Unmasking latent extrapulmonary tuberculosis with newly diagnosed HIV-1 infection in a COVID-19 patient with prolonged fever.

Prolonged fever is a common symptom of COVID-19 infection. However, other febrile diseases continue during the pandemic. Herein, we report a COVID-19-infected patient with prolonged fever despite the lack of oxygen requirement, who was finally diagnosed with tuberculotic lymphadenitis and HIV-1 infection. All symptoms improved rapidly after the initiation of antituberculosis medications. Tuberculosis is an important differential diagnosis for patients with prolonged fever during the COVID-19 pandemic. It is possible that COVID-19 infection could serve to unmask latent infections via a cytokine storm.

Efficacy and safety of a combination regimen of phenothrin and ivermectin lotion in patients with head lice in Okinawa, Japan.

In Japan, pyrethroid-resistant head lice have been increasing; however, only 0.4% phenothrin, a pyrethroid drug, is available as an over the counter formulation. In recent years, Sumithrin® Lotion containing 5% phenothrin (PHT) was approved for scabies. In the USA, Sklice® Lotion containing 0.5% ivermectin (IVM) is used for the treatment of pyrethroid-resistant head lice. Therefore, to enhance the treatment of head lice in Japan, we conducted a clinical study to confirm the efficacy and safety of a combination regimen of PHT and IVM (PI regimen). Twelve cases were enrolled and PHT was applied to all patients on day 1. On day 8, five patients (41.7%) were lice free, and PHT was applied again. Notably, seven patients were not lice free and were switched to IVM. The rate of patients who were lice free on the PI regimen, which was the primary end-point, was 75.0% on day 15 and 91.7% on day 22. No adverse events were reported. A genetic analysis of the head lice collected at each visit revealed a kdr mutation in all patients. These results suggest that the PI regimen is safe and effective for the treatment of pyrethroid-resistant head lice in Japan.

Severer lupus erythematosus-like skin lesions in MRL/lpr mice with homozygous Kitwsh/wsh mutation.

OBJECTIVE: To clarify the roles of mast cells (MCs) on the pathogenesis of lupus erythematosus (LE)-like skin lesions on MRL/lpr mice. METHODS: MRL/lpr mice were mated with C57BL/6-Kitwsh/wsh mice and the heterozygous F1 mice were 10 times backcrossed with the parental MRL/lpr to generate MRL/lpr-Kitwsh/wsh mice. MC-deficient MRL/lpr-Kitwsh/wsh mice were compared with MRL/lpr-Kit+/+ and MRL/lpr-Kitwsh/+ mice with intact MCs. RESULTS: MRL/lpr-Kitwsh/wsh mice developed skin lesions without infiltrating MCs. As similar skin lesions on MRL/lpr-Kit+/+ mice and MRL/lpr-Kitwsh/+ mice contain comparable number of MCs, these mice were collectively analyzed as MRL/lpr mice with MCs. Compared with MRL/lpr mice with MCs, skin lesions developed earlier and showed consistently higher severity, with significantly higher mRNA expressions of many inflammatory cytokines in the dorsal skin on MRL/lpr mice without MCs. Furthermore, survival rate was significantly lower in MRL/lpr mice without MCs. The number of infiltrating MCs significantly increased in association with the severity of skin lesions in MRL/lpr mice with MCs. CONCLUSIONS: These results demonstrated that MCs are infiltrated to suppress the progression of LE-like skin lesions in MRL/lpr mice.

Pharmacokinetics of ivermectin applied topically by whole-body bathing method in healthy volunteers.

As a novel administration method of ivermectin (IVM) for scabies treatment, we proposed a "whole-body bathing method (WBBM)". In this method, the patients would bathe themselves in a bathing fluid containing IVM at an effective concentration. Previously, we demonstrated that WBBM could deliver IVM to the skin but not to the plasma in rats. In the present study, to assess the clinical validity of the method an arm bathing examination (first trial) and a whole-body bathing examination (second trial) were conducted in healthy volunteers. In both the first and second trials, after bathing in fluid containing IVM, the exposure in the stratum corneum was higher compared with that after taking IVM p.o. as reported previously. IVM was not detected in plasma at any sampling point after the whole-body bathing in the second trial. Furthermore no serious adverse events were found. These results in both trials suggest that WBBM can deliver IVM to the human stratum corneum without systemic exposure or serious adverse effects in healthy volunteers, and at concentrations that would be adequate for scabies treatment.

Multiple courses of pulse corticosteroid therapy for alopecia areata.

Various systemic corticosteroid therapies are used for alopecia areata (AA). Pulse therapy using methylprednisolone is a treatment approach for AA. The efficacy of multiple courses of pulse therapy for various severities of AA was evaluated. AA patients with less than 50% hair loss, less than or equal to 6 months after AA onset, needed 1.9 courses of pulse therapy for vellus hair to develop. On the other hand, AA patients with more than 50% hair loss, less than 6 months after AA onset, needed more courses of pulse therapy for vellus hair to develop. Regardless of the disease duration, AA patients with less than 50% hair loss showed a good response rate (100%) after both a short period and a long period after therapy. After receiving multiple courses of pulse therapy, the AA patients with more than 50% hair loss also showed improvement with limited adverse reactions.

Modified immunotherapy for alopecia areata.

Squaric acid dibutylester (SADBE) is a commonly used contact sensitizer in immunotherapy for alopecia areata (AA). Severe contact dermatitis is induced by the currently high recommended sensitization dose of 1%-2% SADBE, often decreasing patient compliance. We assessed a modified immunotherapy for AA using SADBE at a starting concentration of 0.01% without sensitization. After one or two weeks of initial 0.01% SADBE application, the concentration of SADBE was increased gradually to 0.025%, 0.05%, 0.1%, 0.25%, 0.5%, 1% and 2% until the patients felt itching or erythema at the AA lesion site. The modified immunotherapy showed a response rate of 69.4% (25/36), equivalent to conventional immunotherapy using SADBE starting at 1%-2% sensitization. Furthermore, we investigated the combination therapy of SADBE and multiple courses of steroid pulses for AA. The response rate for combination therapy was 73.7% (28/38); however, the group receiving combination therapy showed a significant prevalence of severe AA compared with the group receiving modified immunotherapy only. We reviewed the efficacy and safety of modified immunotherapy without initial sensitization and combination therapy with immunotherapy and multiple courses of pulses for AA.

A novel immunopathological association of IgG4-RD and vasculitis with Hashimoto's thyroiditis.

UNLABELLED: A 73-year-old man with Hashimoto's thyroiditis (HT) suffered from purpura on the lower legs. He was diagnosed with IgG4-related disease (IgG4-RD) with serum IgG4 elevation and dacryo-sialadenitis confirmed histologically. Serum Th2 and Treg cytokines, interleukin 7 (IL7), IL8 and Th2 chemokine levels were elevated, while skewed Th1 balance was seen in fluorescence-activated cell sorting (FACS). Therefore, preferential Th1 balance in HT appeared to be followed by IgG4-RD characterized with Th2 and Treg polarization. The commencement of steroid therapy dramatically exacerbated clinical manifestations including IgG4-RD-associated HT. The measurement of cytokine and chemokine levels as well as FACS analysis in the development of IgG4-RD seemed to be beneficial. In conclusion, an innovative association of HT, IgG4-RD and vasculitis was observed. This report also offers novel diagnostic and therapeutic approaches for IgG4-RD. LEARNING POINTS: Recently, a subtype of HT has been considered to be a thyroid manifestation of IgG4-RD, although the etiology of IgG4-RD is not established yet.Immunologically a close association between HT and vasculitis was reported.Leukocytoclastic vasculitis is a rare skin presentation of IgG4-RD.In the current case, during the course of HT, IgG4-RD and leukocytoclastic vasculitis occurred; thus, innate immunity and acquired immunity seem to be involved in the development of IgG4-RD.The measurement of cytokine and chemokines appeared to be beneficial in the development of IgG4-RD.Remarkably, effectiveness of steroid therapy for HT suggested presence of IgG4-RD-associated HT. Therefore, this report highlights the pathogenesis of IgG4-RD and proposes novel therapeutic mechanisms. Clinicians should pay attention to the development of IgG4-RD and vasculitis during long course of HT.

Effect of high-fat meal intake on the pharmacokinetic profile of ivermectin in Japanese patients with scabies.

Ivermectin (IVM) is used as an anthelmintic agent in many countries. To evaluate the effect of high-fat (HF) meal intake on the pharmacokinetics of IVM, a clinical trial was conducted in Japanese patients with scabies. The patients were administrated Stromectol(®) tablets in the fasted state, and after 1 week they were also administrated it after a HF meal (fed state). After the administration, IVM concentrations in plasma and the stratum corneum were determined. The geometric mean of fed/fasted ratio of area under IVM concentration-time curve (AUC) in plasma was 1.25 (90% confidence interval, 1.09-1.43), suggesting the tendency to increased absorption after a HF meal. The fed/fasted ratio of the maximum IVM concentration in the stratum corneum was well correlated with that in plasma. In addition, no serious adverse events were observed during the trial, while a mild increase of aspartate aminotransferase and alanine aminotransferase activity in plasma was observed under the fed state in two patients. The mean AUC of IVM in plasma of those two patients were approximately threefold higher than that of the other patients at that time. On the other hand, the treatment success rate was 76.9% at 7 days after the second administration, which was comparable with the expected level. The present study not only demonstrates that HF meal intake increases the IVM concentration in plasma and the stratum corneum in Japanese patients with scabies, but also suggests the possibility that HF meals increase the risk of hepatic dysfunction by the increased exposure of IVM.

Experimental study of pharmacokinetics of external, whole-body bathing application of ivermectin.

As a novel method improving the safety of conventional oral ivermectin (IVM) for scabies treatment, we conceived an idea called the "whole-body bathing method". In this method, the patients would bathe themselves in a bathing fluid containing IVM at an effective concentration. To evaluate the feasibility of the method, we investigated the IVM concentration in the skin and plasma after bathing rats in a fluid containing 100 ng/mL of IVM. After the bathing, the concentration of IVM in the skin was more than 400 ng/g wet weight and was maintained until 8 h after the bathing. The concentration was clearly higher than that in patients taking IVM p.o. as previously reported; IVM was not detected in plasma in the present study. Thus, the method would be a preferable drug delivery system for the skin application of IVM compared with p.o. administration.

Efficacy of 0.1% adapalene in a non-inflammatory Kyoto Rhino Rat acne model.

BACKGROUND: Acne vulgaris is a disorder of the pilosebaceous unit of the skin, and the underlying mechanism is still obscure. Kyoto rhino (krh/krh) rats were made by ethylnitrosourea (ENU) mutagenesis and harbor S413X nonsense mutation of the rat hairless (Hr) gene. Krh/krh rats develop comedones with hair loss on their back as they grow. OBJECTIVE: Our purpose is to assess whether or not the krh/krh rat is a suitable model of non-inflammatory acne, and to investigate the comedolytic effects of adapalene in krh/krh rats. METHODS: Krh/krh rats at 12weeks of age were topically treated with adapalene or a vehicle 6 times a week, for 12weeks. Skin lesions were clinically investigated and skin samples were obtained from treated skins from each animal after 6 and 12weeks of treatments. RESULTS: Comedone was clinically enlarged in the control group compared with the adapalene group. The adapalene group showed significantly increased epidermal thickness as compared to the control group. Furthermore, open comedone areas were also significantly decreased in the adapalene group as compared to the control group. The adapalene group also showed reduced lipid production in open comedones as compared to the control group. Cytokine productions including IL-10 and IL-12a tended to increase in skin treated with adapalene as compared to the control group. CONCLUSION: Krh/krh rats represented a new model for non-inflammatory acne with abnormalities in both hair follicles and sebaceous glands. It is hypothesized that adapalene is a superior drug to decrease open comedones by modifying lipid metaboism and cytokine production in krh/krh rats.

Eradication therapy for urticaria with high titers of anti H. pylori IgG antibody.

BACKGROUND: It is known that idiopathic chronic urticaria occasionally develops with Helicobacter pylori (H. pylori) infection, but the association between urticaria and H. pylori remains unknown. METHODS: We focused on the relationship between the titer of anti H. pylori IgG antibodies and urticaria. Sixty-five patients with idiopathic urticaria were divided into 3 groups by a difference of their titers. All patients in the high titer (≥40U/ml) group underwent endoscopy of the upper gastrointestinal tract with antral biopsy for the Rapid Urease Test (RUT) or a culture test. We investigated the relationship between the efficacy of eradication therapy against H. pylori and urticaria. RESULTS: The positive rate for H. pylori was 100% (20/20) by RUT or culture test in the high titer group. A CR using antihistamines alone was 0% (0/20) in the high titer group, 27.2% (3/11) in the low titer group and 38.2% (13/34) in the negative group respectively. A CR or PR using antihistamines was 70% (14/20) in the high titer group, 81.8% (9/11) in the low titer group and 97.1% (33/34) in the negative group. After successful eradication therapy, the CR was increased to 56% (9/16) in the high titer group. CONCLUSIONS: Regardless of acute or chronic urticaria, a high titer of anti H. pylori IgG antibody can be an indicator for undergoing upper endoscopy, and eradication therapy is strongly recommended. It will be necessary to develop diagnostic criteria for urticaria associated with H. pylori.

Effects of sarpogrelate hydrochloride on skin ulcers and quality of life in patients with systemic sclerosis.

5-Hydroxytryptamine 2A serotonin receptor (5-HT(2A) ) is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Sarpogrelate hydrochloride (sarpogrelate) is a selective 5-HT(2A) antagonist and was supposed to be effective for Raynaud's phenomenon with collagen disease. Sarpogrelate has not been investigated regarding the effects, safety and quality of life (QOL) in patient with skin ulcers of collagen disease. Eleven patients with skin ulcers and systemic sclerosis (SSc) were administrated sarpogrelate p.o. three times a day for 3-6 months. The area (mean ± standard error) of skin ulcer at the pretreatment, and after 3 and 6 months of sarpogrelate intake was 2.1 ± 0.8, 0.2 ± 0.1 and 0.1 ± 0.1 mm(2), respectively. The reduction of skin ulcer area was significant after 3 months of sarpogrelate intake. In assessment of QOL, scores of symptoms and emotions but not of functioning were significantly improved after sarpogrelate intake. The global score (mean ± SE) of Skindex-16 at pretreatment, and after 3 and 6 months of sarpogrelate intake was 31.8 ± 8.7, 23.7 ± 8.3 and 10.9 ± 4.6, respectively. The score was significantly improved after 6 months of sarpogrelate intake. There were no obvious side-effects during this study. Sarpogrelate was considered to be a useful drug to improve skin ulcers and QOL in patients with SSc.

Identification of 736T>A mutation of lipase H in Japanese siblings with autosomal recessive woolly hair.

Woolly hair is characterized by fine and tightly curled hair. It has recently been revealed that both LPAR6 and lipase H (LIPH) mutations cause autosomal recessive woolly hair (ARWH)/hypotrichosis. This notion has provided critical evidence to the concept that LPA6 activation by LIPH-catalyzed lipid mediator lysophosphatidic acid has a key role in regulation of hair follicle development. Very recently, novel mutations in exon 6, homozygous 736T>A and compound heterozygous 736T>A and 742C>A have been identified in Japanese ARWH/hypotrichosis patients. Here, we report on siblings (a 7-year-old Japanese girl and her 5-year-old brother) both showing woolly hair. Determination of their genomic sequence showed presence of a homozygous 736T>A transition in exon 6 of the LIPH gene changing cysteine at position 246 to serine, without any mutation in the LPAR6 gene. Additionally, the same mutation was found in one out of a 100 alleles of Japanese healthy controls and identified homozygously in three out of four other Japanese sporadic cases with woolly hair. Collectively, it has been suggested that 736T>A transition is highly specific and common in ARWH/hypotrichosis of Japanese origin.

[Pathogenesis of cutaneous lupus erythematosus from LE-prone mice].

Mouse models are similar but not identical to human diseases. However, they are important for research into the pathogenesis underlying autoimmune diseases because they allow us to evaluate similarities and differences between human diseases and mouse models. There are many inbred strains of systemic lupus erythematosus (SLE)-prone mice including New Zealand Black (NZB), F1 hybrids of NZB x New Zealand White (NZW) (B/W F1), MRL/Mp-lpr/lpr (MRL/lpr), and BXSB mice. The postulated etiology of these murine diseases includes many genetic and extrinsic factors such as retroviruses, an impaired balance of T cell interaction, ultraviolet irradiation, etc. For examples, genetic studies of MRL/lpr mice revealed that the appearance of macroscopic LE-like skin lesions needs the lpr mutation plus an additional factor in an autosomal dominant fashion. The candidate is ultraviolet (UV) B light, the susceptibility to which is regulated by the genetic background. Such abnormalities described in SLE now span the spectrum from innate immunity to acquired immunity. In this review, based on historical review, we focus on skin lesions from the well-studied MRL/lpr and B/W F1 mouse and discuss how SLE-prone mice can contribute to a better understanding of cutaneous LE pathogenesis.

The protective effects of ultraviolet A1 irradiation on spontaneous lupus erythematosus-like skin lesions in MRL/lpr mice.

We investigated the effects of ultraviolet A1 (UVA1) irradiation on spontaneous lupus erythematosus- (LE-) like skin lesions of MRL/lpr mice, using a disease prevention model. UVA1 irradiation significantly inhibited the development of LE-like skin lesions, without obvious changes of the disease including renal disease and serum antinuclear antibody levels. Besides the massive infiltration of mast cells in the LE-like skin lesions, in the nonlesional skins, more mast cells infiltrated in the UVA1-irradiated group compared with the nonirradiated group. Although apoptotic cells were remarkably seen in the dermis of UVA1-irradiated mice, those cells were hardly detectable in the dermis of the nonirradiated mice without skin lesions. Further analysis showed that some of those apoptotic cells were mast cells. Thus, UVA1 might exert its effects, at least in part, through the induction of the apoptosis of pathogenic mast cells. Our results supported the clinical efficacy of UVA1 irradiation for skin lesions of lupus patients.

Mast cells and histamine metabolism in skin lesions from MRL/MP-lpr/lpr mice.

It is likely that mast cell and histamine metabolism are involved in autoimmune tissue injury such as cutaneous lupus erythematosus (LE) because different histamine receptors can regulate Th1 and Th2 cells. In order to verify the role of the axis of mast cell-histamine metabolism-histamine receptor, the autoimmune mouse has been investigated. The MRL/Mp-lpr/lpr (MRL/lpr) mouse is a good model for the spontaneous development of skin lesions similar to those seen in human LE. In skin lesions from MRL/l mice, there are many infiltrating T cells and mast cells in the dermis and impaired histamine metabolism, in which the low activity of histamine-N-methyltransferase and the related prolonged effects of histamine in the skin tissue seem to play a definite pathological role in the development of spontaneous lupus-like eruptions. The expression of H2R on the mast cell decreases within these skin lesions at 5 months of age. It is interesting that the activity of HMT runs in parallel with the expression of H2R over the time course of the skin changes in MRL/l mice, but the relationship between these two observations remains obscure. The accumulation of mast cells expressing H2R and prolonged effects of histamine may occur to regulate the production of Th1 and Th2 cytokines in the skin lesions of MRL/l mice.

Animal models of spontaneous and drug-induced cutaneous lupus erythematosus.

Skin lesions are one of the most common manifestations of lupus erythematosus (LE) disorders such as systemic LE and discoid LE. The etiology of cutaneous LE is not fully understood. To address this issue, appropriate animal models frequently clarify the etiology and pathogenesis of autoimmune diseases, although no single animal model perfectly mimics a human disease. A common dermatological finding in many SLE-prone mouse strains is the deposition of immunoglobulins at the dermoepidermal junction. Over the past decade, the most exciting and important finding has been the discovery of the Fas-defect in the pathogenesis of the autoimmune MRL/lpr mouse, which is a good model for the spontaneous development of skin lesions similar to those seen in human LE. The analysis of MRL/lpr mice showed a close association between immunoglobulin deposits and the appearance of skin lesions. Transgenic and knock out mice have advanced the investigation of cutaneous LE. Furthermore, the model of drug-induced cutaneous LE can yield additional insight since the trigger is clear in drug-induced LE. Cutaneous LE lesions can also be induced in TCRalpha-/- mice treated with fluorouracil and ultraviolet B light irradiation. Studies on both spontaneous and experimental models will elucidate the pathogenesis of complicated and multifactorial cutaneous LE.

Comparison of anti 60 and 52 kDa SS-A/Ro antibodies in the pathogenesis of cutaneous lupus erythematosus.

Anti SS-A/Ro antibodies are involved in the pathogenesis of cutaneous lupus erythematosus (CLE) in a part through antibody dependent cellular cytotoxicity (ADCC). However, it is still obscure which and how anti 60 and anti 52 kDa Ro antibodies are involved. To address the issue, we examined both types of anti Ro antibodies of sera from patients with systemic LE (SLE) or discoid LE (LE). The titer of anti 60 kDa antibody in SLE was significantly much higher than that of DLE or control. The positive ratio of DLE showed more higher tendency than control, but it was not statistically significant. The similar tendency was observed in the titer of anti 52 kDa antibody. An association between the anti 60 kDa antibody and the anti 52 kDa antibody was statistically significant in SLE patients. Although the relative index (RI) was statistically significant in DLE, they included many negative sera, which biased the statistics. Both anti 60 kDa antibody and anti 52 kDa antibody could induce significant ADCC of ultraviolet B (UVB) light-irradiated keratinocytes from neonatal foreskins and/or normal adults, in which anti 60 kDa antibody showed higher cytotoxicity than anti 52 kDa antibody. The autologous combination studies (keratinocytes and monospecific anti 60 or anti 52 kDa antibody from patients) suggested anti 60 kDa antibody was more potent to induce ADCC activity than anti 52 kDa antibody. Taken together, it is likely that anti 60 kDa antibody dependent keratinocyte damage plays more significant role in the pathogenesis of SLE skin lesions than anti 52 kDa dependent damage. However, both type antibodies seemed to have little contribution to the pathogenesis of DLE skin lesion.