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Key Clinical Message While the initial lesions of tinea capitis are often overlooked due to their small size and numerous hairs emerging from the follicle, it is crucial not to dismiss the partial presence of comma or harpin hairs and black spots.

Tumors developed in 2 old women presented with pathological findings similar to seborrheic keratosis, although the clinical feature of tumor showed typical keratoacanthoma. In addition to these two cases, we compared the pathological findings of a total of four cases, one case each of keratoacanthoma and seborrheic keratosis, which were clinically and histopathological typical. These two cases and the typical keratoacanthoma showed cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and infiltration of cytotoxic T cells. The keratoacanthoma in the decompensated stage may be histologically similar to seborrheic keratosis. TUNEL staining can help in the diagnosis of fading keratoacanthoma.

A 91-year-old woman visited our department with scattered small nodule lesions and multiple pules or plaques with a stuck-on appearance. The lesions were intractable and resistant to several treatments. Immunodeficiency was excluded by examinations including a CT scan, white blood cell (WBC) counts, natural killer and neutrophil function assays, and IgG titers against human papillomavirus (HPV) 20. HPV20 was identified using the PCR method. The finding of the skin biopsy showed an irritated type of feature of seborrheic keratosis. Additionally, immunohistochemical staining of the lesion revealed that both TNF-α and IFN-ɤ were produced at the skin lesions. The patient‘s serum zinc level was slightly low. We noticed that zinc deficiency has been reported to decrease the cytotoxic activity of natural killer cells, which play an important role in eliminating virus-infected cells and tumor cells. Finally, zinc oxide ointment was found to improve the lesions dramatically. HPV20 causes tumors only in immunodeficient patients or in patients with epidermodysplasia verruciformis (EV). In EV, EVER1- or EVER2-encoding membrane proteins, of which are related to zinc transport protein-1 expressed on the membrane of the endoplasmic reticulum, were mutated, leading to increased susceptibility to various viral and bacterial infections due to the decreased intracellular zinc concentration. We speculated that the reduction in local zinc concentration was ameliorated by using zinc oxide ointment, resulting in the recovery from HPV20 infection.

Key Clinical Message IL‐36 might play a role as an initial immune mechanism against chikungunya fever, and regulating IL‐36 production could be a potential treatment approach for this condition. Abstract Two Japanese siblings visited Cook Islands in 2015 and developed Chikungunya fever upon their return. The sister experienced high fever, joint pain, and leg swelling, while the brother had joint pain and a rash. Both siblings had a confirmed CHIKV infection and continued to experience prolonged joint pain, with the sister enduring chronic pain for about a year. In this study, the levels of IL‐36 in the serum of two siblings who were infected with chikungunya fever during the acute and recovery phases were compared using ELISA. IL‐36 is a cytokine that induces inflammation and is produced by cells in tissues such as the skin and mucosa. It was hypothesized that IL‐36 may be involved in persistent joint pain after chikungunya fever infection. Both siblings experienced long‐lasting joint pain after chikungunya fever infection. The levels of IL‐36α and IL‐36β decreased by 56 days after infection. In the results, IL‐36 plays an important role in host immunity and may act as part of the immune response during chikungunya virus infection. Inhibiting the release of IL‐36 could be a promising approach for developing new treatment methods for chikungunya fever.

Key Clinical message A patient with eosinophilic granulomatosis with polyangiitis, who was well‐controlled by pharmacotherapy, developed a psoriasis‐like rash due to a local infection. It represents the consequence of an immunologic imbalance. Abstract A 48‐year‐old woman was diagnosed with eosinophilic granulomatosis with polyangiitis and treated with mepolizumab. While on treatment, she developed a psoriasis‐like rash on her lower legs following a local ear infection. The rash promptly disappeared after the ear infection cleared and did not recur. The psoriasis‐like rash that appeared was pathologically similar to psoriasis. Excessive production of inflammatory cytokines by the immune system is believed to be involved in the pathogenesis of psoriasis vulgaris. These cytokines are known to induce inflammatory responses and promote epidermal cell proliferation. It is possible that mepolizumab treatment suppressed Th2‐type cytokines, while the local ear infection temporarily induced a strong Th1‐type immunity. This immunologic imbalance may have led to the development of a psoriasis‐like rash.

Key Clinical Message After the infection with COVID‐19, pyoderma gangrenosum worsened and further led to necrosis following pyogenic osteomyelitis. Infection is a major exacerbating factor in pyoderma gangrenosum.

A 76-year-old Japanese man presented with a 6-year history of a sore throat. He was treated at several clinics without any improvement before being referred to us. Physical examination revealed widespread erosions and ulcers from the palate to the larynx. Approximately 25 × 15 mm in size, erosive lesions were present on the retroauricular regions, forearms, and glans penis. Pseudomembranous conjunctivitis was also observed. The skin biopsy revealed a partial cleft formation below the epidermis, suggesting subepidermal bullous disease. Immuno-serological tests were negative for anti-desmoglein 1 (Dsg1), anti-Dsg3, anti-BP180, and anti-BP230 antibodies by ELISAs. A whole-body examination revealed gastric cancer. The possibility of mucous membrane pemphigoid (MMP) or paraneoplastic pemphigus (PNP) was considered. Indirect immunofluorescence using rat bladders showed positive IgG reactivity with cell surfaces on the transitional epithelia. Immunoblotting using recombinant proteins of laminin-332 showed both IgG and IgA reactivities with laminin-α3, and immunoblotting using normal human epidermal extract showed double-positive reactivities with envoplakin and periplakin for both IgG and IgA antibodies. Based on the clinical and histopathological features and results of various immuno-serological tests, our case was diagnosed as anti-laminin-332-type MMP with serological findings of PNP. Twenty days after laparoscopic gastrectomy, treatment with oral methylprednisolone 32 mg/day was initiated, and mucosal and skin lesions improved.

Papuloerythroderma is an erythroderma characterized by the composition of dense paving stone shape papules and intertriginous uninvolved skin on the abdominal wall and is often intractable and accompanied by itching. Topical or oral corticosteroids are treatment measures, but immunosuppressive drugs are sometimes required. Herein, we report a case of papuloerythroderma treated with dupilumab, a completely humanized immunoglobulin monoclonal antibody against interleukin-4 receptor subunit α (IL-4Rα) of IL-4 and IL-13 receptors, with rapid and marked improvement. Dupilumab is one of the treatment options to treat refractory papuloerythroderma.

Eccrine angiomatous hamartoma (EAH) is a relatively rare benign skin disease characterized by the proliferation of eccrine sweat glands associated with capillary hemangioma and the proliferation of other skin elements such as adipose tissue, hair, and epidermis. The onset of the disease is usually at birth or in childhood and tends to occur in the extremities of females, but it occurred in an adult male in this case. The patient was a 72-year-old man with a 12 × 12 mm light brown, elastic, slightly firm skin nodule on the flexor aspect of his right forearm. A biopsy revealed enlargement of blood vessels, sweat glands, sweat ducts, and erector spongiosum with both lumen dilation and narrowing, leading to the diagnosis of EAH. The histopathological features of EAH include a marked proliferation of microvessels, epithelial-like changes in vascular endothelial cells (such as enlarged nuclei), and infiltration of inflammatory cells, mainly lymphocytes and plasma cells. In adult-onset cases, EAH can be clinically difficult to distinguish from epithelioid hemangioma (EH), which differs in the predominance of microvascular proliferation and the presence of eosinophils in the infiltrating inflammatory cells. It can also be distinguished from EAH by the negative results of S100 and anti-EMA in immunohistological staining. In the current cases, we were able to differentiate the two cases from characteristic findings on HE staining.

We present a case of extramammary Paget’s disease with bilateral inguinal lymph node metastasis treated by monthly docetaxel chemotherapy. He has also well-controlled psoriasis vulgaris for 20 years. One day after completing monthly chemotherapy, cellulitis by Group G Streptococcus occurred on both legs, resulting in septic shock and disseminated intravascular coagulation. During the infection, the tumor nodule volume and the exudate from the tumor decreased, and tumor markers carcinoembryonic antigen and cancer antigen 19-9 showed low values. Simultaneously, the psoriatic eruption reoccurred. We proposed that cytokine storm including tumor necrosis factor-alpha (TNF-α) during sepsis might have suppressed tumor lesions, and also TNF-α-dependent psoriatic rash appeared temporarily on his body.

A 70-year-old healthy woman was referred to our hospital for chronic urticaria. She did not have a history of allergy, asthma, and rhinitis. She was initially diagnosed with α-gal-related urticaria based on an episode of delayed-type urticaria after eating red meat. The results of the intracutaneous allergen test for beef and pork were negative. Fluorenzyme immunoassays specific for IgE against α-gal, beef, and pork were also negative. She was diagnosed with an α-gal-unrelated red meat allergy following the reproduction of urticaria by a food challenge test. The patient was unresponsive to several drugs, including antihistamines or immunosuppressants. However, omalizumab administration suppressed her symptoms. Key Clinical Message: The diagnosis of red meat allergy may require a repeatability test by consuming red meat even though serum α-gal IgE antibody might be negative. The α-gal-unrelated red meat urticaria may be responsive to omalizumab.

Abstract A man with pityriasis rubra pilaris (PRP) showed no improvement in skin symptoms despite treatment with several drugs. The patient was diagnosed as having type 1 PRP. Combination therapy with cyclosporine and guselkumab improved his skin condition. Here, we propose a novel therapeutic strategy for intractable PRP.

A male infant had the very fragile skin and easily formed bullas by rubbing and scratching from his birth. He was diagnosed with severe recessive dystrophic epidermolysis bullosa (RDEB) due to the lack of type VII collagen by performing an immunofluorescence mapping method from a skin biopsy specimen of the patient’s bulla. We analyzed the skin microbiome using next-generation sequencer. The species from the patient’s skin revealed the dominance of Staphylococcus aureus (S. aureus) similar to the reports from Austria and Chile severe RDEB patients, and these results are same as the pattern isolated from the skin of atopic dermatitis (AD) patients with flares. The interaction of microbiome and skin microenvironment may be similar between RDEB and AD worldwide.

Lymphocytic infiltration of the skin (LIS), first reported by Jessner and Kanof in 1953, is a disease of unknown etiology characterized by erythematous papules and plaques on the head, neck, and upper back and histopathological findings of a normal epidermis with underlying lymphocytic infiltration of the reticular dermis without mucin deposition. A 69-year-old man and a 21-year-old woman presented with edematous indurative erythema of the left upper eyelid. Lymphocytic infiltration of the dermis with CD4+ T cell predominance was noted on biopsy. A 68-year-old man presented with a four-year history of recurrent edematous indurative erythema of the right upper eyelid that extended up to the right cheek. Predominantly dermal infiltration of CD8+ T lymphocytes was found on biopsy. We treated all three patients with 8–16 mg of methylprednisolone daily, and the erythema and induration improved. CD4+ T cells were predominant in the acute phase (patients 1 and 2), whereas CD8+ T cells were predominant in the chronic phase (patient 3). CD8+ T cells may be involved in LIS recurrence. Lymphocytic infiltration of the eyelid may be associated with isolated circumscribed, edematous, indurative, colorless lesions that are responsive to daily low-to-middle doses of oral methylprednisolone.

Here, we report two cases of cutaneous adverse effects possibly induced by the use of tumor necrosis factor-alpha (TNF-α) inhibitors. The first case presented alopecia areata (AA) and atopic dermatitis (AD) that developed during the treatment of ulcerative colitis using infliximab; the other case presented urticaria and AD that developed during the treatment of rheumatoid arthritis using etanercept. AA, AD, and urticaria are relatively common skin diseases; however, they are not well known as adverse effects of TNF-α inhibitors. Although immunological studies were not performed, the clinical courses suggested that these skin disorders might have developed as a result of an immune four-way imbalance in T helper 1 (Th1), Th2, Th17, and regulatory T cells by the administration of TNF-α inhibitors.

The skin is one of the major immune organs producing large amounts of proinflammatory and inflammatory cytokines in response to internal or exogenous stimuli, inducing systemic inflammation in various internal organs. In recent years, organ damage associated with inflammatory skin diseases such as psoriasis and atopic dermatitis has received increasing attention, and vascular disorder such as arteriosclerosis is one of the serious complications of chronic inflammatory skin diseases. However, the detailed mechanism of arteriosclerosis in dermatitis and the role of cytokines have not been clarified so far. In the current study, using a spontaneous dermatitis model, we investigated the pathophysiology of arteriosclerosis and the treatment option for inflammatory skin conditions. We employed spontaneous dermatitis model mice overexpressing human caspase-1 in the epidermal keratinocyte (Kcasp1Tg). The thoracic and abdominal aorta was investigated histologically. GeneChip and RT-PCR analysis were performed to measure the changes in mRNA levels in the aorta. To elucidate the direct effect on the artery by major inflammatory cytokines, endothelial cells, vascular smooth muscle cells, and fibroblast cells were co-cultured with several cytokines, and mRNA expression levels were measured. In order to observe the efficacy of IL-17A/F in arteriosclerosis, cross-mating with IL-17A, IL-17F, and IL-17A/F deficient mice was performed. Finally, we also measured snap tension in the abdominal aorta in WT, Kcasp1Tg, and IL17A/F-deficient mice. Kcasp1Tg showed a decrease in the diameter of the abdominal aorta compared to wild-type mice. mRNA levels for six genes including Apol11b, Camp, Chil3, S100a8, S100a9, and Spta1 were increased in the abdominal aorta of Kcasp1Tg. Some of the above mRNA levels were also increased in the co-culture with major inflammatory cytokines, IL-17A/F, IL-1β, and TNF-α. Dermatitis improved and mRNA levels were partially ameliorated in Kcasp1Tg with IL-17A/F deletion. Arterial fragility was also evidenced in the inflammatory model, but arterial flexibility was revealed in the IL-17A/F deletion model. Severe dermatitis is closely related to secondary arteriosclerosis caused by the persistent release of inflammatory cytokines. The results also proved that treatment against IL-17A and F may ameliorate arteriosclerosis.

Intense itching significantly reduces the quality of life, and atopic dermatitis is associated with psychiatric conditions, such as anxiety and depression. Psoriasis, another inflammatory skin disease, is often complicated by psychiatric symptoms, including depression; however, the pathogenesis of these mediating factors is poorly understood. This study used a spontaneous dermatitis mouse model (KCASP1Tg) and evaluated the psychiatric symptoms. We also used Janus kinase (JAK) inhibitors to manage the behaviors. Gene expression analysis and RT-PCR of the cerebral cortex of KCASP1Tg and wild-type (WT) mice were performed to examine differences in mRNA expression. KCASP1Tg mice had lower activity, higher anxiety-like behavior, and abnormal behavior. The mRNA expression of S100a8 and Lipocalin 2 (Lcn2) in the brain regions was higher in KCASP1Tg mice. Furthermore, IL-1β stimulation increased Lcn2 mRNA expression in astrocyte cultures. KCASP1Tg mice had predominantly elevated plasma Lcn2 compared to WT mice, which improved with JAK inhibition, but behavioral abnormalities in KCASP1Tg mice did not improve, despite JAK inhibition. In summary, our data revealed that Lcn2 is closely associated with anxiety symptoms, but the anxiety and depression symptoms caused by chronic skin inflammation may be irreversible. This study demonstrated that active control of skin inflammation is essential for preventing anxiety.

We report a case of pruritic urticarial papules and plaques of pregnancy (PUPPP) starting with target lesions on both forearms at the end of second pregnancy. The patient’s target lesions became generalized itchy edematous eczema lesions especially on her abdomen extended by pregnancy, which immediately disappeared postpartum. The mechanism PUPPP has not been elucidated so far; however, the typical target lesion was the initial phenotype in the current case. To approach the pathophysiology of PUPPP, we examined the cytokine profile in the patient’s serum before and after delivery. The upregulated Th2 cytokine profile including IL-9 and IL-33, and the reaction against skin-resident bacteria and fungus might be involved in PUPPP.

(1) Background. Rickettsia japonica (R. japonica) infection induces severe inflammation, and the disappearance of eosinophil in the acute stage is one of the phenomena. (2) Materials and Methods. In the current study, we measured the serum concentrations of Th1, Th2, and Th17 cytokines in the acute and recovery stages. (3) Results. In the acute phase, IL-6 and IFN-γ levels were elevated and we speculated that they played a role as a defense mechanism against R. japonica. The high concentration of IFN-γ suppressed the differentiation of eosinophil and induced apoptosis of eosinophil, leading to the disappearance of eosinophil. On day 7, IL-6 and IFN-γ concentrations were decreased, and Th2 cytokines such as IL-5 and IL-9 were slightly increased. On day 14, eosinophil count recovered to the normal level. The transition of serum cytokine concentration in R. japonica infection was presented. (4) Conclusions. IL-6 and IFN-γ seem to be critical cytokines as defense mechanism against R. japonica in the acute phase, and this may deeply connect to the decrease of eosinophil.

Atopic dermatitis (AD) is classified as a type 2 disease owing to the majority of type 2 lymphocytes that constitute the skin-infiltrating leukocytes. However, all of the type 1–3 lymphocytes intermingle in inflamed skin lesions. Here, using an AD mouse model where caspase-1 was specifically amplified under keratin-14 induction, we analyzed the sequential changes in type 1–3 inflammatory cytokines in lymphocytes purified from the cervical lymph nodes. Cells were cultured and stained for CD4, CD8, and γδTCR, followed by intracellular cytokines. Cytokine production in innate lymphocyte cells (ILCs) and the protein expression of type 2 cytokine IL-17E (IL-25) were investigated. We observed that, as inflammation progresses, the cytokine-producing T cells increased and abundant IL-13 but low levels of IL-4 are produced in CD4-positive T cells and ILCs. TNF-α and IFN-γ levels increased continuously. The total number of T cells and ILCs peaked at 4 months and decreased in the chronic phase. In addition, IL-25 may be simultaneously produced by IL-17F-producing cells. IL-25-producing cells increased in a time-dependent manner during the chronic phase and may work specifically for the prolongation of type 2 inflammation. Altogether, these findings suggest that inhibition of IL-25 may be a potential target in the treatment of inflammation.

Abstract Previously positive lymphocyte transformation test (LTT) results changed to negative during influenza infection. As observed in the current article, results of LTT may be influenced by infection; therefore, it is crucial to consider the timing of LTT.

Abstract Determining whether the treatment intensity needs to be increased or can be maintained at a constant level may be suggested after 2–4 weeks of treatment. The use of TNF‐α inhibitor, removal of necrotic tissue, and skin grafting may promote epithelialization.

Abstract The administration of glucocorticoid and hydroxychloroquine (HCQ) may be able to control systemic lupus erythematosus (SLE) activities under COVID‐19 infection by suppress the cytokine storm.

We present a case of psoriasiform dermatitis developing during the treatment of juvenile idiopathic arthritis with tocilizumab (TCZ). The keratotic erythema with central healing showed a periodicity of growing worse 1 week after TCZ infusion, and then disappeared within 3 weeks. Skin biopsy showed parakeratosis, microabscess, rete ridge elongation, and abundant lymphocytes as well as a few neutrophil infiltrate in the upper dermis. TCZ is a humanized monoclonal antibody against interleukin 6 (IL-6) receptor. IL-6 plays a critical role in the differentiation from naïve T cells into Th17 cells in cooperation with transforming growth factor-β. IL-6 may be important in psoriasis pathogenesis, and therefore this phenomenon may be the adverse effect. The mechanism of TCZ-associated psoriasiform dermatitis is unclear. The serum IL-6 level seems to be elevated transitorily after TCZ administration, probably due to the competitive inhibition of IL-6 receptor alpha to IL-6. Excess free IL-6 may effect on other IL-6 family receptors. Since TCZ does not alter serum IL-17F level, another cytokine may be involved in the psoriasis formation in our case. Psoriasiform dermatitis during the use of TCZ may be due to relative cytokine balance disturbance.

We report two cases of alopecia diffusa during the treatment of psoriasis vulgaris with interleukin (IL)-17 inhibitors. Psoriasis is one of the most common immune-mediated chronic skin diseases, strongly associated with IL-17A. Clinically, the monoclonal antibodies to IL-17A or its receptor, IL-17R, show a dramatic effect against psoriasis. Alopecia is also an IL-17-mediated autoimmune disease, and IL-17 inhibitors have been expected to be the gold standard for the treatment of alopecia; therefore, the complication of alopecia while using IL-17 may be regarded as an unexpected “paradoxical reaction.” T helper (Th)17 cells are not cytotoxic enough by themselves to undermine the hair follicle under normal circumstances, they need the coexistence of CD8+ cytotoxic Th1 cells. Th17 cells may be the initiator of the damage of the hair follicle, but CD8 T cells or more powerful Th1 cells are required as followers. The Th17/Th1 axis might convert into a Th1-dominant immune status using IL-17 inhibitors, and the destruction of the hair follicle might result in alopecia. An accumulation of cases is to be expected.

Ten years ago, a 56-year-old woman with a history of IgA nephropathy who received a living-donor kidney transplant across ABO barriers was managed with immunosuppressive drugs. The kidney transplant donor was her father who had poor kidney function. The patient’s renal function was stable for 10 years. The patient visited our department with a complaint of skin rash, occurring 2 days after an onset of fever. Although a skin rash is atypical for Japanese spotted fever (JSF), we suspected JSF and started treatment with minocycline because we found a scar suggestive of an eschar. Furthermore, the blood test results were similar to those associated with JSF, and the patient lived in a JSF-endemic area. The patient’s symptoms improved after 1 week. She was diagnosed with JSF by serological tests against Rickettsia japonica. JSF usually does not cause any complications after recovery. However, the patient’s renal function did not completely recover. JSF can cause an atypical rash in patients taking excessive immunosuppressive drugs. Early treatment is required for patients with suspected JSF to prevent complications of renal dysfunction after receiving a living-donor kidney transplant.

Systemic amyloidosis is recognized as a serious complication of rheumatoid arthritis or inflammatory bowel disease, but also of inflammatory skin disease. However, the detailed molecular mechanism of amyloidosis associated with cutaneous inflammation remains unclear, and therapeutic approaches are limited. Here, we investigated the pathophysiology of amyloidosis secondary to cutaneous inflammation and the therapeutic effects of Janus kinase (JAK) inhibitors by examining a mouse model of spontaneous dermatitis (KCASP1Tg mice). Moreover, KCASP1Tg mice were crossed with interleukin-17A (IL-17A) knockout mice to generate IL-17A-/KCASP1Tg and examine the role of IL-17A in amyloidosis under cutaneous inflammation. KCASP1Tg mice showed severe amyloid deposition in the liver and spleen. Increased serum-neutral fat levels and decreased lymphocyte production were observed in the spleen. Overproduction of amyloidosis was partially ameliorated by the administration of JAK inhibitors and was further improved in IL-17A-/KCASP1Tg mice. IL-17A-producing cells included CD4, gamma delta, and CD8 T cells. In summary, our results from the analysis of a mouse model of dermatitis revealed that skin-derived inflammatory cytokines can induce amyloid deposition in the liver and spleen, and that the administration of JAK inhibitors and, even more, IL-17A ablation, reduced amyloidosis. This study demonstrates that active control of skin inflammation is essential to prevent internal organ amyloidosis.

Verruca vulgaris is an infectious disease caused by the human papillomavirus and characterized by hyperkeratotic papules or plaques with a clear boundary. Seborrheic keratosis is a commonly encountered lesion on the face, trunk, or extremities and is described as seborrheic verruca because of its clinical similarity to warts; furthermore, it is occasionally associated with immune suppression, especially in cases of Leser-trélat syndrome. Although these diseases are frequently found in healthy individuals, they typically show a good response to cryotherapy. However, cases in immunosuppressed patients are intractable to therapy. Overall immune status is evaluated via complete blood count (CBC); however, white blood count does not show the exact immune ability, and NK cell activity is often decreased in cases of malignancy. Here, we present two cases of exacerbated verruca vulgaris and seborrheic verruca observed in patients with malignancy. Although the patients seemed to be in good condition and had a normal CBC, immunosuppression was suspected based on the degree of skin rashes. NK cell activity was decreased in both patients, and both cases had malignancy. The measurement of NK cell activity may be a useful approach to evaluate immune status.

Malnutrition is not only regarded as a complication of rheumatoid arthritis and inflammatory bowel disease but also that of inflammatory skin disease; however, the mechanisms and efficacy of its treatment have not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of malnutrition in inflammatory skin conditions and efficacy of its treatment. We employed spontaneous skin inflammation mice models overexpressing human caspase-1 in the epidermal keratinocytes. Body weight, nutrition level, and α1-antitrypsin fecal concentration were measured. The gastrointestinal tract was histologically and functionally investigated. Fluorescein isothiocyanate (FITC)-dextran was forcibly fed on an empty stomach, and plasma FITC-dextran was measured. The treatment efficacy of antibodies against tumor necrosis factor-α (TNF-α) and interleukin (IL)-α/β as well as Janus kinase (JAK) inhibitors was investigated. Compared with wild-type littermates, the inflammatory skin mice models showed a lowered body weight, reduction of serum albumin level, amyloid deposition in the stomach, small intestine, and large intestine, and increased α1-antitrypsin fecal concentration. However, the plasma FITC-dextran was unchanged between the dermatitis models and wild-type littermates. The over-produced serum amyloid A1 in the liver was detected in the plasma in the dermatitis model. Antibodies against TNF-α and IL-α/β showed partial effects on amyloid deposition; however, JAK inhibitors improved gastrointestinal amyloidosis with the improvement of skin symptoms. Chronic dermatitis is closely related to secondary amyloidosis in the gastrointestinal tract, resulting in hypoalbuminemia. Therefore, active control of skin inflammation is essential for preventing gastrointestinal complications.

The medical comorbidities including skin diseases are associated with male infertility. The most common cause of male infertility is the inability of testes to produce sperm; however, the influence of persistent dermatitis on testicular function has not been elucidated so far. We investigated the relationship between skin inflammation and impaired sperm production using a spontaneous dermatitis mouse model. We examined the breeding records of dermatitis mice and their wild-type littermates. Sperm count, motility, and viability were analyzed by direct microscopic observation and flow cytometry. In addition, testis and epididymis were histologically examined. Finally, sperm viability was evaluated in another dermatitis mouse model and in wild-type mice in which inflammatory cytokines were intraperitoneally administered. Compared to wild-type littermate mice, the number of children born was lower in mice with dermatitis. The body weight and testis size were decreased age-dependently. In the skin disease group, the sperm count and movement ratio were clearly decreased, and reduced sperm viability was observed. Histological examination revealed the detachment of Sertoli cells and reduced spermatogenesis. The fibrosis of epididymal stroma was severe, and it might affect defective sperm maturation in the epididymis. In addition, this phenomena was reproduced by a hapten applied dermatitis mouse model and the intraperitoneal administration of inflammatory cytokines. Once the skin is inflamed, inflammatory cytokines are produced and released, which may affect testicular and sperm function. Additional studies are needed to determine the relationship between male infertility and severe dermatitis in human.

Secondary osteoporosis can also be caused by chronic inflammatory skin disease as well as rheumatoid arthritis or inflammatory bowel disease. However, the exact role of osteoporosis in inflammatory skin conditions has not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of osteoporosis in inflammatory skin conditions and the therapeutic impact of osteoporosis medication on inflammatory skin disease. We employed model mice of spontaneous skin inflammation, specifically overexpressing human caspase-1 in the epidermis. Bone density and the expression of various mRNAs in the femur were examined by micro CT and RT-PCR. The effects of minodronate and anti-RANKL antibody on bone structure, histology, and femur blood flow were studied. The mouse model of skin inflammation showed a marked decrease in bone density compared to wild-type littermates with abnormalities in both bone resorption and formation. Minodronate improved bone density by decreasing osteoclasts, but anti-RANKL antibody did not improve. In the dermatitis model, the blood flow in the bone marrow was decreased, and minodronate restored this parameter. A model of persistent dermatitis exhibited marked osteoporosis, but the impact of chronic dermatitis on osteoporosis has not been thoroughly investigated. We should explore the pathogenesis of osteoporosis in skin inflammatory diseases.