Multiple courses of steroid pulse therapy are required in treating acquired idiopathic generalized anhidrosis patients with a large anhidrotic area: A retrospective study of 28 cases.

Patients with acquired idiopathic generalized anhidrosis (AIGA) demonstrate a sudden loss of sweating function without neurological or endocrine abnormalities. The main treatment is steroid pulse therapy. However, the number of courses required for improvement has been unclear. This study aims to clarify the factors associated with AIGA disease severity and with AIGA patients' responses to steroid pulse therapy. We retrospectively analysed the clinical information of 28 patients with AIGA in our department from the last 10 years. Univariate analysis revealed that patients with a large anhidrotic area need multiple courses of steroid pulse therapy.

Association of Genetic Variants of HLA-DQA1 with Bullous Pemphigoid Induced by Dipeptidyl Peptidase-4 Inhibitors.

Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Several factors, including an antidiabetic (dipeptidyl peptidase-4 inhibitor [DPP-4i]), have been reported to trigger BP. To identify the genetic variants associated with BP, GWAS and HLA fine-mapping analyses were conducted. The 21 cases of noninflammatory BP induced by DPP-4i (i.e., DPP-4i-induced noninflammatory BP) and 737 controls (first cohort) and the 8 cases and 164 controls (second cohort) were included in the GWAS. Combining GWAS satisfied the genome-wide significant association of HLA-DQA1 (chromosome 6, rs3129763 [T/C]) with the risk of DPP-4i-induced noninflammatory BP (allele T carrier of 72.4% [21 of 29] in cases vs. 15.3% [138 of 901] in controls; dominant model, OR = 14, P = 1.8 × 10-9). HLA fine mapping revealed that HLA-DQA1∗05 with serine at position 75 of HLA-DQα1 (Ser75) had the most significant association with the combined cohort of DPP-4i-induced noninflammatory BP (79.3% [23 of 29] cases vs. 16.1% [145 of 901] controls; dominant model, OR = 21, P = 2.0 × 10-10). HLA-DQα1 Ser75 polymorphism was located inside the functional pocket of HLA-DQ molecules, suggesting the impact of HLA-DQα1 Ser75 on DPP-4i-induced noninflammatory BP.

Clinical characteristics and outcomes of bullous pemphigoid patients with versus without oral prednisolone treatment.

Bullous pemphigoid (BP) varies in severity and stratified treatments are needed. However, there are no definitive standards for choosing appropriate treatments. To elucidate the factors involved in choosing treatments and the clinical outcomes of BP, we retrospectively reviewed the clinical records of 78 BP patients at a single center. Of the 78 patients, 49 (62.8%) were treated with oral prednisolone (PSL) and 29 (37.2%) were treated without PSL. The patients with older age, lower Bullous Pemphigoid Disease Area Index (BPDAI), and/or lower anti-BP180NC16a antibody titer at onset tended to be treated without oral PSL. Notably, only 9.1% patients without PSL experienced relapse, whereas 36.7% patients with oral PSL experienced relapse when the PSL was around 0.1 mg/kg. It suggests that the patients with mild disease severity could be well controlled without oral PSL. Receiver-operator curve analysis demonstrated that the cut-off value for the use of oral PSL was 31 for total BPDAI and was 7 for BPDAI skin urticaria/erythema, with a high (>0.9) area under the curve. Notably, none of the patients who were negative for the anti-BP180NC16a antibody at onset experienced relapse even though they were treated without PSL. In conclusion, in BP patients who were negative for anti-BP180NC16a antibody at onset, with a total BPDAI score of less than 31 or with an urticaria/erythema score of less than 7 can be treated without PSL. When the PSL is tapered to around 0.1 mg/kg, we should carefully monitor the patients to detect relapse.

Regulatory T cell subsets in bullous pemphigoid and dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid.

BACKGROUND: Regulatory T (Treg) cells play an essential role in peripheral immune tolerance. Bullous pemphigoid (BP) is the most common blistering disease and is caused by autoantibodies to two BP antigens: type XVII collagen and BP230. Recently, we reported that Treg cell dysfunction may cause the production of autoantibodies to BP antigens. Several studies have suggested an association between Treg cells and BP pathogenesis. However, Treg cells are heterogeneous in humans, leading to inconsistent results in previous studies. OBJECTIVE: To assess functional Treg subsets in BP. METHODS: We examined three distinct Treg subsets in conventional BP (cBP) patients before versus after systemic corticosteroid treatment, dipeptidyl peptidase-4 inhibitor-associated BP (DPP-4i-BP) patients, younger controls and older controls. RESULTS: We found that total Treg cells and all Treg cell subsets were increased in cBP patients before treatment and decreased by systemic corticosteroid treatment. In contrast, neither total Treg cells nor all Treg subsets were increased in DPP-4i-BP. Notably, CD45RA- Foxp3hi effector Treg cells positively correlated with disease severity in cBP, whereas CD45RA+Foxp3lo naïve Treg cells positively correlated with the disease severity in DPP-4i-BP. CONCLUSION: These findings suggest that Treg cells are differently involved in the pathogeneses of cBP and DPP-4i-BP.

Prevalence of infectious diseases in patients with autoimmune blistering diseases.

A long-term immunosuppressive treatment can provoke latent infections. Autoimmune blistering diseases (AIBD) are mostly treated with systemic immunosuppressive agents. To prevent the reactivation or exacerbation of existing latent infections, patients must be screened for infectious diseases before immunosuppressive treatments are initiated. However, the prevalence of infectious diseases in AIBD remains to be elucidated. To evaluate the necessity of screening infectious diseases in AIBD, we retrospectively reviewed the clinical records of 215 patients at a single center with AIBD for hepatitis B virus (HBV), hepatitis C virus (HCV), Mycobacterium tuberculosis, Treponema pallidum, human T-cell leukemia virus type 1 (HTLV-1) and HIV infections. Approximately 40% of patients were infected with HBV. During systemic corticosteroid treatment, HBV DNA became positive in 3.4% of cases. Antibodies to HCV, interferon-γ release assays for M. tuberculosis and the T. pallidum latex agglutination test were positive in 0.6%, 6.6% and 1.2% cases, respectively. Neither HTLV-1 nor HIV infections were detected. In conclusion, checks for HBV and M. tuberculosis infections should be made before immunosuppressive treatments are started, because of the high prevalence of these potentially life-threatening infections. Other infections should be tested for depending on the patient's risk factors.

Immune Reaction to Type XVII Collagen Induces Intramolecular and Intermolecular Epitope Spreading in Experimental Bullous Pemphigoid Models.

Bullous pemphigoid (BP), the most common autoimmune blistering disease, is induced by autoantibodies to type XVII collagen (COL17). Previous studies demonstrated that COL17 harbors several epitopes targeted by autoreactive T and B cells and that the target epitopes change sequentially during the disease course. To elucidate the details of the humoral immune response to COL17, we used an active BP mouse model in which BP is induced by the adoptive transfer of spleen cells from wild-type mice immunized with human COL17-expressing skin grafting to immunodeficient COL17-humanized (Rag-2-/-, mouse Col17-/-, human COL17+) mice. By immunoblot analysis, antibodies to the NC16A domain and other extracellular domains (ECDs) of COL17 were detected earlier than antibodies to intracellular domains (ICDs) in the active BP model. Time course analysis by enzyme-linked immunosorbent assay demonstrated a delayed peak of antibodies to ICD epitopes in active BP model. The blockade of CD40-CD40 ligand interaction soon after the adoptive transfer suppressed the production of antibodies to the non-collagenous 16A (NC16A) domain but not to an ICD epitope, suggesting the sequential activation from T and B cells against the ECD epitopes including the NC16A domain to those against ICD epitopes in vivo. Both wild-type mice immunized with a fragment of the NC16A domain and the recipients of those spleen cells produced IgG antibodies to ICD and ECD epitopes, showing intramolecular epitope spreading from the NC16A domain to other epitopes of COL17. Furthermore, we found that a portion of the active BP model mice show intermolecular epitope spreading from human COL17 to murine BP230. The appearance of antibodies to ICD epitopes of COL17 or of antibodies to murine BP230 did not correlate with the skin changes in the mice, suggesting that those antibodies have low pathogenicity. These results suggest that the immune response to the ECD epitopes of COL17, especially to the NC16A domain, triggers intramolecular, and intermolecular epitope spreading to ICD epitopes of COL17 and to murine BP230. These novel findings provide insight into the mechanism of epitope spreading in organ-specific, antibody-mediated autoimmune disorders.

Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects.

BACKGROUND: Regulatory T (Treg) cells play a crucial role in peripheral immune tolerance in multiple organs, including the skin. Thus far, the effect of peripheral immune tolerance failure on autoantibody-related autoimmune reactions to the skin is unclear. OBJECTIVE: We sought to elucidate the target autoantigens in the skin under the condition of Treg cell dysfunction caused by forkhead box P3 (Foxp3) gene mutations in scurfy mice and patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Sera and skin from scurfy mice and sera from patients with IPEX syndrome were analyzed to detect target autoantigens by using immunofluorescence studies, ELISAs, and immunoblotting. The pathogenicity of scurfy IgG was examined by using a passive transfer experiment. CD4+ T cells from scurfy mice were transferred to immunodeficient mice to examine their pathogenicity. Signal transducer and activator of transcription 6 (Stat6)-/- scurfy mice were analyzed to further clarify the molecular pathway of autoantibody production. Follicular helper T-cell counts are measured in Stat6-/- scurfy mice and scurfy mice. RESULTS: Scurfy mice spontaneously generated IgG autoantibodies to the dermal-epidermal junction, which had been class-switched from IgM within 12 days after birth. The target autoantigens were murine BP230 and type XVII collagen (COL17). The scurfy polyclonal autoantibodies did not induce skin fragility in neonatal mice. Autoantibody production was induced by CD4+ T cells from scurfy mice and was ameliorated by Stat6 gene knockout in association with a decrease of follicular helper T cells. We also identified autoantibodies to COL17 and BP230 in patients with IPEX syndrome and found an association between production of autoantibodies to COL17 and an eczematous skin phenotype. CONCLUSIONS: Dysregulation of Treg cells generates autoantibodies to COL17 and BP230 in vivo.

Portable negative-pressure wound therapy for pyoderma gangrenosum: Report of two cases.

Pyoderma gangrenosum is a chronic non-infectious neutrophilic dermatosis that causes undermining ulcers. Topical therapies for the deep ulcers of pyoderma gangrenosum have not been established. To investigate whether negative-pressure wound therapy is effective for a pyoderma gangrenosum ulcer, we used the PICO single use negative-pressure wound therapy system (Smith & Nephew, London, UK) for two pyoderma gangrenosum patients. In these cases, the ulcers decreased in size and necrolytic tissue was removed notably. Moreover, there were no secondary infections nor was there Koebner phenomena. Our cases suggest that portable negative-pressure wound therapy can be a treatment option for deep, intractable ulcers caused by pyoderma gangrenosum. Because portable negative-pressure wound therapy devices afford increased mobility to patients, they can give the patient a better quality of life than standard negative-pressure wound therapy systems do.