Immunological Medicine最新文献

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM)-associated interstitial lung disease (ILD) is a rapidly progressive and life-threatening condition that often requires aggressive immunosuppressive therapy, including Janus kinase (JAK) inhibitors, whose safety profile remains incompletely understood. We report an extremely rare case of secondary pulmonary alveolar proteinosis (PAP) that developed during tofacitinib treatment for multidrug-refractory anti-MDA5 antibody-positive DM-associated ILD. A 74-year-old Japanese woman with rapidly progressive DM-associated ILD was treated with high-dose glucocorticoids, intravenous cyclophosphamide, and cyclosporine, followed by tofacitinib due to an insufficient response. Although the ILD initially improved, she later developed progressive elevation of serum KL-6 levels and diffuse ground-glass opacities on chest computed tomography despite only mild respiratory symptoms. Transbronchial lung biopsy revealed periodic acid-Schiff-positive material within the alveolar spaces, and serum anti-granulocyte-macrophage colony-stimulating factor antibodies were negative, leading to a diagnosis of secondary PAP. Discontinuation of tofacitinib alone resulted in rapid clinical and radiological improvement. This case highlights PAP as a rare, potentially reversible complication during JAK inhibitor therapy in anti-MDA5 antibody-positive DM-associated ILD and underscores the importance of considering PAP when elevated KL-6 levels and radiological abnormalities occur despite only mild respiratory symptoms.

The clinical significance of serum lysozyme in sarcoidosis remains unclear. This study aimed to evaluate the clinical characteristics and kidney function of sarcoidosis patients with elevated serum lysozyme. We retrospectively analyzed 28 patients with sarcoidosis and measured levels of serum lysozyme. Clinical characteristics, laboratory data, and estimated glomerular filtration rate (eGFR) were evaluated. Median age was 57 years (interquartile range, 43-70 years), and 21% were men. High serum lysozyme levels were associated with a greater number of organ involvements (median 4 vs. 2, p = 0.022) and more frequent renal involvement (50 vs. 7%, p = 0.033). Serum lysozyme levels correlated inversely with eGFR (r = -0.814). Median serum lysozyme level was significantly higher in patients with renal sarcoidosis (RS) (30.2 μg/mL) than in non-RS patients (9.5 μg/mL, p = 0.003). Prominent intracytoplasmic lysozyme staining in proximal tubular epithelial cells was observed in the kidney of RS patients. Multiple regression analysis identified serum lysozyme as an independent risk factor for eGFR decline. Elevated serum lysozyme in sarcoidosis was associated with multiorgan involvements and renal impairment. Lysozyme may contribute to tubulointerstitial injury in RS, potentially through tubular reabsorption and cytotoxic effects. Further studies are warranted to clarify the role of lysozyme in the pathogenesis of RS.

We report a case of cold agglutinin disease (CAD) considered as other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD) in a patient with rheumatoid arthritis (RA) and Sjögren's disease. A 69-year-old woman developed hemolytic anemia and renal dysfunction after long-term methotrexate and infliximab therapy. Laboratory findings demonstrated monoclonal IgM-κ paraproteinemia and a high cold agglutinin titer, confirming CAD, while imaging studies and bone marrow evaluation revealed no evidence of overt malignancy. Renal biopsy revealed membranoproliferative glomerulonephritis-like lesions with C3-dominant deposition, consistent with C3 glomerulonephritis (C3GN). These findings suggest that both CAD and C3GN may represent manifestations of OIIA-LPD associated with long-term immunosuppressive therapy. Rituximab combined with glucocorticoids led to a prompt and marked improvement in anemia and renal lesions, resulting in sustained remission of both CAD and C3GN while maintaining RA remission. This case suggests the dual pathogenesis of B-cell dysregulation and complement activation and indicates that B-cell-targeted therapy may contribute to controlling both abnormalities. Accumulation of similar cases will be essential to refine disease classification and to optimize therapeutic strategies for immune-mediated overlap disorders.

Azathioprine (AZA) is widely used during pregnancy to manage autoimmune diseases; however, concerns regarding fetal immunological vulnerability persist. Although neonatal lymphocytopenia and chromosomal abnormalities have been reported following prenatal AZA exposure, little is known about immune recovery in infants after congenital infections in these infants. Here, we describe an infant with congenital cytomegalovirus (CMV) infection, who was born to a mother treated with azathioprine for systemic lupus erythematosus and developed hemophagocytic lymphohistiocytosis (HLH) during immune reconstitution during lymphocytopenia. The preterm infant presented with lymphocytopenia, anemia, thrombocytopenia, and congenital CMV infection. Despite initiating antiviral therapy, immune reconstitution inflammatory syndrome (IRIS) developed, thus fulfilling the diagnostic criteria for HLH, including increased alanine aminotransferase, ferritin, triglycerides, and soluble interleukin-2 receptor levels. A chromosomal analysis revealed mosaicism with 46,XX and i [18](q10) in the bone marrow cells. In the absence of definitive HLH treatment, such as corticosteroids or other immunosuppressive therapies, fever, splenomegaly, and laboratory abnormalities resolved spontaneously, and the chromosomal alterations normalized. This indicates that prenatal AZA exposure induces transient immunosuppression, leading to the development of IRIS. Our case highlights the necessity of vigilant immunological surveillance in neonates exposed to AZA in utero.

Lupus nephritis (LN) is one of the most important manifestations in patients with systemic lupus erythematosus (SLE). Although LN is associated with increased morbidity, mortality and healthcare costs, the advent of new immunosuppressive drugs and biologics in recent years has led to significant improvements in treatment outcomes. In addition to conventional dual therapy, evidence for triple therapy has been established. Triple therapy, which combines mycophenolate mofetil (MMF) with belimumab (BEL) or calcineurin inhibitors (CNIs, including voclosporin), or intravenous cyclophosphamide with BEL, has been recommended, particularly for active nephritis with poor prognostic factors. Since rapid reductions in proteinuria have been observed with CNIs, triple therapy combining MMF and CNIs have been conditionally recommended for LN patients with preserved renal function and severe proteinuria. In contrast, because BEL reduced disease activity and severe flares in non-renal symptoms, triple therapy including BEL has been conditionally recommended in LN patients with significant extra-renal SLE disease. Furthermore, the latest treatment recommendations from the European League Against Rheumatism had added the combination therapy of MMF plus obinutuzumab as an initial treatment option. In this review, we discuss the latest guidelines and recommendations for LN.

Azathioprine (AZA) is an established treatment for rheumatic diseases, but real-world safety data in Japanese patients remain limited. This study aimed to evaluate the real-world use and safety of AZA in Japan. A nationwide questionnaire survey was conducted, distributing forms to 1163 facilities, including university hospitals and Japan College of Rheumatology-certified institutions. Of these, 170 facilities (14.6%) responded. A total of 1943 patients with rheumatic diseases who initiated AZA between November 2000 and September 2023 were enrolled. Among them, 33.9% experienced adverse events (AEs), including hepatobiliary disorders (13.9%), gastrointestinal disorders (10.4%), blood and lymphatic system disorders (9.3%), infections (5.1%), and skin/subcutaneous disorders (2.4%). AZA therapy was discontinued in 468 (71.6%) of the 660 patients with AEs. The incidence of serious AEs (grade ≥3) was 2.7% and varied by rheumatic disease. Multivariate analysis identified older age (odds ratio [OR] 2.47, 95% confidence interval [CI]: 1.32-4.59) and systemic lupus erythematosus (OR 2.31, 95% CI: 1.09-4.87) as risk factors for serious AEs. This nationwide survey provides evidence of AZA-related AEs in Japanese patients with rheumatic diseases. AE incidence was relatively high, and serious AEs (grade ≥3) occurred more frequently in patients aged over 65 years and those with systemic lupus erythematosus.

The current study investigated acute circulatory dynamics changes induced by high-dose intravenous methylprednisolone pulse therapy (steroid pulse therapy). Eight patients who underwent steroid pulse therapy were included in the study. After steroid pulse therapy, plasma levels of brain and atrial natriuretic peptides were significantly increased compared with those before steroid pulse therapy (both p < 0.001). Echocardiography revealed that left ventricular end-diastolic diameter (LVDd) tended to increase after steroid pulse therapy (p = 0.055). Left atrial volume index (LAVI) also increased after steroid pulse therapy (p < 0.05). Peak early diastolic transmitral flow velocity (E wave) increased significantly (p < 0.05), and early diastolic mitral annular velocity tended to increase (p = 0.09). These findings indicate that steroid pulse therapy may increase cardiac preload, as suggested by the observed increases in LVDd, LAVI, and E wave velocity. Clinicians should remain mindful of this potential effect when administering steroid pulse therapy.

Inflammatory bowel disease (IBD) is a debilitating and treatment-refractory condition with a complex and incompletely understood etiology. Recent advances in neuroimmunology have revealed that intestinal homeostasis is regulated by bidirectional communication between the autonomic nervous system and the immune system. In particular, vagus nerve-mediated cholinergic anti-inflammatory signaling plays a central role in modulating intestinal immune responses and represents a key mechanism linking neural regulation to IBD pathogenesis and therapy. In parallel, the gut-brain axis has emerged as a critical regulator of intestinal inflammation and systemic disease. Psychological stress alters gut immune function through mechanisms involving enteric glial activation and microbiota-derived metabolites, contributing to treatment-resistant depression via immune activation and changes in short-chain fatty acid profiles. Moreover, gut microbiota dysbiosis has been implicated in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, potentially preceding central pathology through vagal signaling and systemic inflammation. Together, these findings position the gut microbiota as an immunological and neurological hub connecting intestinal, systemic, and brain health. This review summarizes recent advances in gut-brain axis-mediated immune regulation in IBD and highlights emerging bioelectronic neuromodulation strategies targeting autonomic circuits as promising non-pharmacological approaches to restore gut immune balance.

This study was conducted to reveal specific clinical features, outcomes and risk factors of organ damage in patients with systemic lupus erythematosus (SLE) with neuropsychiatric (NP) symptoms upon initial onset. Patients with newly diagnosed SLE at our institute between 2010 and 2022 were enrolled. Patients who exhibited NP symptoms at initial onset constituted the initial onset NPSLE (Ini-NPSLE) group, and their clinical features were compared with those of patients without NP symptoms (SLE NP- group). Among 90 patients with newly onset SLE (mean age 37.7 years), there were 20 patients in the Ini-NPSLE group and 70 patients in the SLE NP- group. General clinical characteristics were similar between the two groups, except for diagnostic delay, arthritis and avascular necrosis. The Ini-NPSLE group showed significantly higher SLE Disease Activity Index scores at admission (24.8 vs. 15.6) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) scores (1.55 vs. 0.53) at the end of follow-up. Logistic regression analysis revealed that patients' age and NPSLE were associated with organ damage (SDI ≥ 1) in patients with newly onset SLE. This study suggests that clinicians must focus on early NP symptoms to manage later organ damage in patients with SLE.