cases, in which the severity of BPDAI was improved by one or more levels, or all symptoms disappeared.
      b. Proportion of cases, in which all symptoms disappeared in the BPDAI (Total BPDAI score is 0 points).
      c. Evaluation on the latest day between days 60 and 90.

      3.5.2 Clinical course following initial IVIG administration

      Fig. 2 shows the clinical course up to day 90 after the initial IVIG administration.
      Fig. 2
      Fig. 2Course of patients with BP after the first IVIG administration. This shows the clinical course after the initial IVIG administration in IVIG-naïve cases. (a) The changes in the BPDAI score in 152 IVIG-naïve patients before the initial administration (baseline) and after 15, 30, and 90 days are presented. On day 15, the BPDAI score decreased significantly for all severity levels (p < .001) and continued to decline over time. Paired t-test; Total: baseline vs day 15, p < .001**; day 15 vs day 30, p < .001**, day 30 vs days 60–90, p < .001**; severe: baseline vs day 15, p < .001**; day 15 vs day 30, p < .001**, day 30 vs days 60–90, p < .001**; moderate: baseline vs day 15, p < .001**; day 15 vs day 30, p = .002**, day 30 vs days 60–90, p = .664 n.s.; mild: baseline vs day 15, p < .001**; day 15 vs day 30, p = .040*, day 30 vs days 60–90, p = .664 n.s. In total and moderate cases on day 30 vs days 60–90, the BPDAI change distribution was not normal because of one outlier (deterioration from 47 to 170). Therefore, the Wilcoxon signed-rank test (non-parametric test) was performed (p < .001**).(b) The changes in corticosteroid dose in 285 patients before the initial IVIG administration and after 15, 30, 60, and 90 days are presented. At all points, the dose declined significantly compared with that immediately before administration. In the final observation on day 90, the corticosteroid dose was half of that before IVIG therapy. Paired t-test: before IVIG therapy vs day 15, p < .001**; day 15 vs day 30, p < .001**, day 30 vs day 60, p < .001**, day 60 vs day 90, p < .001** (c) This panel shows box-and-whisker plots for the rate of decrease in antibody titer in the 249 cases that could be evaluated at the initial administration (day 15: 111 cases; day 30: 156 cases; days 60–90: 155 cases). The anti-BP180 antibody titer declined by more than half (− 60 %) on day 15 and declined significantly by − 76.1 % and − 90.9 % on days 30 and 60–90, respectively. The middle line of the box-and-whisker plots shows the median, the lower line the 25th percentile, the upper line the 75th percentile, the upper whisker the 75th percentile plus 1.5* the IQR or the maximum value if it falls within it, and the lower whisker the 25th percentile minus 1.5* IQR or the minimum value. In the figure, an increase> 100 % is indicated as + 100 %. Wilcoxon signed-rank test: before IVIG therapy vs. day 15, p < .001**; before IVIG therapy vs. day 30, p < .001**; before IVIG therapy vs days 60–90, p < .001** BP, bullous pemphigoid; IVIG, intravenous immunoglobulin; BPDAI, Bullous Pemphigoid Disease Area Index; IQR, interquartile range.

      3.5.2.1 BPDAI

      Fig. 2a shows the change in the mean (95 % CI) BPDAI score in 152 cases according to severity at baseline and at 15, 30, and 90 days. The BPDAI score in all cases decreased from 50.9 (44.7, 57.2) at baseline to 17.7 (13.6, 21.8) points on day 15, 11.8 (7.92, 15.7) points on day 30, and 6.27 (2.77, 9.77) points on day 90. The between-point differences, e.g., baseline vs day 15, were significant at all time points (p < .001). Additionally, the BPDAI score significantly decreased following IVIG therapy in all severity groups.

      3.5.2.2 Corticosteroid dose

      Fig. 2b shows the changes in mean (95 % CI) corticosteroid dose in 285 cases up to day 90. The corticosteroid dose decreased from 32.1 mg (30.2, 34.1) at baseline to 28.4 mg (26.7, 30.1) on day 15 (p < .001); then, it decreased further with time to 24.5 mg (23, 26) on day 30, 19.4 mg (18.2, 20.6) on day 60, and 17.2 mg (16.1, 18.3) on day 90.

      3.5.2.3 Anti-BP180 antibody titer

      In the 207 cases where the anti-BP180 antibody titer was measured, the median (25th, 75th percentiles) pre-treatment antibody titer was 1000 (419, 3660) with CLEIA (n = 114) and 682 (205, 1330) with ELISA (n = 93). Fig. 2c shows that compared to before IVIG therapy, the antibody titers declined significantly to − 60.2 % (− 76.6, − 21.9) on day 15, − 76.1 % (− 89.2, − 56.2) on day 30, and − 90.9 % (−;96, − 68.5) on day 90 (p < .001).

      3.5.3 Evaluation of patients with DPP-4i treatment history

      Table 3 shows the severity at baseline and improvement rate after treatment in patients with history of DPP-4i use. There were 93 patients with history of DPP-4i use and 235 without (non-DPP-4i BP). Severity tended to be lower in patients with DPP-4i BP than in those without (mean skin urticaria/erythema at 12.0 vs. 20.0). Furthermore, a clinical effect was observed in 83.1 % of cases with DPP-4i and in 83.7 % of cases with non-DPP-4i BP, with no statistical difference.
      Table 3Feature and severity improvement rate of BP with a history of DPP-4i treatment.
      History of DPP-4i treatmentYes (n = 93)No (n = 235)
      n(%)Median [25th, 75th]n(%)Median [25th, 75th]
      Disease severity based on BPDAIMild28(35.0 %)62(31.0 %)
      Moderate28(35.0 %)3765(32.5 %)43
      Severe24(30.0 %)[16.0, 61.5]73(36.5 %)[14.0, 73.5]
      Skin erosions/blisters (BPDAI)Mild30(37.5 %)78(39.0 %)
      Moderate26(32.5 %)24.562(31.0 %)20
      Severe24(30.0 %)[6.0, 36.0]60(30.0 %)[5.0, 38.5]
      Skin urticaria/erythema (BPDAI)Mild50(62.5 %)96(48.0 %)
      Moderate20(25.0 %)1259(29.5 %)20
      Severe10(12.5 %)[1.5, 27.5]45(22.5 %)[5.0, 33.0]
      Mucosa: erosions/blisters (BPDAI)Mild78(97.5 %)186(93.0 %)
      Moderate2(2.5 %)014(7.0 %)0
      Severe0(0.0 %)[0,0]0(0.0 %)[0,0]
      Efficacy on Day 30a83.1 %(54/65)83.7 %(139/166)
      Abbreviations: BPDAI, Bullous Pemphigoid Disease Area Index; DPP-4, dipeptidyl peptidase-4.
      a. Cases for which the severity based on BPDAI could not be calculated were excluded.

      3.5.4 Improvement rate and time course in multiple IVIG administrations

      Supplementary eTable 3 shows the improvement rate in 57 patients treated with multiple IVIG administrations. The improvement rate, in terms of severity before the first and after the second cycle, was 84.2 %. Similarly, the improvement rates were 81.5 %, 93.8 %, 100.0 % at the third, fourth, and fifth cycles, respectively. Moreover, in the 234 cases treated with single or multiple administration, the improvement and remission rates were 88 % and 44 % after the final cycle, respectively. Supplementary eFigure 1 shows the change in the BPDAI score after each cycle according to the number of total IVIG administrations (one, two, more than three cycles). In single IVIG treatment cases, the BPDAI score decreased to< 5 points after one cycle (p < .001). In multiple-treatment cases, while a significant decrease in the BPDAI was observed after one cycle (p < .001), symptoms were not sufficiently suppressed, and further improvement was achieved after the subsequent IVIG cycles.

      3.5.5 Improvement rate, BPDAI, corticosteroid dose, and anti-BP180 antibody titer per cycle

      As the description of the efficacy in this article is biased toward initial administration in naïve-IVIG cases, the evaluations for all cycles are shown in eTable 4.

      3.6 Safety analysis

      Table 4 shows all ADRs over 719 cycles in 378 cases. The incidence rate per cycle was 8.34 % (60 cycles, 90 reactions in 53 cases), including 1.95 % cases of severe reactions (14 cycles, 14 reactions in 14 cases). Supplementary eTable 5 shows the incidence rate compared to the baseline characteristics. The most common symptom was thrombocytopenia (platelet count decrease) (3.2 %) followed by hepatic function abnormality (1.67 %). Supplementary eFigure 2 shows the platelet count in patients with thrombocytopenia. The minimum [median (25th, 75th)] was 8.7 × 104/μL (4.5, 10), and was reached at 10 days (7, 13) after initiating IVIG. Furthermore, 27 days (19, 44) were needed for symptoms to improve or recover. Although no bleeding events were reported in these cases, platelet transfusion was performed in two cases.
      Table 4List of adverse drug reaction.
      AllSevere
      Safety analysis set719-
      Occurrence of ADR6014
      Rate of ADR8.34 %1.95 %
      Number of ADR9024
      Adverse drug reaction nameAll: n (%)Severe: n (%)
      Infections and infestations4 (0.56)2 (0.28)
      Cytomegalovirus infection1 (0.14)0 (0.00)
      Pneumonia1 (0.14)1 (0.14)
      Urinary tract infection1 (0.14)1 (0.14)
      Cytomegalovirus gastrointestinal infection1 (0.14)1 (0.14)
      Urinary tract infection pseudomonal1 (0.14)0 (0.00)
      Immune system disorders1 (0.14)0 (0.00)
      Anaphylactic reaction1 (0.14)0 (0.00)
      Metabolism and nutrition disorders6 (0.83)2 (0.28)
      Dehydration2 (0.28)1 (0.14)
      Hyperammonemia1 (0.14)1 (0.14)
      Hyperkalemia1 (0.14)0 (0.00)
      Hypoalbuminemia1 (0.14)0 (0.00)
      Hyponatremia1 (0.14)0 (0.00)
      Nervous system disorders4 (0.56)1 (0.14)
      Cerebral hemorrhage1 (0.14)1 (0.14)
      Head discomfort1 (0.14)0 (0.00)
      Headache1 (0.14)0 (0.00)
      Taste disorder1 (0.14)0 (0.00)
      Cardiac disorders2 (0.28)1 (0.14)
      Atrial fibrillation1 (0.14)1 (0.14)
      Palpitations1 (0.14)0 (0.00)
      Tachycardia1 (0.14)0 (0.00)
      Vascular disorders3 (0.42)1 (0.14)
      Hypertension1 (0.14)0 (0.00)
      Deep vein thrombosis2 (0.28)1 (0.14)
      Respiratory, thoracic, and mediastinal disorders2 (0.28)1 (0.14)
      Hypoxia1 (0.14)0 (0.00)
      Pulmonary embolism1 (0.14)1 (0.14)
      Gastrointestinal disorders5 (0.70)3 (0.42)
      Diarrhea1 (0.14)0 (0.00)
      Gastrointestinal hemorrhage1 (0.14)1 (0.14)
      Hematemesis1 (0.14)0 (0.00)
      Melaena1 (0.14)1 (0.14)
      Rectal hemorrhage1 (0.14)1 (0.14)
      Hepatobiliary disorders15 (2.09)0 (0.00)
      Hepatic function abnormal12 (1.67)0 (0.00)
      Liver disorder3 (0.42)0 (0.00)
      Skin and subcutaneous tissue disorders3 (0.42)0 (0.00)
      Urticaria2 (0.28)0 (0.00)
      Toxic skin eruption1 (0.14)0 (0.00)
      Renal and urinary disorders4 (0.56)2 (0.28)
      Dysuria1 (0.14)0 (0.00)
      Renal disorder1 (0.14)1 (0.14)
      Renal impairment2 (0.28)1 (0.14)
      General disorders and administration site conditions2 (0.28)1 (0.14)
      Pyrexia2 (0.28)1 (0.14)
      Investigations28 (3.89)5 (0.70)
      Amylase increased1 (0.14)0 (0.00)
      Gamma-glutamyltransferase increased1 (0.14)0 (0.00)
      Hemoglobin decreased1 (0.14)1 (0.14)
      Platelet count decreased23 (3.20)5 (0.70)
      Red blood cell count decreased1 (0.14)0 (0.00)
      White blood cell count decreased4 (0.56)2 (0.28)
      Blood beta-D-glucan increased1 (0.14)0 (0.00)
      Hepatic enzyme increased2 (0.28)0 (0.00)
      Hepatic enzyme abnormal1 (0.14)0 (0.00)
      Injury, poisoning, and procedural complications1 (0.14)1 (0.14)
      Femur fracture1 (0.14)1 (0.14)
      Abbreviations: ADR, adverse drug reaction. MedDRA:Ver22.1.
      Of the 589 cycles in 328 IVIG-naïve cases, 84 underwent multiple administrations (total: 261 cycles). The ADR incidence rate at initial administration was 12.5 % (severe: 3.05 %), and it was 2.68 % (severe: 1.15 %) at multiple administrations. ADR timings were 12.5 % in cycle 1 (severe: 3.05 %), 5.95 % in cycle 2 (severe: 2.38 %), 5.13 % in cycle 3 (severe: 2.56 %), and none in cycle 4 or higher (Supplementary eTable 6).

      4. Discussion

      Here, we described the results of a post-marketing surveillance study of IVIG approved for treating patients with BP who were unresponsive to corticosteroid therapy. We observed improvement in severity and total BPDAI and reduction in the anti-BP180 antibody levels, leading to sparing corticosteroid dosing following IVIG treatment. We collected a large amount of nationwide data from Japan, indicating that such cases are not uncommon, regardless of good responsiveness in BP. Older age and high corticosteroid dosage are reportedly risk factors for mortality in BP cases [
      • Rzany B.
      • Partscht K.
      • Jung M.
      • Kippes W.
      • Mecking D.
      • Baima B.
      • et al.
      Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age.
      ]. As the population ages, the need for BP treatment other than corticosteroids increases. Our survey results also indicated that sparing corticosteroids is an important consideration in addition to controlling the condition.
      In 2012, the BPDAI was reported as an objective indicator of disease severity in patients with BP [
      • Murrell D.F.
      • Daniel B.S.
      • Joly P.
      • Borradori L.
      • Amagai M.
      • Hashimoto T.
      • et al.
      Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.
      ]. It was subsequently validated with demonstrated consistency with clinical parameters, such as lesion area of skin, number of daily new blisters, anti-BP180 antibody titer, and blood eosinophil count [
      • Wijayanti A.
      • Zhao C.Y.
      • Boettiger D.
      • Chiang Y.Z.
      • Ishii N.
      • Hashimoto T.
      • et al.
      The reliability, validity and responsiveness of two disease scores (BPDAI and ABSIS) for bullous pemphigoid: which one to use?.
      ,
      • Masmoudi W.
      • Vaillant M.
      • Vassileva S.
      • Patsatsi A.
      • Quereux G.
      • Moltrasio C.
      • et al.
      International validation of the Bullous pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.
      ,
      • Lévy-Sitbon C.
      • Barbe C.
      • Plee J.
      • Goeldel A.L.
      • Antonicelli F.
      • Reguiaï Z.
      • et al.
      Assessment of bullous pemphigoid disease area index during treatment: a prospective study of 30 patients.
      ]. However, a correlation with the anti-BP230 antibody was not observed [
      • Masmoudi W.
      • Vaillant M.
      • Vassileva S.
      • Patsatsi A.
      • Quereux G.
      • Moltrasio C.
      • et al.
      International validation of the Bullous pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.
      ,
      • Lévy-Sitbon C.
      • Barbe C.
      • Plee J.
      • Goeldel A.L.
      • Antonicelli F.
      • Reguiaï Z.
      • et al.
      Assessment of bullous pemphigoid disease area index during treatment: a prospective study of 30 patients.
      ]. Higher serum BP180 antibody levels are also predictive indicators of relapse [
      • Fichel F.
      • Barbe C.
      • Joly P.
      • Bedane C.
      • Vabres P.
      • Truchetet F.
      • et al.
      Clinical and immunologic factors associated with bullous pemphigoid relapse during the first year of treatment: a multicenter, prospective study.
      ].
      Regarding efficacy, the improvement rate evaluated according to BPDAI-based severity was 70.7–84.3 % at 15, 30, and 60–90 days, with the total BPDAI scores decreasing significantly. Furthermore, 88 % of cases exhibited improvement between the initial and final IVIG administrations. The anti-BP180 antibody titer rapidly declined to − 60 % of baseline on day 15 and further declined thereafter. Consequently, the corticosteroid dose decreased by half from baseline.
      As DPP-4i BP was first reported before our survey [

      E. Pasmatzi, A. Monastirli, J. Habeos, S. Georgiou, D. Tsambaos, Dipeptidyl peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases, Diabetes Care, vol. 34(no. 201), e133.

      ,
      • Aouidad I.
      • Fite C.
      • Marinho E.
      • Deschamps L.
      • Crickx B.
      • Descamps V.
      A case report of bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors.
      ,
      • Attaway A.
      • Mersfelder T.L.
      • Vaishnav S.
      • Baker J.K.
      Bullous pemphigoid associated with dipeptidyl peptidase IV inhibitors. a case report and review of literature.
      ,
      • Béné J.
      • Moulis G.
      • Bennani I.
      • Auffret M.
      • Coupe P.
      • Babai S.
      • et al.
      Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French pharmacovigilance Database.
      ], we collected data on the history of DPP-4i use. Recent studies have reported that previous DPP-4i use is associated with increased odds for developing BP of 1.92 (95 % CI: 1.55–2.38) according to a meta-analysis [
      • Liu S.D.
      • Chen W.T.
      • Chi C.C.
      Association between medication use and bullous pemphigoid: a systematic review and meta-analysis.
      ], and 87.6 (72.6–105.6) according to the Japanese Drug Event Report Database [
      • Arai M.
      • Shirakawa J.
      • Konishi H.
      • Sagawa N.
      • Terauchi Y.
      Bullous pemphigoid and dipeptidyl peptidase 4 inhibitors: a disproportionality analysis based on the Japanese adverse drug event report database.
      ]. DPP-4i BP has clinical manifestations distinct from those of typical BP [
      • Izumi K.
      • Nishie W.
      • Mai Y.
      • Wada M.
      • Natsuga K.
      • Ujiie H.
      • et al.
      Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid.
      ,
      • Ujiie H.
      • Muramatsu K.
      • Mushiroda T.
      • Ozeki T.
      • Miyoshi H.
      • Iwata H.
      • et al.
      HLA-DQB1*03:01 as a biomarker for genetic susceptibility to bullous pemphigoid induced by DPP-4 inhibitors.
      ,
      • Chanprapaph K.
      • Pratumchart N.
      • Limtong P.
      • Rutnin S.
      • Sukasem C.
      • Kungvalpivat P.
      • et al.
      Dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid: a comparative study of 100 patients with bullous pemphigoid and diabetes mellitus.
      ,
      • Kinyó Á.
      • Hanyecz A.
      • Lengyel Z.
      • Várszegi D.
      • Oláh P.
      • Gyömörei C.
      • et al.
      Clinical, laboratory and histological features of dipeptidyl peptidase-4 inhibitor related noninflammatory bullous pemphigoid.
      ], which is considered to be related to the difference in target epitopes of the autoantibody [
      • Izumi K.
      • Nishie W.
      • Mai Y.
      • Wada M.
      • Natsuga K.
      • Ujiie H.
      • et al.
      Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid.
      ]. Here, even patients with history of DPP-4i use showed improvement in ≥ 80 % cases, not unlike conventional BP cases.
      In the clinical trial conducted for IVIG approval, efficacy was evaluated using the modified PDAI, as the BPDAI was not completed when the trial was being planned. The sum score, calculated separately as "erosion/blisters" and "new erythema" according to the BPDAI, was calculated as the secondary endpoint, and the superiority of IVIG to placebo was established [
      • Amagai M.
      • Ikeda S.
      • Hashimoto T.
      • Mizuashi M.
      • Fujisawa A.
      • Ihn H.
      • et al.
      A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.
      ]. For post-hoc analysis, the median (25th, 75th percentiles) rate of score decrease in the clinical trial (29 cases) was − 66.6 % (− 86.8, − 30.0), while in our survey (225 cases) was − 74.1 % (− 95.5, − 52.3), demonstrating similar trends and supporting the results of the clinical trial.
      BP is caused mainly by anti-BP180 IgG [
      • Liu Z.
      • Diaz L.A.
      • Troy J.L.
      • Taylor A.F.
      • Emery D.J.
      • Fairley J.A.
      • et al.
      A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180.
      ,
      • Liu Z.
      • Giudice G.J.
      • Swartz S.J.
      • Fairley J.A.
      • Till G.O.
      • Troy J.L.
      • et al.
      The role of complement in experimental bullous pemphigoid.
      ,
      • Iwata H.
      • Kamio N.
      • Aoyama Y.
      • Yamamoto Y.
      • Hirako Y.
      • Owaribe K.
      • et al.
      IgG from patients with bullous pemphigoid depletes cultured keratinocytes of the 180-kDa bullous pemphigoid antigen (type XVII collagen) and weakens cell attachment.
      ] and IgE [
      • Cozzani E.
      • Gasparini G.
      • Di Zenzo G.
      • Parodi A.
      Immunoglobulin E and bullous pemphigoid.
      ,
      • Moriuchi R.
      • Nishie W.
      • Ujiie H.
      • Natsuga K.
      • Shimizu H.
      In vivo analysis of IgE autoantibodies in bullous pemphigoid: a study of 100 cases.
      ] antibodies, leading to increased levels of cytokines (such as interleukin [IL]-1β, IL-5, IL-6, IL-17A, tumor necrosis factor-α, and CCL18) [
      • Genovese G.
      • Di Zenzo G.
      • Cozzani E.
      • Berti E.
      • Cugno M.
      • Marzano A.V.
      New insights into the pathogenesis of bullous pemphigoid: 2019 update.
      ,
      • Kasperkiewicz M.
      • Zillikens D.
      • Schmidt E.
      Pemphigoid diseases: pathogenesis, diagnosis, and treatment.
      ] and inflammatory infiltration consisting of eosinophils, lymphocytes, and neutrophils [
      • Genovese G.
      • Di Zenzo G.
      • Cozzani E.
      • Berti E.
      • Cugno M.
      • Marzano A.V.
      New insights into the pathogenesis of bullous pemphigoid: 2019 update.
      ,
      • Kershenovich R.
      • Hodak E.
      • Mimouni D.
      Diagnosis and classification of pemphigus and bullous pemphigoid.
      ] with or without complement activation [
      • Liu Z.
      • Giudice G.J.
      • Swartz S.J.
      • Fairley J.A.
      • Till G.O.
      • Troy J.L.
      • et al.
      The role of complement in experimental bullous pemphigoid.
      ,
      • Iwata H.
      • Kitajima Y.
      Bullous pemphigoid: role of complement and mechanisms for blister formation within the lamina lucida.
      ,
      • Ujiie H.
      • Sasaoka T.
      • Izumi K.
      • Nishie W.
      • Shinkuma S.
      • Natsuga K.
      • et al.
      Bullous pemphigoid autoantibodies directly induce blister formation without complement activation.
      ]. BP pathogenesis is likely multifactorial and concerted.
      The mechanism of action of IVIG has not been sufficiently elucidated, but its beneficial effect is likely derived from multiple complex pathways [
      • Li N.
      • Culton D.
      • Diaz L.A.
      • Liu Z.
      Modes of action of intravenous immunoglobulin in bullous pemphigoid.
      ]. Research on pathogenesis is progressing, and a specific pathway inhibitor is expected to be developed for therapeutic effect, such as rituximab for CD20 on B cells [
      • Cho Y.T.
      • Chu C.Y.
      • Wang L.F.
      First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid.
      ,
      • Ahmed A.R.
      • Shetty S.
      • Kaveri S.
      • Spigelman Z.S.
      Treatment of recalcitrant bullous pemphigoid (BP) with a novel protocol: a retrospective study with a 6-year follow-up.
      ], omalizumab for the IgE autoantibody [
      • Moriuchi R.
      • Nishie W.
      • Ujiie H.
      • Natsuga K.
      • Shimizu H.
      In vivo analysis of IgE autoantibodies in bullous pemphigoid: a study of 100 cases.
      ,
      • Yu K.K.
      • Crew A.B.
      • Messingham K.A.
      • Fairley J.A.
      • Woodley D.T.
      Omalizumab therapy for bullous pemphigoid.
      ], ixekizumab for IL-17 [
      • Wu K.K.
      • Dao H.
      Off-label dermatologic uses of IL-17 inhibitors.
      ], dupilumab for IL-4 receptor α [
      • Kaye A.
      • Gordon S.C.
      • Deverapalli S.C.
      • Her M.J.
      • Rosmarin D.
      Dupilumab for the treatment of recalcitrant bullous pemphigoid.
      ], and bertilimumab for exotoxin-1 on eosinophils [
      • Wang S.H.
      • Zuo Y.G.
      Commentary: efficacy and safety of Dupilumab in moderate-to-severe bullous pemphigoid.
      ]. Future targets would be the Fc gamma receptor, complement factor 5a, and others.
      IVIG has advantages in terms of safety and effectiveness. The incidence rate of ADRs with IVIG was approximately 10 % [
      • Hoffmann J.H.O.
      • Enk A.H.
      High-dose intravenous immunoglobulin in skin autoimmune disease.
      ] in a previous report. Additionally, IVIG can enhance protection against infections, in contrast to corticosteroids or immunomodulators. Here, the incidence rate was 8.3 %, comparable to that of the previous report. Additionally, in approximately ¼ of patients who underwent multiple IVIG administrations, the ADR incidence per cycle was 2.68 %, lower than at initial administration (12.5 %), showing no increased risk from multiple administrations. Thrombocytopenia was the most frequent (3.2 %) ADR, similar to that in IVIG treatment for pemphigus (2.4 %) (data not shown). There are generally few case reports of thrombocytopenia due to IVIG therapy for other diseases, and the pathogenesis is not well understood [
      • Gurevich-Shapiro A.
      • Bonstein L.
      • Spectre G.
      • Atweh N.
      • Gruenewal T.
      • Shapiro M.
      • et al.
      Intravenous immunoglobulin-induced acute thrombocytopenia.
      ]. However, the symptoms in BP cases were transient, and most patients recovered without intervention.
      From the results of this survey, the efficacy and safety of IVIG as proven by the clinical trial [
      • Amagai M.
      • Ikeda S.
      • Hashimoto T.
      • Mizuashi M.
      • Fujisawa A.
      • Ihn H.
      • et al.
      A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.
      ] were confirmed in clinical practice, indicating that IVIG is an important alternative for patients with BP with insufficient response to corticosteroid treatment.

      4.1 Limitations

      First, this was an observational study and, thus, the data we collected were likely biased. We widely gathered cases from 143 facilities throughout Japan, mainly large medical institutions, such as university hospitals. Moreover, this was the first approved IVIG preparation for BP in Japan. Therefore, we believe that our sample was mostly representative of patients with BP who had insufficient response to corticosteroids.
      Second, as we examined clinical settings and did not use a control group, we cannot conclude regarding the drug's therapeutic effects or the effectiveness of multiple administrations. However, before IVIG treatment, most enrolled patients had been treated with systemic corticosteroids, and in many of them, steroid pulse therapy, immunosuppressant administration, plasmapheresis, or diaphenylsulfone administration was also added. However, the therapy effect was insufficient. Still, both the clinical trial and our study showed similar trends for the early treatment outcomes of single IVIG treatment, suggesting that IVIG therapy would also have a therapeutic effect over the long term in clinical settings. A randomized, controlled trial should be conducted to verify this hypothesis.

      4.2 Conclusion

      We showed that IVIG treatment improved the BPDAI, reduced anti-BP180 antibody titers, and spared corticosteroid doses in patients with BP with insufficient response to corticosteroids. Although innovative drugs targeting new pathways will be developed, there will remain patients unresponsive to ordinary treatments because of individual heterogeneity. Further studies should be performed to optimize the use of IVIG for BP treatment.

      CRediT authorship contribution statement

      HU and YA conceived the study. HU and MA drafted the manuscript. HU and MA performed the statistical analysis. YA revised the manuscript.

      Funding

      The surveillance was funded by Nihon Pharmaceutical Co., Ltd, Tokyo, Japan.

      Declaration of Conflicting Interests

      This study was supported by Nihon Pharmaceutical Co. Ltd., Tokyo, Japan. HU received consulting and lecture fees from Nihon Pharmaceutical Co., Ltd. YA received consulting and lecture fees from Nihon Pharmaceutical Co., Ltd. MA is an employee of Nihon Pharmaceutical Co., Ltd.

      Acknowledgments

      We would like to express our gratitude to all physicians and others involved in the nationwide medical institutions that participated in this study. We would like to thank Editage for English language editing.

      Appendix A. Supplementary material

      References

        • Schmidt E.
        • Zillikens D.
        Pemphigoid diseases.
        Lancet. 2013; 381: 320-332
        • Amber K.T.
        • Murrell D.F.
        • Schmidt E.
        • Joly P.
        • Borradori L.
        Autoimmune subepidermal bullous diseases of the skin and mucosae: clinical features, diagnosis, and management.
        Clin. Rev. Allergy Immunol. 2018; 54: 26-51
        • Ujiie H.
        • Iwata H.
        • Yamagami J.
        • Nakama T.
        • Aoyama Y.
        • Ikeda S.
        • et al.
        Japanese guidelines for the management of pemphigoid (including epidermolysis bullosa acquisita).
        J. Dermatol. 2019; 46: 1102-1135
        • Feliciani C.
        • Joly P.
        • Jonkman M.F.
        • Zambruno G.
        • Zillikens D.
        • Ioannides D.
        • et al.
        Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology.
        Br. J. Dermatol. 2015; 172: 867-877
        • Venning V.A.
        • Taghipour K.
        • Mohd Mustapa M.F.
        • Highet A.S.
        • Kirtschig G.
        British Association of Dermatologists, British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012.
        Br. J. Dermatol. 2012; 167: 1200-1214
        • Ahmed A.R.
        Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment.
        J. Am. Acad. Dermatol. 2001; 45: 825-835
        • Kirtschig G.
        • Middleton P.
        • Bennett C.
        • Murrell D.F.
        • Wojnarowska F.
        • Khumalo N.P.
        Interventions for bullous pemphigoid.
        Cochrane Database Syst. Rev. 2010; 2012: CD002292
        • Amagai M.
        • Ikeda S.
        • Hashimoto T.
        • Mizuashi M.
        • Fujisawa A.
        • Ihn H.
        • et al.
        A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.
        J. Dermatol. Sci. 2017; 85: 77-84
      1. Review Report, Pharm Devices Agency, 2015. 〈https://www.pmda.go.jp/files/000223353.pdf〉.

        • Murrell D.F.
        • Daniel B.S.
        • Joly P.
        • Borradori L.
        • Amagai M.
        • Hashimoto T.
        • et al.
        Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.
        J. Am. Acad. Dermatol. 2012; 66: 479-485
        • Kobayashi M.
        • Amagai M.
        • Kuroda-Kinoshita K.
        • Hashimoto T.
        • Shirakata Y.
        • Hashimoto K.
        • et al.
        BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid.
        J. Dermatol. Sci. 2002; 30: 224-232
        • Sakuma-Oyama Y.
        • Powell A.M.
        • Oyama N.
        • Albert S.
        • Bhogal B.S.
        • Black M.M.
        Evaluation of a BP180-NC16a enzyme-linked immunosorbent assay in the initial diagnosis of bullous pemphigoid.
        Br. J. Dermatol. 2004; 151: 126-131
        • Rzany B.
        • Partscht K.
        • Jung M.
        • Kippes W.
        • Mecking D.
        • Baima B.
        • et al.
        Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age.
        Arch. Dermatol. 2002; 138: 903-908
        • Wijayanti A.
        • Zhao C.Y.
        • Boettiger D.
        • Chiang Y.Z.
        • Ishii N.
        • Hashimoto T.
        • et al.
        The reliability, validity and responsiveness of two disease scores (BPDAI and ABSIS) for bullous pemphigoid: which one to use?.
        Acta Derm. Venereol. 2017; 97: 24-31
        • Masmoudi W.
        • Vaillant M.
        • Vassileva S.
        • Patsatsi A.
        • Quereux G.
        • Moltrasio C.
        • et al.
        International validation of the Bullous pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.
        Br. J. Dermatol. 2021; 184: 1106-1112
        • Lévy-Sitbon C.
        • Barbe C.
        • Plee J.
        • Goeldel A.L.
        • Antonicelli F.
        • Reguiaï Z.
        • et al.
        Assessment of bullous pemphigoid disease area index during treatment: a prospective study of 30 patients.
        Dermatology. 2014; 229: 116-122
        • Fichel F.
        • Barbe C.
        • Joly P.
        • Bedane C.
        • Vabres P.
        • Truchetet F.
        • et al.
        Clinical and immunologic factors associated with bullous pemphigoid relapse during the first year of treatment: a multicenter, prospective study.
        JAMA Dermatol. 2014; 150: 25-33
      2. E. Pasmatzi, A. Monastirli, J. Habeos, S. Georgiou, D. Tsambaos, Dipeptidyl peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases, Diabetes Care, vol. 34(no. 201), e133.

        • Aouidad I.
        • Fite C.
        • Marinho E.
        • Deschamps L.
        • Crickx B.
        • Descamps V.
        A case report of bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors.
        JAMA Dermatol. 2013; 149: 243-245
        • Attaway A.
        • Mersfelder T.L.
        • Vaishnav S.
        • Baker J.K.
        Bullous pemphigoid associated with dipeptidyl peptidase IV inhibitors. a case report and review of literature.
        J. Dermatol. Case Rep. 2014; 8: 24-28
        • Béné J.
        • Moulis G.
        • Bennani I.
        • Auffret M.
        • Coupe P.
        • Babai S.
        • et al.
        Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French pharmacovigilance Database.
        Br. J. Dermatol. 2016; 175: 296-301
        • Liu S.D.
        • Chen W.T.
        • Chi C.C.
        Association between medication use and bullous pemphigoid: a systematic review and meta-analysis.
        JAMA Dermatol. 2020; 156: 891-900
        • Arai M.
        • Shirakawa J.
        • Konishi H.
        • Sagawa N.
        • Terauchi Y.
        Bullous pemphigoid and dipeptidyl peptidase 4 inhibitors: a disproportionality analysis based on the Japanese adverse drug event report database.
        Diabetes Care. 2018; 41: e130-e132
        • Izumi K.
        • Nishie W.
        • Mai Y.
        • Wada M.
        • Natsuga K.
        • Ujiie H.
        • et al.
        Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid.
        J. Invest. Dermatol. 2016; 136: 2201-2210
        • Ujiie H.
        • Muramatsu K.
        • Mushiroda T.
        • Ozeki T.
        • Miyoshi H.
        • Iwata H.
        • et al.
        HLA-DQB1*03:01 as a biomarker for genetic susceptibility to bullous pemphigoid induced by DPP-4 inhibitors.
        J. Invest. Dermatol. 2018; 138: 1201-1204
        • Chanprapaph K.
        • Pratumchart N.
        • Limtong P.
        • Rutnin S.
        • Sukasem C.
        • Kungvalpivat P.
        • et al.
        Dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid: a comparative study of 100 patients with bullous pemphigoid and diabetes mellitus.
        J. Dermatol. 2021; 48: 486-496
        • Kinyó Á.
        • Hanyecz A.
        • Lengyel Z.
        • Várszegi D.
        • Oláh P.
        • Gyömörei C.
        • et al.
        Clinical, laboratory and histological features of dipeptidyl peptidase-4 inhibitor related noninflammatory bullous pemphigoid.
        J. Clin. Med. 2021; 10: 1916
        • Liu Z.
        • Diaz L.A.
        • Troy J.L.
        • Taylor A.F.
        • Emery D.J.
        • Fairley J.A.
        • et al.
        A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180.
        J. Clin. Invest. 1993; 92: 2480-2488
        • Liu Z.
        • Giudice G.J.
        • Swartz S.J.
        • Fairley J.A.
        • Till G.O.
        • Troy J.L.
        • et al.
        The role of complement in experimental bullous pemphigoid.
        J. Clin. Invest. 1995; 95: 1539-1544
        • Iwata H.
        • Kamio N.
        • Aoyama Y.
        • Yamamoto Y.
        • Hirako Y.
        • Owaribe K.
        • et al.
        IgG from patients with bullous pemphigoid depletes cultured keratinocytes of the 180-kDa bullous pemphigoid antigen (type XVII collagen) and weakens cell attachment.
        J. Invest. Dermatol. 2009; 129: 919-926
        • Cozzani E.
        • Gasparini G.
        • Di Zenzo G.
        • Parodi A.
        Immunoglobulin E and bullous pemphigoid.
        Eur. J. Dermatol. 2018; 28: 440-448
        • Moriuchi R.
        • Nishie W.
        • Ujiie H.
        • Natsuga K.
        • Shimizu H.
        In vivo analysis of IgE autoantibodies in bullous pemphigoid: a study of 100 cases.
        J. Dermatol. Sci. 2015; 78: 21-25
        • Genovese G.
        • Di Zenzo G.
        • Cozzani E.
        • Berti E.
        • Cugno M.
        • Marzano A.V.
        New insights into the pathogenesis of bullous pemphigoid: 2019 update.
        Front. Immunol. 2019; 10: 1506
        • Kasperkiewicz M.
        • Zillikens D.
        • Schmidt E.
        Pemphigoid diseases: pathogenesis, diagnosis, and treatment.
        Autoimmunity. 2012; 45: 55-70
        • Kershenovich R.
        • Hodak E.
        • Mimouni D.
        Diagnosis and classification of pemphigus and bullous pemphigoid.
        Autoimmun. Rev. 2014; 13: 477-481
        • Iwata H.
        • Kitajima Y.
        Bullous pemphigoid: role of complement and mechanisms for blister formation within the lamina lucida.
        Exp. Dermatol. 2013; 22: 381-385
        • Ujiie H.
        • Sasaoka T.
        • Izumi K.
        • Nishie W.
        • Shinkuma S.
        • Natsuga K.
        • et al.
        Bullous pemphigoid autoantibodies directly induce blister formation without complement activation.
        J. Immunol. 2014; 193: 4415-4428
        • Li N.
        • Culton D.
        • Diaz L.A.
        • Liu Z.
        Modes of action of intravenous immunoglobulin in bullous pemphigoid.
        J. Invest. Dermatol. 2018; 138: 1249-1251
        • Cho Y.T.
        • Chu C.Y.
        • Wang L.F.
        First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid.
        Br. J. Dermatol. 2015; 173: 302-304
        • Ahmed A.R.
        • Shetty S.
        • Kaveri S.
        • Spigelman Z.S.
        Treatment of recalcitrant bullous pemphigoid (BP) with a novel protocol: a retrospective study with a 6-year follow-up.
        Am. Acad. Dermatol. 2016; 74: 700-708
        • Yu K.K.
        • Crew A.B.
        • Messingham K.A.
        • Fairley J.A.
        • Woodley D.T.
        Omalizumab therapy for bullous pemphigoid.
        J. Am. Acad. Dermatol. 2014; 71: 468-474
        • Wu K.K.
        • Dao H.
        Off-label dermatologic uses of IL-17 inhibitors.
        J. Dermatol. Treat. 2022; 33: 41-47
        • Kaye A.
        • Gordon S.C.
        • Deverapalli S.C.
        • Her M.J.
        • Rosmarin D.
        Dupilumab for the treatment of recalcitrant bullous pemphigoid.
        JAMA Dermatol. 2018; 154: 1225-1226
        • Wang S.H.
        • Zuo Y.G.
        Commentary: efficacy and safety of Dupilumab in moderate-to-severe bullous pemphigoid.
        Front. Immunol. 2021; 12800609
        • Hoffmann J.H.O.
        • Enk A.H.
        High-dose intravenous immunoglobulin in skin autoimmune disease.
        Front. Immunol. 2019; 10: 1090
        • Gurevich-Shapiro A.
        • Bonstein L.
        • Spectre G.
        • Atweh N.
        • Gruenewal T.
        • Shapiro M.
        • et al.
        Intravenous immunoglobulin-induced acute thrombocytopenia.
        Transfusion. 2018; 58: 493-497