Jun Yamagami

Autoantibody Profile Differentiates between Inflammatory and Noninflammatory Bullous Pemphigoid

Bullous pemphigoid (BP) is a major autoimmune blistering skin disorder, in which a majority of the autoantibodies (autoAbs) target the juxtamembranous extracellular noncollagenous 16A domain (NC16A) domain of hemidesmosomal collagen XVII. BP-autoAbs may target regions of collagen XVII other than the NC16A domain; however, correlations between epitopes of BP-autoAbs and clinical features have not been fully elucidated. To address correlations between the clinical features and specific epitopes of BP-autoAbs, we evaluated the epitope profiles of BP-autoAbs in 121 patients. A total of 87 patients showed a typical inflammatory phenotype with erythema and autoAbs targeting the anti-NC16A domain, whereas 14 patients showed a distinct noninflammatory phenotype, in which autoAbs specifically targeted the midportion of collagen XVII, but not NC16A. Interestingly, this group clinically showed significantly reduced erythema associated with scant lesional infiltration of eosinophils. Surprisingly, 7 of the 14 cases (50.0%) received dipeptidyl peptidase-IV inhibitors for the treatment of diabetes. Dipeptidyl peptidase-IV inhibitors were used in 3 of 76 (3.9%) typical cases of BP with autoAbs targeting NC16A; thus, dipeptidyl peptidase-IV inhibitors are thought to be involved in the development of atypical noninflammatory BP. This study shows that the autoAb profile differentiates between inflammatory and noninflammatory BP, and that noninflammatory BP may be associated with dipeptidyl peptidase-IV inhibitors.

Anti‐desmoglein IgG autoantibodies in patients with pemphigus in remission

Background  Desmoglein (Dsg) enzyme‐linked immunosorbent assay (ELISA) is a highly sensitive and specific method to detect anti‐Dsg3 and anti‐Dsg1 IgG autoantibodies in pemphigus vulgaris (PV) and pemphigus foliaceus (PF), respectively. Whereas ELISA index values fluctuate in parallel with disease activity, ELISA positivity during clinical remission has been observed.

A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.

BACKGROUND Patients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. OBJECTIVE A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/kg/day) administered. METHODS We evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57days as secondary endpoints. RESULTS We enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p=0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p=0.041). Furthermore, when analyzed only in severe cases (DAS≥40), the DAS15 differed significantly (p=0.046). The anti-BP180 antibody titers showed no difference between the two groups. CONCLUSION IVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

Unilateral bullous pemphigoid without erythema and eosinophil infiltration in a hemiplegic patient

In this report, we describe an 88‐year‐old male stroke patient with unilateral bullous pemphigoid limited to the hemiplegic side. Physical examinations revealed multiple tense bullae with clear and/or bloody contents without apparent erythema on the right thigh and lower leg, accompanied by erosions on the right chest. Histopathologically, no eosinophils were infiltrated into and around the subepidermal bullae. Immunofluorescence revealed deposited and circulating immunoglobulin (Ig)G anti‐basement membrane zone antibodies. Immunoblot assays using various antigen sources and enzyme‐linked immunosorbent assay revealed that IgG antibodies in this case reacted with unique epitopes between NC16a and C‐terminal domains on the 120‐kDa LAD‐1, the extracellular truncated form of BP180. Three observations were unique in our case. First, the distribution of bullae in our patient was limited to the hemiplegic side. Second, there was no apparent erythema clinically and no eosinophilic infiltration histopathologically. Third, the patient achieved remission without the use of oral corticosteroids. The unusual epitopes in this case may contribute to these phenomena.

Pathogenic Anti-Desmoglein 3 mAbs Cloned from a Paraneoplastic Pemphigus Patient by Phage Display

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease associated with lymphoproliferative neoplasms and characterized by antibodies against plakins and desmoglein 3 (Dsg3). Anti-Dsg3 antibodies have a primary role in blister formation in PNP. In this study, we used phage display to clone monoclonal anti-Dsg3 antibodies from a PNP patient to further characterize their pathogenicity. We isolated 20 unique Dsg3-reactive mAbs, which we classified into four groups according to the heavy-chain complementarity-determining region 3 (CDR3) region. Genetic analyses demonstrated that three antibody groups used the VH1-46 gene (18 clones) and one group used the VH1-02 gene (2 clones). The results of an in vitro keratinocyte dissociation assay and a human skin organ culture injection assay showed that three antibodies displayed pathogenic activity in blister formation with different potencies. Epitope mapping using domain-swapped Dsg3/Dsg2 showed that these pathogenic mAbs bound Ca(2+)-dependent conformational epitopes in the middle portion of the extracellular region of Dsg3 (EC2 and EC3 domains), in contrast to most previously characterized pathogenic pemphigus vulgaris antibodies, which bound to the EC1 domain of Dsg3. These mAbs reflect the unique polyclonal nature of anti-Dsg3 antibodies in PNP and represent an important tool for detailing the pathophysiological mechanisms of blister formation in PNP.

Grading criteria for disease severity by pemphigus disease area index.

Pemphigus is a group of autoimmune blistering diseases that affect the skin and mucous membranes. A reliable and accurate disease severity tool to assess pemphigus severity is crucial for managing pemphigus and for clinical trials. The purpose of this study was to compare the pemphigus disease area index activity score (PDAI), the Japanese pemphigus disease severity score (JPDSS) and the physicians subjective impression, and also to find appropriate severity grading cut‐offs for the PDAI. We also evaluated the correlation between PDAI activity score and the JPDSS. Thirty‐seven pemphigus patients and 110 assessments were analyzed in this study. The optimal points of pemphigus disease severity score in PDAI were: mild (0–8), moderate (9–24) and severe (≥25). In mild or moderate cases, the JPDSS was well correlated with the PDAI, but in severe cases the JPDSS reached a plateau at a PDAI score of approximately 30. The PDAI evaluates disease severity more accurately than the JPDSS, particularly in severe cases. The PDAI is not only a useful tool to measure the extent of cutaneous lesions, but also an excellent scoring system for evaluating pemphigus disease severity.

Alopecia as a rare but distinct manifestation of pemphigus vulgaris.

Background  Pemphigus vulgaris (PV) patients may develop scalp erosions, however, the development of alopecia has been reported to be extremely rare.

CD52 is not a promising immunotherapy target for most patients with multiple myeloma

The aim of our study was to evaluate CD52 as a target molecule for antibody therapy for multiple myeloma. Twenty consecutive bone marrow samples from myeloma patients were studied by flow cytometry using antibodies against CD45, CD38, CD138, CD3, CD19, and CD52. Most myeloma cells did not express CD52; CD52 expression was found only in a small subpopulation of plasma cells with a CD45+CD38++ phenotype. In contrast, the major fraction of myeloma cells (CD45–CD38++) was CD52−.Treatment of myeloma patients with anti—CD52 antibodies with the aim to reduce the number of myeloma cells in the CD45+CD38++ subfraction, which possibly contains a proliferative progenitor cell pool, would be at best a highly experimental approach.We conclude that CD52 is not a promising target for antibody—based therapies for most patients with multiple myeloma.The aim of our study was to evaluate CD52 as a target molecule for antibody therapy for multiple myeloma. Twenty consecutive bone marrow samples from myeloma patients were studied by flow cytometry using antibodies against CD45, CD38, CD138, CD3, CD19, and CD52. Most myeloma cells did not express CD52; CD52 expression was found only in a small subpopulation of plasma cells with a CD45+CD38++ phenotype. In contrast, the major fraction of myeloma cells (CD45–CD38++) was CD52−.Treatment of myeloma patients with anti—CD52 antibodies with the aim to reduce the number of myeloma cells in the CD45+CD38++ subfraction, which possibly contains a proliferative progenitor cell pool, would be at best a highly experimental approach.We conclude that CD52 is not a promising target for antibody—based therapies for most patients with multiple myeloma.

Low pathogenicity of anti-desmoglein 3 immunoglobulin G autoantibodies contributes to the atypical clinical phenotypes in pemphigus.

The clinical phenotypes of pemphigus can be explained by the desmoglein (Dsg) compensation theory. However, some atypical cases such as cutaneous pemphigus vulgaris (cPV), in which patients have anti‐Dsg3 antibodies without oral erosions, do not conform to this theory. To explain the discrepancy between clinical phenotypes and anti‐Dsg antibody profiles, the pathogenic strength of immunoglobulin (Ig)G autoantibodies against Dsg3 must be taken into consideration. We analyzed the epitopes and blister‐inducing pathogenic strength of the sera from three patients having IgG against Dsg3 without oral erosions with domain‐swapped recombinant proteins and dissociation assay using cultured normal human epidermal keratinocytes. The results showed that all sera contained IgG directed against the amino terminal EC1 domain of Dsg3, as is found in most PV sera. However, dissociation assays revealed that the pathogenic strength of the anti‐Dsg3 antibodies in all three cases was extremely lower than that of typical PV cases with mucosal involvement. In conclusion, when anti‐Dsg3 IgG antibodies are not sufficient to inhibit the expression of Dsg3 in the oral mucosa, but can inhibit the expression in the skin, skin blisters can result. Therefore, the pathogenicity of anti‐Dsg3 antibodies should be regarded as a key factor contributing to the clinical phenotype in pemphigus patients with conflicting antibody profiles.

Cicatricial Pemphigoid of the Oropharynx after Allogeneic Stem Cell Transplantation for Relapsed Follicular Lymphoma

A 44-year-old woman with refractory follicular lymphoma underwent allogeneic stem cell transplantation (SCT) and achieved complete remission. Grade III acute graft-versus-host disease (GVHD) developed on day 23, but no chronic GVHD occurred. The patient developed severe erosion with bullous lesions in the oral cavity 18 months after SCT. At that time, the lymphoma remained in complete remission, and she had no clinical or laboratory findings suggesting chronic GVHD. A biopsy of the oral mucosa showed moderate lymphoplasmacytic infiltration and subepidermal bullae, and direct immunofluorescence staining demonstrated linear deposition of C3 at the dermo-epidermal junction. An immunoblotting assay using human epidermal extracts confirmed the presence in her serum of an antibody against the 230-kd bullous pemphigoid antigen 1 (BPAG1). A diagnosis of cicatricial pemphigoid (CP) was made, and complete resolution of the CP was achieved with pred-nisolone therapy. The occurrence of autoimmune blistering diseases is rare after allogeneic SCT.