Chronic graft-versus-host disease (cGVHD) develops with complex interactions between immune cells and cytokines, leading to irreversible fibrosis. Severe cGVHD impairs quality of life and is associated with nonrelapse mortality; however, effective treatments are limited. Recombinant human soluble thrombomodulin (rTM), a novel anticoagulant consisting of the extracellular domains of thrombomodulin, has shown efficacy in patients with transplantation-associated coagulation disorders and, recently, anti-inflammatory properties in animal studies. Here, we investigated the effects of rTM on cGVHD using a sclerodermatous cGVHD (Scl-cGVHD) mouse model. Prophylactic rTM administration suppressed the development of Scl-cGVHD skin lesions both clinically and histopathologically, prolonging event-free and overall survival. The rTM significantly reduced the infiltration of inflammatory cells, including activated T cells and transforming growth factor β1 (TGFβ1)-producing macrophages into the skin, while inflammation in the draining lymph nodes during priming phase and in spleen during chronic phase was unaffected. TGFβ1 expression in keratinocytes also decreased with rTM. Domain analysis suggested that these effects were mainly attributed to the N-terminal lectin-like domain (domain 1) of rTM, whose functions, including inhibition of inflammatory cell activation and recruitment related to interactions with endothelial cells, has recently been recognized in a limited number of preclinical studies. In conclusion, rTM prevented Scl-cGVHD development, likely by inhibiting the recruitment of inflammatory cells to the skin and subsequent TGFβ1 production by keratinocytes. The rTM may represent a novel prophylactic agent for cGVHD.

We report a case of Japanese spotted fever (JSF) showing marked serological cross-reactivity with Rickettsia typhi, which made serological differentiation difficult. An 80-year-old man presented with fever and disseminated erythematous macules. Laboratory finding suggested a rickettsial infection. Minocycline treatment led to clinical improvement. Real-time polymerase chain reaction screening was positive for spotted fever group rickettsiae. Serological testing using paired sera demonstrated comparable increases in antibody titers against R. japonica and R. typhi in the convalescent phase, precluding differentiation based on serology alone. Sequence-based molecular analysis using DNA extracted from the patient's serum revealed 100% identity with R. japonica strain YH, leading to a definitive diagnosis of JSF. This case highlights the diagnostic challenges posed by serological cross-reactivity and underscores the clinical value of molecular diagnostic approaches when serological findings are inconclusive.

Systemic sclerosis (SSc) is an autoimmune disorder marked by fibrosis of the skin and internal organs, with B cells increasingly recognized as key players in its pathogenesis. However, the characteristics of the B cell receptor (BCR) repertoire in SSc remain insufficiently defined. In this study, we performed high-throughput sequencing of immunoglobulin heavy chain genes in 15 female anti-centromere antibody (ACA)-positive SSc patients and five age-matched healthy female controls to explore disease-specific repertoire biases. A total of 2,597,460 in-frame sequence reads and 384,111 unique reads were obtained. While diversity metrics, including the Shannon, Simpson, and Pielou indices, tended to be higher in the SSc group, the differences were not statistically significant. Notably, the average complementarity-determining region 3 (CDR3) length was significantly shorter in SSc patients compared to controls (16.91 ± 3.727 vs. 17.44 ± 3.836, p < 0.0001). Gene usage analysis revealed no significant differences in IGHJ or IGHC segments; however, several IGHV and IGHD segments displayed statistically significant differences. IGHD5-5 (1.636% vs. 0.547%, p = 0.0001) and IGHD5-18 (1.607% vs. 0.547%, p = 0.0001) were significantly overrepresented in the SSc group, whereas IGHV1/OR15-2 was significantly underrepresented (0.062% vs. 0.130%, p = 0.0080). Further analysis demonstrated that IGHD5-5 clones with a 15-nucleotide CDR3 length were more conserved and exhibited distinctive sequence patterns compared to other lengths or genes. Specific nucleotide lengths, including 15, 23, and 24 for IGHD5-5, and 18 for IGHV1/OR15-2, showed significant frequency differences between groups (p < 0.05). Sequence logo plots confirmed reduced variability in these conserved clones, suggesting antigen-driven clonal selection. These findings identify unique BCR repertoire features in ACA-positive SSc patients and suggest their potential utility as disease biomarkers or therapeutic targets.

Systemic sclerosis, a rare autoimmune disease in children, frequently presents with aggressive clinical features and high risk of interstitial lung disease. Tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, has exhibited efficacy in adult systemic sclerosis with interstitial lung disease; however, evidence in pediatric cases remains extremely limited. We report a 12-year-old Japanese girl who developed early-stage juvenile systemic sclerosis with interstitial lung disease, presenting with Raynaud's phenomenon, puffy fingers, positive anti-topoisomerase I antibody, reduced pulmonary function, and ground-glass opacities on high-resolution computed tomography. Consequently, tocilizumab monotherapy was initiated. During a follow-up period of over 3 years, her pulmonary function remained stable, and high-resolution computed tomography showed partial resolution of interstitial changes. No significant adverse events, such as severe infections or cytopenias, were observed. Early tocilizumab initiation may represent a potential therapeutic option for juvenile systemic sclerosis with interstitial lung disease. However, further studies are warranted to validate its role and optimize treatment guidelines for this rare but severe condition.

BackgroundSystemic sclerosis (SSc) is a heterogeneous autoimmune disease in which interstitial lung disease (ILD) is a major determinant of mortality. Given that certain chemokines and adhesion molecules may be involved in the inflammation, subsequent vascular injury, and fibrosis observed in SSc, their circulating levels in peripheral blood may reflect the disease processes ranging from inflammation to vascular damage and fibrotic remodeling. However, the potential of these biomarkers to identify patient subgroups with divergent pulmonary trajectories remains to be elucidated.MethodsWe performed a retrospective analysis of prospectively collected data from patients with early severe SSc (diffuse cutaneous SSc irrespective of ILD status or limited cutaneous SSc with ILD; disease duration <5 years) who were enrolled in a multicenter cohort. Serum levels of five chemokines and four soluble adhesion molecules were quantified at baseline. Patients were classified based on these biomarker profiles using k-means clustering. Changes in pulmonary function were compared among clusters using relative changes in percent vital capacity (%VC).ResultsPatients (n = 92) were classified into three clusters: Cluster 1 (n = 37) with elevated sICAM-1 and sE-selectin; Cluster 2 (n = 13) with elevated CCL2, CXCL8, and sP-selectin; and Cluster 3 (n = 42) with no distinctive biomarker pattern. Cluster 3 showed stable %VC and served as the reference group. Cluster 1 showed early decline (one-year difference: −8.41%; 95% CI: −12.62 to −4.20; p < 0.001) that attenuated by year two. In contrast, Cluster 2 showed progressive decline (two-year difference: −7.77%; 95% CI: −15.25 to −0.29; p = 0.042). These biomarker-defined patterns were consistent with a vasculopathic–fibrotic profile in Cluster 1 and an inflammatory–vascular profile in Cluster 2.ConclusionSerum chemokine and adhesion molecule profiles may help stratify early severe SSc into biologically distinct subgroups with different pulmonary trajectories, supporting their potential utility for early risk stratification in SSc-ILD.

OBJECTIVE:To evaluate clinical and epidemiological features of juvenile-onset systemic sclerosis (jSSc) in Japan and to identify racial and generational differences. METHODS:We surveyed patients with jSSc (developed < 18 years of age) who visited selected facilities in Japan between January 2016 and December 2020. We estimated the number of patients with jSSc and the annual incidence rate in Japan. Thereafter, differences in clinical characteristics by disease subtype, autoantibody, and age at investigation were analyzed and compared with previous cohorts. RESULTS:Of the 3005 institutions selected for the first survey, 1845 (61.4%) responded. The estimated number of patients with jSSc was 299, whereas the estimated annual incidence rate ranged from 0.98 to 1.59 per 1 million children (aged < 18 years) from 2016 to 2020. In the second-stage survey, 130 cases were analyzed, of which 85 (65.4%) had diffuse cutaneous SSc (dcSSc), 77.7% were female, and the median ages at onset and during the survey were 11 and 21 years, respectively. Autoantibody positivity was 62.4% for antitopoisomerase I antibody (ATA) and 12.9% for anticentromere antibody, whereas anti-PM/Scl antibody was very rare. In total, interstitial lung disease was present in 40.8% of patients (predominantly dcSSc and ATA positive), gastrointestinal lesions in 36.9%, pulmonary arterial hypertension in 7.7%, and no renal crisis. CONCLUSION:This is the largest national survey of jSSc characteristics analyzed in detail by autoantibody and disease subtype. Japanese jSSc was characterized by a very high ATA positivity rate. However, the frequency of major organ involvement was similar to previous reports of jSSc in the West.

We investigated nailfold videocapillaroscopy (NVC) findings in antisynthetase syndrome (ASyS) and compared patterns among six anti-aminoacyl-tRNA synthetase (anti-ARS) antibody (Ab) subtypes. In this retrospective study of 66 Japanese patients positive for anti-Jo-1, EJ, PL-7, PL-12, KS, or OJ Abs, seven NVC abnormalities were assessed: enlarged capillaries, reduced capillaries, hemorrhages, capillary ramifications, disorganization of the vascular array, loss of capillaries, and giant capillaries. Enlarged capillaries, reduced capillaries, and hemorrhages were common overall; in contrast, patients with anti-KS Abs exhibited significantly fewer abnormalities, particularly hemorrhages (25% vs. 75%-100% in other groups; p < 0.05). Capillary ramifications, disorganization, and capillary loss were rare across all subtypes. Although ASyS patients may present with similar clinical manifestations, NVC findings vary among anti-ARS Ab subtypes; anti-KS Ab identifies a subset with milder microvascular involvement. Recognizing anti-ARS Ab specificity may help interpretation of vascular heterogeneity in ASyS.

Gastric antral vascular ectasia (GAVE) is a cause of gastrointestinal bleeding in systemic sclerosis (SSc), but its predictors and outcomes in SSc are not fully defined. We aimed to determine the frequency of GAVE in SSc and to compare the clinical characteristics of SSc patients with versus without GAVE in a single-center Japanese cohort. We retrospectively identified SSc patients who underwent upper gastrointestinal endoscopy at our institution between 2006 and 2015. Clinical data including SSc subtype, extent of skin sclerosis, and autoantibody profiles were collected for patients with endoscopically confirmed GAVE and for those without GAVE. Of 272 SSc patients who underwent endoscopy, 19 patients (7.0%) had GAVE. SSc patients with GAVE were significantly more likely to have diffuse cutaneous SSc and had a shorter disease duration since SSc onset compared to those without GAVE. GAVE patients tended to have more severe skin sclerosis and a markedly higher prevalence of anti-RNA polymerase III antibody (42% vs. 9.5% in non-GAVE, p < 0.001), with a corresponding lower frequency of anti-centromere antibody (10.5% vs. 45.4%, p < 0.001). Scleroderma renal crisis occurred in 16% of GAVE patients versus < 1% of non-GAVE patients (p < 0.001). Follow-up endoscopy in GAVE patients showed that in roughly half of the cases the GAVE lesions disappeared over 1-8 years (often after immunosuppressive therapy), whereas the remainder had persistent GAVE changes. GAVE occurred in about 7% of SSc patients, especially those with diffuse, rapidly progressive disease. It was associated with anti-RNA polymerase III positivity and early severe organ involvement. Patients with early diffuse skin disease and this antibody may be at higher risk, highlighting the importance of early detection to prevent bleeding and anemia.

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) is a recently identified clonal disorder caused by somatic UBA1 mutations in hematopoietic stem cells, leading to bone marrow failure (BMF) and systemic inflammation. We screened 1771 patients with BMF who underwent unrelated hematopoietic cell transplantation in Japan between 1995 and 2020 using multitarget real-time PCR. The diagnoses included myelodysplastic syndrome (MDS, n = 1139), myeloproliferative neoplasms (n = 125), plasma cell neoplasms (n = 23), acquired BMF (n = 395), and congenital BMF (n = 89). Pathogenic UBA1 mutations were detected in two male patients with MDS (aged 48 and 63 years), corresponding to a prevalence of 0.11% in the overall cohort and 0.18% in MDS cases; an additional 70-year-old male was diagnosed outside of the cohort. All three underwent unrelated bone marrow transplantation following fludarabine and busulfan-based conditioning. The first and third patients died of idiopathic pneumonia syndrome 5 and 28 months after transplantation. In the third patient, UBA1-mutant cells persisted at low frequency in skin graft-versus-host disease tissue despite clearance from his blood. The second patient survived without relapse or graft-versus-host disease at 28 months. Although VEXAS syndrome is rare among unrelated HCT recipients with malignant and non-malignant BMF in the historical cohort, HCT is positioned as a potentially curative, yet high-risk strategy. Additional studies are essential to refine patient selection, optimize transplant timing, and improve management strategies to mitigate risk and enhance survival. Therefore, the role of tissue-residual UBA1-mutant clones in post-transplant complications warrants further investigation.

OBJECTIVES:Anti-MDA5 autoantibodies are strongly associated with interstitial lung disease (ILD) and rapidly progressive ILD (RP-ILD) in Asian patients with dermatomyositis (DM) or amyopathic DM (ADM). However, this association has not yet been established in Brazilian patients with anti-MDA5(+) DM/ADM. This study aimed to investigate the phenotypic differences between Brazilian and Japanese patients with anti-MDA5(+) DM/ADM, with a particular focus on ILD. METHODS:This was an international, tricentric, retrospective cohort study conducted in one Brazilian and two Japanese tertiary centres. Patients diagnosed with anti-MDA5(+) DM/ADM at the three centres were enrolled. Clinical characteristics and outcomes were collected using a pre-standardised protocol and compared between Brazilian and Japanese patients. RESULTS:Thirty-four Brazilian and 65 Japanese patients were analysed. Brazilian patients were younger at the time of diagnosis than Japanese patients. The prevalence of muscle weakness, myalgia, dysphagia, heliotrope rash, V-sign, calcinosis, Raynaud's phenomenon, and digital ulcers was higher in Brazilian patients, whereas mechanic's hands were more prevalent in Japanese patients. The prevalence of ILD was significantly lower in Brazilian patients than in Japanese patients (50.0% vs. 98.5%, p<0.001). RP-ILD was observed in 34 (52.3%) Japanese patients and in only one (3.3%) Brazilian patient (p<0.001). Outcomes including overall survival and the frequency of relapses and complications, such as severe infection and malignancy, were comparable between the two populations. CONCLUSIONS:Brazilian patients with anti-MDA5(+) DM/ADM had a higher prevalence of skin and muscle involvement, whereas the prevalence of ILD and RP-ILD was significantly lower than in Japanese patients.

We report a rare case of dermatomyositis in a woman in her 60s, presenting with chronic pruritic erythema and symmetrical subcutaneous indurations in both axillae. Physical examination revealed Gottron’s papules and erythematous plaques on the hands and upper extremities. Laboratory tests showed mildly elevated serum CK, aldolase, and CRP levels. CT revealed increased fat density in both axillae, suggestive of panniculitis. Skin and subcutaneous biopsies confirmed interface dermatitis and panniculitis with membranocystic changes. After that, bilateral inguinal panniculitis developed. Autoantibody screening identified strong positivity for anti-NXP-2 and anti-Ki antibodies. Anti-NXP-2 antibody was further confirmed by immunoprecipitation-Western blotting. The diagnosis of dermatomyositis was made, and oral prednisolone (10 mg, 0.2 mg/kg/day) led to marked improvement. These findings may suggest a potential association between anti-NXP-2 antibodies and panniculitis.

Kaposi's sarcoma (KS) is a chronic, multifocal lymphoangioproliferative tumor that occurs mainly in older individuals in the Mediterranean region. KS is often observed as a malignant tumor in patients with acquired immunodeficiency syndrome, and classic KS is rare. An 82-year-old man was referred to our department with bilateral lower-leg edema with purpura and small nodules. When the patient was in his mid-50s, edema with purpura appeared in his lower extremities without any specific trigger. Eight years earlier (in his mid-70s), the purpura lesions gradually turned nodular. A similar skin rash appeared on the forearms and back of the hands two years earlier. Physical examination revealed diffuse brown pitting edema over the entirety of the lower extremities and extending from the dorsum of the bilateral hands to the elbows. Multiple purple-red, elastic, hard nodules ranging from a few millimeters to about 1 cm were localized and fused over the edema. Histological examination of the forearm nodule revealed proliferation of collagen fibers and cellular infiltration in the dermis. The intricately proliferating cells in the dermis were spindle-shaped with round nuclei. Immunohistochemical staining revealed spindle-shaped cells positive for CD31, CD34, and D2-40. These cells were positive for human herpesvirus (HHV)-8 and negative for human immunodeficiency virus (HIV) antigens and antibodies. He was diagnosed with classic KS. We proposed chemotherapy, but he refused to receive any treatment. Our patient did not receive any immunosuppressive therapy, and the HIV test result was negative. Therefore, immunosuppressive status may not be involved in the development of KS in our patient. He had opportunities to consult dermatologists but was never diagnosed with KS. A skin biopsy helps diagnose KS; thus it should be considered when a patient experiences long-standing, slowly progressive, unexplained leg edema accompanied by a skin rash.