Neutrophil to lymphocyte ratio is predictive of severe complications and mortality in patients with dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid: A retrospective longitudinal observational study

Abstract

To the Editor: Dipeptidyl peptidase-4 inhibitors (DPP-4i), which have been used worldwide as a treatment option for type 2 diabetes, are associated with an increased risk of bullous pemphigoid (DPP-4i-BP).1Kim W. Egan J.M. The role of incretins in glucose homeostasis and diabetes treatment.Pharmacol Rev. 2008; 60: 470-512Crossref PubMed Scopus (566) Google Scholar The outcomes of DPP-4i-BP after cessation are heterogenous and unpredictable, owing to the immunomodulatory functions of these agents.2Shao S. Xu Q. Yu X. Pan R. Chen Y. Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions.Pharmacol Ther. 2020; 209: 107503Crossref PubMed Scopus (66) Google Scholar As similar adverse events and heterogenous outcomes occur in patients treated with immune checkpoint inhibitors,3Siegel J. Totonchy M. Damsky W. et al.Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: a retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy.J Am Acad Dermatol. 2018; 79: 1081-1088Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar these drug-induced adverse events could be a manifestation of a common clinical phenotype, referred to as immune reconstitution inflammatory syndrome (IRIS).4Shelburne III, S.A. Hamill R.J. Rodriguez-Barradas M.C. et al.Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy.Medicine (Baltimore). 2002; 81: 213-227Crossref PubMed Scopus (502) Google Scholar,5Singh N. Perfect J.R. Immune reconstitution syndrome associated with opportunistic mycoses.Lancet Infect Dis. 2007; 7: 395-401Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar Here, we investigated the prevalence of infectious complications, outcomes, and 1-year mortality in patients with DPP-4i-BP, who were followed up for >90 days after DPP-4i cessation. The information on methods and figures are provided in the Supplemental information (available via Mendeley at https://doi.org/10.17632/cfdv85gmv5.2). The patients who achieved a spontaneous remission after DPP-4i cessation (remission group, n = 8) were compared with those who experienced BP exacerbations and required systemic corticosteroids (exacerbation group, n = 9). The bullous pemphigoid disease area index score or anti-BP180 IgG level at baseline did not significantly differ between the groups, indicating no significant difference in severity at the baseline. The mean neutrophil to lymphocyte ratio (NLR) at baseline was significantly higher in the exacerbation group than in the remission group (Table I). Receiver-operating characteristic curve analysis showed that a cutoff value of 4.30 at baseline and 6.58 at the peak could differentiate between these groups (Supplemental Figs 1 and 2). When the patients were further classified into 3 subgroups, based on the type of IRIS (Supplemental Fig 1), the mean NLR at baseline and that at the peak were significantly higher in the group with infectious IRIS (n = 11) than in the group with autoimmune IRIS (n = 4) and the group with no complications (n = 8) (Table II). The results suggested that NLR above the cutoff value can predict the development of infectious IRIS. In the group with infectious IRIS, the mean NLR at the peak was significantly higher during 1-4 weeks postcessation than at baseline, and predicted the occurrence of any infectious complications. No significant increase in NLR was observed at the peak during the same period in the group with autoimmune IRIS. The patients treated with corticosteroids had an increased risk of complications after DPP-4i cessation, while no or few complications occurred in those not treated with corticosteroids (Table I). By 1 year, complete remission of BP was achieved without corticosteroids in 100% of the patients in the remission group and in 0% of the exacerbation group (Table I). None of the patients who received supportive care experienced a recurrence of BP in 1 year. Although the patients treated with systemic corticosteroids showed rapid disease clearance by day 60, only 2 patients successfully discontinued corticosteroids (at 603 days and 1165 days). There were 4 deaths within 1 year, all in the cases of infectious IRIS treated with corticosteroids, despite no in-hospital mortality (Supplemental Fig 3). The limitations of this study are its small study population and potential selection bias, stemming from a retrospective, single-center design.Table IClinical characteristics of patients with DPP-4i-BP who showed spontaneous remission and those who experienced exacerbations after DPP-4i cessationSpontaneous remission of BP/supportive care n = 8Exacerbation of BP/corticosteroids n = 9P valueDuration of DPP-4i therapy†Wilcoxon rank-sum test., mo; median (IQR)27.7 (16.5, 38.5)47 (5, 60).25BPDAI at baseline (before DPP-4i cessation), mean ± SD (range)§t test.8.0 ± 7.0 (1-18)12.3 ± 2.4 (9-14).27Serum BP180Ab level at baseline (before DPP-4i cessation), mean (range)§t test.67.1 (0-387.5)144.0 (0-791.7).51Time until clinical remission after DPP-4i cessation, d§t test. Mean (range)101.1 (20-245)∗P < .05.21.8 (9-61).04 Median (IQR)73 (44-140)∗P < .05.16 (9-30.3).01Baseline§t test. (before DPP-4i cessation) NLR, mean ± SEM2.33 ± 0.715.66 ± 0.92∗P < .05..02 Neutrophil count, mean ± SEM3276 ± 6304826 ± 483.07 Lymphocyte count, mean ± SEM1806 ± 425970 ± 122.07Peak§t test. NLR, mean ± SEM2.72 ± 0.6810.56 ± 2.74∗P < .05..01 Neutrophil count, mean ± SEM3677 ± 5067844 ± 460∗P < .05.<.001 Lymphocyte count, mean ± SEM1638 ± 293952 ± 233.11Very early postcessation period (1-2 wk)§t test. NLR, mean ± SEM2.25 ± 0.384.72 ± 1.30.11 Neutrophil count, mean ± SEM3186 ± 2835774 ± 795∗P < .05..02 Lymphocyte count, mean ± SEM1582 ± 3061402 ± 240.66Late postcessation period (1-4 mo)§t test. NLR, mean ± SEM2.52 ± 0.603.48 ± 0.77.34 Neutrophil count, mean ± SEM3546 ± 4524334 ± 613.31 Lymphocyte count, mean ± SEM1630 ± 2491426 ± 232.58Initial corticosteroid dose, mg, mean ± SEM030.5 ± 3.4Cases free of BP without corticosteroids at 1 year, n (%)‡Fisher's exact test. Complications (number of cases);8 (100)∗P < .05.0 (0)<.01Complications, number of cases (%)‡Fisher's exact test. Complications (number of cases);2‖pneumonia (2), (25.0)7¶cellulitis (1), cytomegalovirus reactivation (2), impetigo (3), and pneumonia (1). (77.8).06Supportive care included oral doxycycline, minocycline, and very potent topical corticosteroids. The mean topical corticosteroid dosage used was 4.0 g/day.BP, Bullous pemphigoid; BPDAI, bullous pemphigoid disease area index; DPP-4i, dipeptidyl peptidase-4 inhibitor; IQR, interquartile range; NLR, neutrophil to lymphocyte ratio; SD, standard deviation; SEM, standard error of the mean.∗ P < .05.† Wilcoxon rank-sum test.‡ Fisher's exact test. Complications (number of cases);§ t test.‖ pneumonia (2),¶ cellulitis (1), cytomegalovirus reactivation (2), impetigo (3), and pneumonia (1). Open table in a new tab Table IINeutrophil to lymphocyte ratio at baseline and changes in this ratio during the postcessation period in patients with DPP-4i-BP, who developed infectious or autoimmune IRISNo complications n = 8Infectious IRIS n = 11Autoimmune IRIS n = 4P valueBaseline†t test. (before DPP-4i cessation) NLR, mean ± SEM2.07 ± 0.496.11 ± 1.15∗P < .05.4.92 ± 0.98∗P < .05..01 Neutrophil count, mean ± SEM3234 ± 5965044 ± 630∗P < .05.6238 ± 1105∗P < .05..04 Lymphocyte count, mean ± SEM1859 ± 412936 ± 1361299 ± 133.13Peak in very early to early postcessation period (1-4 wk)†t test. NLR, mean ± SEM2.24 ± 0.5912.2 ± 2.84∗P < .05.4.58 ± 0.54<.01 Neutrophil count, mean ± SEM3400 ± 5187985 ± 566∗P < .05.6170 ± 1110∗P < .05.<.01 Lymphocyte count, mean ± SEM1768 ± 322740 ± 1261395 ± 405.08Very early postcessation period (1-2 wk)†t test. NLR, mean ± SEM2.16 ± 0.475.03 ± 1.633.05 ± 0.41.25 Neutrophil count, mean ± SEM3105 ± 3505875 ± 10184440 ± 930.09 Lymphocyte count, mean ± SEM1645 ± 3861365 ± 3061440 ± 110.82Late postcessation period (1-4 mo)†t test. NLR, mean ± SEM2.09 ± 0.493.41 ± 0.994.44 ± 0.67.17 Neutrophil count, mean ± SEM3293 ± 4444088 ± 7245190 ± 184.18 Lymphocyte count, mean ± SEM1737 ± 2661430 ± 2991200 ± 210.52Change in NLR, peak–early (3-4 wk), mean ± SEM†t test.0.37 ± 0.263.95 ± 0.77∗P < .05.1.53 ± 0.94.01Systemic corticosteroids, n (%)‡Fisher's exact test.2 (25.0)10 (90.9)∗P < .05.3 (75.0)<.01Epitope spreading, n (%)‡Fisher's exact test.0 (0)4 (36.4)3 (75.0)∗P < .05..021-year mortality rate, n (%)§Pearson chi-squared test.0 (0)4 (36.4)0 (0).07DPP-4i, Dipeptidyl peptidase-4 inhibitor; IRIS, immune reconstitution inflammatory syndrome; NLR, neutrophil to lymphocyte ratio; SD, standard deviation; SEM, standard error of the mean.∗ P < .05.† t test.‡ Fisher's exact test.§ Pearson chi-squared test. Open table in a new tab Supportive care included oral doxycycline, minocycline, and very potent topical corticosteroids. The mean topical corticosteroid dosage used was 4.0 g/day. BP, Bullous pemphigoid; BPDAI, bullous pemphigoid disease area index; DPP-4i, dipeptidyl peptidase-4 inhibitor; IQR, interquartile range; NLR, neutrophil to lymphocyte ratio; SD, standard deviation; SEM, standard error of the mean. DPP-4i, Dipeptidyl peptidase-4 inhibitor; IRIS, immune reconstitution inflammatory syndrome; NLR, neutrophil to lymphocyte ratio; SD, standard deviation; SEM, standard error of the mean. Before advocating the widespread routine use of systemic corticosteroids for DPP-4i-BP, we must consider the risk of potentially life-threatening adverse reactions associated with these agents. None disclosed.