Analysis of clinical characteristics, prognosis and antibody pathogenicity of pemphigus patients positive for anti-desmoglein IgG autoantibodies in remission: a retrospective cohort study.

BACKGROUND: The detection of serum anti-desmoglein (Dsg) IgG autoantibodies has been reported to be useful for assessment of disease activity in pemphigus. However, previous studies have reported that anti-Dsg autoantibodies remain detectable in some patients without active pemphigus lesions. OBJECTIVES: To investigate the clinical characteristics and antibody pathogenicity of pemphigus patients positive for anti-Dsg IgG autoantibodies in remission. METHODS: We retrospectively investigated pemphigus patients with a history of clinical remission who visited the Department of Dermatology of Keio University during 2019 and 2020. The antibody pathogenicity was assessed by bead aggregation assay. RESULTS: When patients were recognized as having entered remission (PDAI = 0 and PSL ≦ 10 mg/day for 2 months), serum autoantibodies against Dsg were detected in 72 of 132 patients (54.5%, positive group; PG), but were not detected in 60 patients (45.5%, negative group; NG). Anti-Dsg antibody titres in remission declined from the active phase in 33 patients in the PG for whom data were available. There were no differences in the chance of reducing PSL to 5 mg/day (P = 0.885) and rate of relapse (P = 0.279) between PG and NG, but fewer patients in PG discontinued corticosteroids (P = 0.004). The ability of patients' sera to block aggregation of Dsg/desmocollin beads was significantly reduced in remission compared to the active phase. However, our results revealed that whole sera in remission still had pathogenic activity in seven of nine patients, and the approximately equal amounts of anti-Dsg antibodies in active phase and remission showed similar pathogenicity. CONCLUSIONS: This study will provide guidance in cases where autoantibodies are found to be positive in pemphigus patients during remission or steroid reduction.

Results of the guideline-based treatment for pemphigus: a single-centre experience with 84 cases.

BACKGROUND: The Japanese guidelines for the management of pemphigus (JG) were published in 2010. However, further progress in the treatment of pemphigus requires their validation. OBJECTIVES: To examine the efficacy and safety of treatments based on the JG. METHODS: A retrospective study of 84 Japanese patients with moderate to severe pemphigus, who were initially treated in accordance with the JG and then followed up for >2 years, was performed in a single centre. Treatment typically consisted of 0.5-1 mg prednisone (PSL)/kg/day accompanied by 100 mg azathioprine/day as a steroid-sparing agent. RESULTS: In 83 of the 84 patients (98.8%), complete remission on minimal therapy (≤10 mg PSL/day and concomitant immunosuppressive agent) was achieved. The time between initiation of therapy and remission was 13.9 ± 9.4 months. In 78 patients (92.9%), remission was accomplished within the 2-year follow-up. The 32 patients with recalcitrant disease (38.1%) received additional treatment. Relapse occurred in 12 patients (14.3%) either during tapering of the PSL dose (six patients) or after achieving remission (six patients). Adverse events, mostly liver enzyme elevation, infections and diabetes, occurred in 67 patients (79.8%). One patient (1.2%) died during the observation period after gastrointestinal haemorrhage. CONCLUSIONS: Our results suggested that the elderly and patients requiring additional therapies were at higher risk of adverse events, including severe infections, and should thus be monitored carefully. This study provided clinical data that could inform revised guidelines and contribute to the evaluation of future novel therapies.

Effects of Hydroxychloroquine in Patients With Cutaneous Lupus Erythematosus: A Multicenter, Double-Blind, Randomized, Parallel-Group Trial.

OBJECTIVE: To assess the efficacy and tolerability of hydroxychloroquine (HCQ) in patients with cutaneous lupus erythematosus (CLE), in a phase III clinical trial conducted in Japan. METHODS: We conducted a double-blind, randomized, parallel-group clinical trial. This was a baseline-controlled study, and the group differences were evaluated in an exploratory analysis. A total of 103 patients with active CLE (according to a Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI] activity score of ≥4) were included. Patients were randomized 3:1 to receive HCQ or placebo during the 16-week double-blind period, and all patients were given HCQ during the following 36-week single-blind period. The primary efficacy end point was a reduction in the CLASI activity score at week 16. The secondary end points included the central photo evaluation (5-point scale), patient's global assessment (7-point scale), the Skindex-29 score, and investigator's global assessment (7-point scale, based on the other 3 secondary end points). In patients with systemic lupus erythematosus, fatigue and musculoskeletal pain were assessed. Safety was assessed up to week 55. RESULTS: The mean CLASI score at week 16 was significantly improved from baseline in both the HCQ group and the placebo group: mean change -4.6 (95% confidence interval [95% CI] -6.1, -3.1) (P < 0.0001), and mean change -3.2 (95% CI -5.1, -1.3) (P = 0.002), respectively, without between-group difference (P = 0.197). The investigator's global assessment demonstrated a greater proportion of "improved" and "remarkably improved" patients in the HCQ group (51.4% versus 8.7% in the placebo group [P = 0.0002 between groups]). The other secondary end points supported the efficacy of HCQ. Cellulitis, drug eruption, hepatic dysfunction, and Stevens-Johnson syndrome were shown to be serious adverse events related to HCQ use. CONCLUSION: The results of this randomized clinical trial support the efficacy and tolerability of HCQ in patients with CLE.

Two cases of atretic cephalocele, and histological evaluation of skin appendages in the surrounding skin.

Atretic cephalocele is a small skin-covered lesion, usually located at or near the mid-line of the scalp. Histologically, it is composed of syncytial cells expressing neurone-specific enolase and epithelial membrane antigen. The syncytial cells form capillary-like structures *(pseudovascular areas) and collagenic fibrosis with densely packed collagen bundles (fibrous areas). Such findings suggest that the atretic cephalocele is a mild form of cephalocele, with its pathogenesis lying in the spectrum of neural tube closure abnormalities. However, few descriptions of abnormalities of the skin overlying and surrounding atretic cephalocele are available. We report two cases of atretic cephalocele that showed hamartomatous change in the surrounding cutaneous appendages. These findings suggest that atretic cephalocele is associated with abnormalities not only of the neural tube, but also of the surrounding skin.

Ehrlichia canis in dogs in a semiarid region of Northeastern Brazil: serology, molecular detection and associated factors.

This study investigated infection by Ehrlichia spp. agents by PCR, immunofluorescence assay test (IFAT), and by Giemsa-stained blood smears in 108 dogs from a semiarid region of the state of Paraíba, Northeastern Brazil. Seventy-five (69.4%) of the 108 dogs were found to be seropositive to Ehrlichia canis, while only four dogs (3.7%) were positive in real-time PCR for E. canis. In six dogs (5.6%) E. canis-like morulae were observed in monocytes. Animals that stayed in environment whose floor was dried dirt, and dogs whose owners reported low frequency of cleaning the dog environment had higher (P<0.05) PCR positivity for E. canis. Increasing seropositivity was found in older dogs (P=0.012). This study provides the first molecular detection of E. canis in the semiarid region of Northeastern Brazil.

Comparison of the reliability and validity of outcome instruments for cutaneous dermatomyositis.

BACKGROUND: Reliable and validated measures of skin disease severity are needed for cutaneous dermatomyositis (DM). Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Dermatomyositis Skin Severity Index (DSSI) and Cutaneous Assessment Tool (CAT) skin indices have been developed as outcome instruments. OBJECTIVES: We sought to demonstrate reliability and validity of the CDASI, and to compare the CDASI with other potential tools for use in measuring disease severity in cutaneous dermatomyositis. PATIENTS AND METHODS: CDASI has four activity and two damage measures, with scores from 0 to 148. DSSI assesses activity based on body surface area and severity on a scale of 0-72. CAT uses 21 activity and damage items, for a range of 0-175 for activity and 0-33 for damage. Ten dermatologists used the instruments to score the same 12-16 patients in one session. Global validation measures were administered to physicians and patients. RESULTS: Global validation measures correlated with the three outcome instruments (P < 0.0001). CAT displayed lower inter- and intrarater reliability relative to the CDASI. All scales correlate better with physician than patient global skin measures. CONCLUSIONS: It appears that the CDASI may be a useful outcome measure for studies of cutaneous DM. Further testing to compare responsiveness of all three measures is necessary.

Indeterminate cell histiocytosis successfully treated with ultraviolet B phototherapy.

Indeterminate cell histiocytosis (ICH) is a rare disorder, characterized by infiltration of the skin by neoplastic cells that are characteristically positive for S-100 and CD1a, but lack Birbeck's granules. A 75-year-old man presented with a 4-year history of multiple papules on the trunk, limbs, face and neck. Skin biopsy revealed dense infiltration of histiocytic cells that were CD1a+/S100+, but lacked Birbeck's granules. No other abnormality was seen during a general examination including a computed tomography scan of the body, gallium scintigraphy, and an abdominal sonography. Broadband ultraviolet B (UVB) treatment was used for the skin lesions, and partial but almost complete remission was obtained. The case suggests that UVB phototherapy is an option for treatment of ICH.

Evaluating efficacy of plasmapheresis for patients with pemphigus using desmoglein enzyme-linked immunosorbent assay.

BACKGROUND: Pemphigus is an autoimmune bullous disease caused by circulating IgG autoantibodies against cell-cell adhesion molecules between keratinocytes: desmoglein (Dsg) 3 and Dsg1. Plasmapheresis is often used to treat severe cases of pemphigus. Enzyme-linked immunosorbent assays (ELISAs) against recombinant Dsg3 and Dsg1 have recently become available, allowing us to quantify IgG autoantibodies against Dsg3 and Dsg1. OBJECTIVES: Using ELISA against recombinant Dsg3 and Dsg1, to evaluate the efficacy of plasmapheresis in pemphigus. METHODS: Sera obtained from 10 patients with pemphigus vulgaris and one with pemphigus foliaceus following a total of 16 cycles of centrifugal plasmapheresis and 12 effluents from the plasmapheresis were subjected to ELISA against Dsgs. The percentage of IgG autoantibodies removed was calculated using two different formulae: one used serum titres before and immediately after plasmapheresis and the other used the absolute amounts of IgG autoantibodies in the effluents. The percentage fall of anti-Dsg antibody level was also calculated using the serum titres 1 day after plasmapheresis. RESULTS: Using serum titres immediately after plasmapheresis, there was a mean fall per treatment in anti-Dsg 3 antibody level of 43.0% (n = 12) and in anti-Dsg1 antibody level of 48.4% (n = 7). By contrast, calculated from the effluents, on average one treatment removed only 14.6% of anti-Dsg3 antibodies (n = 12) and 16.4% of anti-Dsg1 antibodies (n = 7). This should reflect the correct percentage as it is based on the absolute amounts of IgG autoantibodies removed. Using serum titres 1 day after plasmapheresis, there was a mean fall per treatment in anti-Dsg 3 antibody level of 12.9% (n = 2) and in anti-Dsg1 antibody level of 8.4% (n = 4). The percentage of IgG autoantibodies removed 1 day after plasmapheresis was lower than that found to be removed immediately after plasmapheresis (n = 6). CONCLUSIONS: One centrifugal plasmapheresis procedure eliminates about 15% of the IgG autoantibodies from the whole body. The percentage fall of anti-Dsg IgG antibody level differed depending on when the serum samples were obtained after plasmapheresis. The change in the percentage fall of anti-Dsg antibody level within 1 day after plasmapheresis is thought to be attributable to the passive diffusion of the IgG autoantibodies from the extravascular space to the intravascular space. Therefore, removal of IgG autoantibodies calculated using serum titres only should be evaluated carefully considering the equilibration of the IgG autoantibodies between the different body spaces.

Aleukaemic leukaemia cutis as an initial manifestation of myeloid/NK cell precursor acute leukaemia.

Aleukaemic leukaemia cutis is a rare condition characterized by infiltration of leukaemic cells into the skin before they appear in the peripheral blood. We report a case of an aleukaemic leukaemia cutis, which had a history of exposure to atomic bomb radiation. A 57-year-old Japanese woman initially presented with a 20-week history of multiple red papules and plaques mainly over the trunk. Histological examination revealed the infiltration of atypical monocytic cells in the dermis, but no leukaemic cells were detected in the peripheral blood. Twenty-three weeks after the appearance of the eruption, leukaemic cells were detected in the peripheral blood for the first time. The results of immunohistochemistry of the skin biopsy specimen and flow cytometry of the peripheral blood indicated the rare phenotype of myeloid/NK cell precursor acute leukaemia. This is the first case report of myeloid/NK cell precursor acute leukaemia presenting as aleukaemic leukaemia cutis in the English literature, and awareness of this clinical presentation may be important to reach the correct diagnosis.

A case of drug-induced hypersensitivity syndrome showing transient immunosuppression before viral reactivation during treatment for pemphigus foliaceus.

Drug-induced hypersensitivity syndrome (DIHS) is one of the most severe drug adverse reactions, with characteristic biphasic symptoms. Reactivation of human herpesvirus-6 (HHV-6) is frequently observed, although the cause of DIHS is still unknown. A patient developed DIHS during treatment with diaminodiphenylsulphone for pemphigus foliaceus. The number of lymphocytes in his peripheral blood, and titres of serum total IgG and IgM and anti-desmoglein1 antibody transiently decreased just before reactivation of HHV-6, cytomegalovirus and Epstein-Barr virus. This observation suggests that transient suppression of both cellular and humoral immunity may trigger viral reactivation, which leads to the development of the second phase of DIHS.

Decline of anti-desmoglein 1 IgG ELISA scores by withdrawal of D-penicillamine in drug-induced pemphigus foliaceus.

A case of pemphigus foliaceus arising during the administration of D-penicillamine was reported. A 72-year-old woman with systemic sclerosis developed flaccid vesicles and crusted erythema of the skin after administration of D-penicillamine for 1-year. She was positive for anti-desmoglein 1 IgG by ELISA. The withdrawal of D-penicillamine resulted in improvement of the skin lesions and ELISA scores for anti-demoglein 1 antibodies revealed a surprisingly rapid decline. This case is a classical incidence of drug-induced pemphigus foliaceus, in which D-penicillamine was constantly required not only to induce, but also to maintain the production of the autoantibodies.

Parallel fluctuation of anti-desmoglein 3 and anti-BP180 autoantibody titres in a patient with bullous pemphigoid.

We report a 73-year-old Japanese female who developed IgG autoantibodies against BP180 as well as desmoglein 3 (Dsg3). She showed tense blisters on the extremities without apparent mucosal involvement and a skin biopsy indicated subepidermal blisters with eosinophilic spongiosis. Her clinical and histologic features indicated the diagnosis of bullous pemphigoid while anti-Dsg3 IgG might not show an apparent pathogenic effect. Interestingly, titres of anti-Dsg3 IgG fluctuated in parallel with those of anti-BP180 IgG throughout the course with two flares. Although the exact mechanism for autoantibody production is still unknown, the close link in the production of IgG autoantibodies against two independent skin antigens suggests a shared immunoregulatory mechanism against cutaneous autoantigens.

Monitoring disease activity in pemphigus with enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3.

BACKGROUND: Pemphigus is an antidesmoglein (Dsg) autoimmune disease that is divided into two major subtypes: pemphigus foliaceus (PF) and pemphigus vulgaris (PV). We previously developed enzyme-linked immunosorbent assays (ELISAs) using recombinant Dsg1 and Dsg3 to detect IgG autoantibodies in patients with pemphigus. The protocol for the ELISAs was optimized for serological diagnosis, but under the conditions used, these assays were not particularly useful for monitoring disease activity in certain patients. That is, the sera from some patients with high-titre antibodies continued to show high index values in the ELISA after clinical improvement. OBJECTIVES: In the study reported here, we modified the ELISA protocol to obtain 'true' index values that exhibit a better correlation with disease activity. METHODS: We tested two cases of pemphigus foliaceus (PF) and four cases of pemphigus vulgaris (PV), each with ELISA index values greater than 150 for Dsg1 or Dsg3. We ran an ELISA with sera from these patients serially diluted from 1 : 100 to 1 : 12,800. We then performed ELISA with a series of PV No. 1 sera diluted to 1 : 800 and PV No. 2-4 and PF No. 1-2 sera diluted to 1 : 1600, after which we plotted the ELISA index values against the time course of disease activity. RESULTS: In each of these cases, there was no apparent decline, over the course of the disease activity, in the ELISA index values at a serum dilution of 1 : 100, probably because the antigen-antibody reaction was saturated at that dilution. After running an ELISA with sera serially diluted from 1 : 100 to 1 : 12,800 we found that a linear dose-dependency between the dilution value and the index value was only observed when sera were diluted to 1 : 800 or more in one case (PV No.1) and to 1 : 1600 or more in the other five cases (PV No. 2-4, PF No. 1-2). After performing ELISA with these series as outlined above we plotted the ELISA index values against the time course of disease activity and found that the index values obtained from these appropriately diluted sera fluctuated in parallel with disease activity, and declined with clinical improvement. CONCLUSIONS: These findings indicate that when appropriate dilutions are used in Dsg1 and Dsg3 ELISA, these assays can provide useful serological information for assessing disease activity in PF and PV.

A contact lens electrode with built-in high intensity white light-emitting diodes. A contact lens electrode with built-in white LEDs.

We determined the clinical usefulness of a new contact lens electrode with built-in, white light-emitting diodes (LEDs) for full-field electroretinograms (ERGs). Three, high-brightness white LEDs were incorporated into a contact lens electrode and served as the source for the stimulus and the background. The stimulus intensity, stimulus duration and background illumination were regulated by a small LED control device. Maximum stimulus and background intensities were 3.9 and 3.6 log cd/m2, respectively. We successfully recorded intensity-response series for scotopic and photopic ERGs. We also recorded a duration-series for photopic ERGs, and ERGs that were comparable to the ISCEV standardized ERGs. The compactness and ease of using this system suggest that it will be clinically useful under different conditions.

Multifocal ERG findings in complete type congenital stationary night blindness.

PURPOSE: To study the multifocal electroretinogram (mfERG) in patients with the complete type of congenital stationary night blindness (cCSNB), which is thought to be due to a defect in neurotransmission from the photoreceptors to the ON-bipolar cells. METHODS: mfERGs were recorded with the VERIS recording system from four patients with cCSNB, none of whom had nystagmus. The stimulus array consisted of 61 hexagons, and the total recording time was approximately 4 minutes. The amplitudes and implicit times of the first- and second-order kernels of the local responses were compared with those from 20 myopic controls. Waveforms of the summed response from all locations were also compared between the two groups. RESULTS: The first-order kernels of the mfERGs of cCSNB patients had normal amplitudes but delayed implicit times for nearly the whole field tested. The second-order kernel was severely attenuated in amplitude in cCSNB patients. The ratios of the second- to first-order kernel amplitudes were significantly reduced in cCSNB and clearly separated the cCSNB group from the control group without any overlap of the values. CONCLUSIONS: The second-order kernel, which is involved in adaptative mechanism of the retina to repeated flashes, is selectively reduced in cCSNB. The delay of the implicit times of the first-order kernel in patients with cCSNB may be related to the severe amplitude reduction of the second-order kernel.

Eosinophilic pustular folliculitis (Ofuji's disease): indomethacin as a first choice of treatment.

Eosinophilic pustular folliculitis (EPF) is characterized by erythematous patches of large follicular papules and pustules involving mainly the face. Although various treatments have been attempted for EPF, including systemic and topical steroid, diaphenylsulphone, colchicine, minocycline as well as UVB phototherapy, there is no consensus on the first choice of treatment. We report a typical case and summarize 25 patients with EPF treated in our hospital between 1978 and 1998. Indomethacin was most frequently used (12/25) and showed clinical improvement in the majority of the cases (11/12). The effect of indomethacin was usually observed within 1--2 weeks after initiation of treatment. Decrease of peripheral blood eosinophils accompanied the clinical improvement. Thus, indomethacin should be considered as a first choice of treatment for EPF.

Whole-genome effects of ethyl methanesulfonate-induced mutation on nine quantitative traits in outbred Drosophila melanogaster.

We induced mutations in Drosophila melanogaster males by treating them with 21.2 mm ethyl methanesulfonate (EMS). Nine quantitative traits (developmental time, viability, fecundity, longevity, metabolic rate, motility, body weight, and abdominal and sternopleural bristle numbers) were measured in outbred heterozygous F3 (viability) or F2 (all other traits) offspring from the treated males. The mean values of the first four traits, which are all directly related to the life history, were substantially affected by EMS mutagenesis: the developmental time increased while viability, fecundity, and longevity declined. In contrast, the mean values of the other five traits were not significantly affected. Rates of recessive X-linked lethals and of recessive mutations at several loci affecting eye color imply that our EMS treatment was equivalent to approximately 100 generations of spontaneous mutation. If so, our data imply that one generation of spontaneous mutation increases the developmental time by 0.09% at 20 degrees and by 0.04% at 25 degrees, and reduces viability under harsh conditions, fecundity, and longevity by 1.35, 0.21, and 0.08%, respectively. Comparison of flies with none, one, and two grandfathers (or greatgrandfathers, in the case of viability) treated with EMS did not reveal any significant epistasis among the induced mutations.