Unique clinical and serological features of bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors

Dear Editor, Recently, several cases of bullous pemphigoid (BP) associated with the use of a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, a type of antihyperglycaemic drug, have been reported (DPP4i‐BP).1,2 Béné et al. reported a strong association between DPP‐4 inhibitor use and the risk of BP.3 The juxtamembranous extracellular noncollagenous 16a (NC16a) domain of type XVII collagen (also termed BP180) is a major target epitope of autoantibodies in BP.4 A recent study found that in individuals with BP, whose autoantibodies bound to BP180 at regions other than NC16a, exhibited a noninflammatory phenotype with fewer erythemas. Intriguingly, half of these patients had taken DPP‐4 inhibitors at the time of development of BP.5 In this study, we explored whether individuals with DPP4i‐BP exhibited any unique clinical and serological features as suggested by the previous study. We retrospectively analysed patients with BP who visited Keio University Hospital from April 2014 (at which time we recorded the first case of DPP4i‐BP) to September 2016. All patients were diagnosed from the presence of subepidermal blisters on pathological examination, and by linear deposition of IgG and/or C3 along the basement membranes on direct immunofluorescence tests. We defined patients with DPP4i‐BP as those who were taking DPP‐4 inhibitors at the time of BP onset. Clinical features were scored using the Bullous Pemphigoid Disease Area Index (BPDAI).6 We defined a noninflammatory phenotype as that of a patient whose BPDAI urticaria/erythema (U/E) was zero. We used an enzyme‐linked immunosorbent assay (ELISA) and/or a chemiluminescence enzyme immunoassay (BML, Nagoya, Japan) to detect autoantibodies against NC16a (anti‐NC16a Ab) in patients’ sera. The ELISA‐mediated detection of autoantibodies against full‐length BP180 (anti‐fBP180 Ab) has been previously described.5 Data were compared using the Mann–Whitney U‐test or Fisher's exact test, as appropriate, with a P <0·05 considered significant. The study was approved by the Institutional Review Board of Keio University (IRB‐ID 20120180). We enrolled 35 patients; 12 (34%) with DPP4i‐BP and 23 (66%) with non‐DPP4i‐BP (Fig. 1a). The DPP‐4 inhibitors used by patients in the DPP4i‐BP group were vildagliptin (five patients), linagliptin (four patients), teneligliptin (two patients) and sitagliptin (one patient) (Fig. 1b). (a) Summary of the patients enrolled in this study. (b) Summary of the patients with DPP4i‐BP. (c) A typical case of non‐DPP4i‐BP with inflammatory phenotype. The BPDAI (erosions/blisters) and (urticaria/erythema) scores were 45 and 72, respectively. (d) A typical case of DPP4i‐BP with noninflammatory phenotype. BPDAI (erosions/blisters) and (urticaria/erythema) scores were 22 and 0, respectively. (e, f) The BPDAIs of the DPP4i‐BP and non‐DPP4i‐BP groups. (g, h) The BPDAI scores of patients with DPP4i‐BP who were anti‐NC16a Ab‐positive and anti‐NC16a Ab‐negative. BP, bullous pemphigoid; BPDAI, Bullous Pemphigoid Disease Area Index; DPP4i‐BP, bullous pemphigoid associated with the use of dipeptidyl peptidase‐4 inhibitors (DPP4is); non‐DPP4i‐BP, bullous pemphigoid not associated with the use of DPP4is; anti‐NC16a Ab, antibodies targeting the noncollagenous domain 16a of type XVII collagen (BP180); anti‐fBP180 Ab, antibodies targeting full‐length BP180; ND, no data; I, inflammatory phenotype; N, noninflammatory phenotype; vilda, vildagliptin; lina, linagliptin; teneli, teneligliptin; sita, sitagliptin; ns, no significant difference. The BPDAI ranges from 0 (no lesion) to 120 (maximal disease activity). Anti‐NC16a Ab titres were measured using the chemiluminescence enzyme immunoassay; cut‐off: 9·0 U mL−1. Anti‐fBP180 Ab titres were measured via enzyme‐linked immunosorbent assay; cut‐off: 9·0 index. In total, 6 of 12 (50%) patients in the DPP4i‐BP group had noninflammatory phenotypes, compared with 3 of 23 (13%) in the non‐DPP4i‐BP group (Fig. 1c, d). The proportion of noninflammatory cases was significantly higher in the DPP4i‐BP group (P =0·038; Fig. 1a). In the DPP4i‐BP group, the BPDAI erosions/blisters (E/B) ranged from 5 to 72; the mean ± SD and median scores were 37·4 ± 20·2 and 32·0, respectively and in the non‐DPP4i‐BP group were 2 to 68, 29·5 ± 17·5 and 28·0, respectively. The BPDAI (E/B) did not differ significantly between the DPP4i‐BP and non‐DPP4i‐BP groups (P =0·195; Fig. 1e). In the DPP4i‐BP group, the BPDAI (U/E) ranged from 0 to 37; the mean ± SD and median scores were 11·2 ± 14·6 and 3·0, respectively and those in the non‐DPP4i‐BP group were 0 to 72, 24·2 ± 17·1 and 26·0, respectively. The BPDAI (U/E) was significantly lower in the DPP4i‐BP group (P =0·034; Fig. 1f). In the DPP4i‐BP group, the sera of 7 of 12 patients contained anti‐NC16a Ab (58%), compared with 21 of 23 (91%) in the non‐DPP4i‐BP group (Fig. 1b). The DPP4i‐BP group exhibited a significantly lower frequency of anti‐NC16a Ab‐positivity (P =0·033; Fig. 1a). Anti‐fBP180 Ab were detected in all five patients with DPP4i‐BP lacking anti‐NC16a Ab. All six sera of the patients with inflammatory DPP4i‐BP contained anti‐NC16a Ab; however, only one of the patients with noninflammatory DPP4i‐BP had anti‐NC16a Ab. In the DPP4i‐BP group, the BPDAI (U/E) was significantly lower in the anti‐NC16a Ab‐negative cases (P =0·010), but the BPDAI (E/B) was not (P =0·343; Fig. 1g, h). We confirmed that the patients with DPP4i‐BP tend to exhibit a noninflammatory phenotype with fewer erythemas, and synthesize autoantibodies against full‐length BP180, but not the NC16a domain. However, half of our DPP4i‐BP group exhibited typical BP characteristics (inflammation and anti‐NC16a Ab‐positivity). Thus, DPP4i‐BP patients may be divided into two groups: (i) those with BP caused by DPP‐4 inhibitor ingestion, which have a noninflammatory phenotype, anti‐NC16a Ab‐negativity and anti‐fBP180 Ab‐positivity, and (ii) typical BP cases that coincide with DPP‐4 inhibitor ingestion. Advanced age is associated with the onset of both BP and diabetes; the fact that DPP‐4 inhibitors are first‐line antidiabetes drugs in Japan renders this coincidence reasonable. Although further research on a larger scale is required to confirm our conclusion, we suggest that DPP4i‐BP status plays an important role in BP epidemiology. In cases with noninflammatory BP lacking anti‐NC16a Ab, DPP4i‐BP should be considered.