Risankizumab is a selective interleukin (IL)-23p19 inhibitor used for psoriasis. Although IL-23 is implicated in giant cell arteritis (GCA), biologic therapy can occasionally be associated with paradoxical immune-mediated events. We report a 67-year-old woman who developed GCA during long-term risankizumab therapy for psoriasis vulgaris. She presented with progressive night sweats and fatigue, with marked systemic inflammation. Contrast-enhanced computed tomography and gadolinium-enhanced magnetic resonance imaging demonstrated large-vessel inflammation involving the aorta and its major branches. Temporal artery biopsy showed intimal hyperplasia, fragmentation of the internal elastic lamina, and mild inflammatory cell infiltration. She fulfilled the 2022 ACR/EULAR classification criteria for GCA and was treated with high-dose prednisolone, followed by methotrexate. Her symptoms and inflammatory markers improved rapidly, and risankizumab was continued because of excellent psoriasis control. Pretreatment serum cytokine analysis showed low IL-17 levels, whereas IFN-γ, IL-6, and TNF-α were comparable to or higher than those in other patients with GCA. This case highlights that GCA can develop during selective IL-23 blockade and may involve Th1-skewed inflammation or a paradoxical immune reaction.
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been implicated in Epstein-Barr virus (EBV) reactivation. In this study, we aimed to investigate the role of iguratimod, an NF-κB activator inhibitor, in EBV lytic cycle activation in EBV-infected cells. EBV-producing cells, AKATA, and B-lymphoblastoid cells (BLBC) with 1 μM iguratimod. EBV DNA copy numbers were measured using real-time polymerase chain reaction. The inhibitory effect of iguratimod on NF-κB nuclear translocation in AKATA cells was examined. Immunohistochemical staining revealed significantly increased EBV early antigen diffuse type (EA-D) production in IgG-stimulated AKATA cells and IgM-stimulated BLBC compared with unstimulated cells, whereas co-culture with iguratimod suppressed the production of EBV EA-D. Additionally, AKATA cells/BLBC stimulated with anti-human IgG/IgM showed a significant increase in EBV DNA copy number compared to unstimulated cells, which was significantly reduced by co-culture with iguratimod. Nuclear expression of NF-κB was observed in AKATA cells stimulated with anti-human IgG, and NF-κB expression was suppressed by treatment with iguratimod. These findings suggest that iguratimod may reduce rheumatoid arthritis disease activity by partially inhibiting EBV reactivation. This may partially suppress the onset of RA.
Lipopolysaccharide (LPS)-induced endotoxemia is widely used to model sepsis. This study aimed to identify the LPS dose that reliably induces hyperlactatemia, Murine Sepsis Score (MSS) ≥3 (clinically defined sepsis), dose-dependent differences in 48-hour survival, and optimal histone H3K18 lactylation in male BALB/c mice. Sixty-six male BALB/c mice (8-10 weeks) received intraperitoneal LPS at doses of 1, 2.5, 5, 10, 15, and 20 mg/kgBW (N = 11 per group). Blood lactate was measured at 6 h, MSS was used to assess disease severity, and survival was monitored for 48 h. Peritoneal macrophages were isolated, and histone H3K18 lactylation normalized to total H3 (H3K18la/H3) was quantified. All groups developed hyperlactatemia (>4 mmol/L) without dose-dependent differences (p = 0.289). Meanwhile, MSS increased proportionally with LPS dose (ρ = 0.785; p= <0.001) and negatively correlated with lactate (ρ=-0.527; p = 0.025). Survival showed a general dose-related downward trend that did not reach significance, with a non-monotonic exception at 5 mg/kgBW. Macrophage yield varied across groups, while H3K18la/H3 levels were markedly elevated at LPS 15 and 20 mg/kgBW. To conclude, lactate rises early and non-uniformly across LPS doses, limiting its value as severity marker in male BALB/c endotoxemia. MSS provides a more dose-responsive indicator of clinical severity. An LPS dose of 15 mg/kg provides an optimal model for studying immunometabolic and immunoepigenetic responses in sepsis.
To perform cross-disease immunological comparison across the broader spondyloarthritis (SpA) spectrum and examine their association with disease activity. We analyzed 111 patients with active broader SpA spectrum (ankylosing spondylitis, inflammatory bowel disease-associated SpA, psoriatic arthritis, pustulotic arthro-osteitis, and chronic non-bacterial osteitis) and 24 age- and sex-matched healthy controls (HC). Serum IL-17A, IL-17F, TNFα, and Oncostatin M levels were higher in the broader SpA spectrum than in HC. These cytokines levels did not differ among the broader SpA spectrum. Activated Th17, activated Th1-17, classical and intermediate monocytes were increased in the broader SpA spectrum compared with HC. Although Kruskal-Wallis test showed differences among the spectrum for activated Th17, activated Th1-17, and classical monocytes, post hoc analyses did not identify a specific disease driving these differences. Intermediate monocytes positively correlated with CRP and MMP-3 levels. Circulating immune subsets remained unchanged following DMARDs treatment despite clinical improvement. Systemic immune alterations, including activation of IL-17 axis, elevated Oncostatin M, and expansion of intermediate monocytes, are broadly shared across the broader SpA spectrum. Although global differences among the spectrum were observed for some immune cell populations, post hoc analyses did not identify disease-specific enrichment.
IgG4-related retroperitoneal fibrosis (IgG4-related RPF) often causes hydronephrosis requiring ureteral stenting. While glucocorticoid (GC) therapy is generally effective, predictors of successful stent removal remain unestablished. This retrospective study investigated whether the interval from radiological diagnosis to GC initiation predicts stent-free outcomes. Twenty-one patients with IgG4-related RPF requiring ureteral stenting between April 2010 and December 2024 were categorized into stent-free (n = 12) and stent-dependent (n = 9) groups. Baseline serological markers (IgG, IgG4, and C-reactive protein) and renal function did not differ significantly between groups. However, the interval from radiological diagnosis to GC initiation was significantly shorter in the stent-free group compared to the stent-dependent group (median 110.5 vs. 264.0 days; p = 0.028). In the primary analysis, patients were dichotomized at the pre-specified cohort median of the diagnosis-to-GC interval (160 days), and Kaplan-Meier analysis showed that early initiation (≤ 160 days) was associated with a significantly higher stent removal rate (p = 0.031). An exploratory ROC analysis yielded a convergent optimal cutoff of 195 days (AUC 0.79; sensitivity 83%, specificity 78%). Delayed GC initiation may be associated with an increased risk of long-term stent dependence, suggesting the existence of a potential therapeutic window of approximately six months for achieving stent-free status.
The J-CAT2 study (#jRCT1030240195) aimed to evaluate treatment and patient factors associated with risk of complications/adverse events (AEs) or high corticosteroid exposure in patients with non-infectious uveitis (NIU) using advanced quantitative and visual analytical approaches. The study included data from a nationwide insurance claims database in Japan. Patients with NIU treatment-related claims (2016-2023) were included (n = 98,842). A nested case-control design was used to evaluate patient factors associated with complications/AEs or high corticosteroid exposure. Multivariable logistic regression and decision-tree analyses were performed. Sub-Tenon's corticosteroid injections were associated with dose-dependent increased odds of glaucoma treatment and cataract surgery (OR [95% CI]: 1 sub-Tenon's injection, 3.27 [2.60-4.11] and 3.19 [2.39-4.27], respectively; ≥2 sub-Tenon's injections, 5.54 [4.03-7.60] and 4.86 [3.44-6.85], respectively). Macular edema was the most likely factor associated with ≥2 sub-Tenon injections. Vogt-Koyanagi-Harada disease and sarcoidosis were the most likely factors associated with medium-to-high-dose corticosteroids and long-term oral corticosteroids. The J-CAT2 study used a novel, quantitative and visual framework to understand associations between dose, frequency, and duration of corticosteroid treatment and complications/AE risk in NIU. These findings suggest that optimization of corticosteroid administration protocols and exploration of alternative therapeutic strategies/targeted treatment approaches are necessary to mitigate complication risks.
To evaluate the intermediate treatment targets for Still's disease proposed by EULAR/PReS recently, we conducted this post-hoc analysis of the Phase III trial of tocilizumab and its long-term extension to assess the achievement probability of these targets with tocilizumab. Additionally, we assessed the associations of the intermediate treatment targets with long-term outcomes, including glucocorticoid-free clinically inactive disease (CID) and recurrence. Given the predefined glucocorticoid tapering schedule, we also evaluated the achievement of CID irrespective of glucocorticoid dosage when assessing treatment targets at Months 3 and 6. Twenty-one patients were followed for a median of 39.8 months. The week 4 target was achieved in 57.1%, while 47.6% and 38.1% achieved CID at months 3 and 6, respectively. At the final visit, 57.1% and 28.6% achieved CID and glucocorticoid-free CID, respectively. Achievement of the week 4 target and CID at month 6 was associated with subsequent glucocorticoid-free CID (50% vs. 0%, p = 0.01; 62.5% vs. 7.7%, p = 0.01). Month 6 CID achievers had higher baseline swollen joint counts and lower interferon-γ levels. In conclusion, achievement of intermediate treatment targets was associated with long-term CID, suggesting that these targets may also be useful in treatment with tocilizumab. CLINICAL TRIAL REGISTRATION:UMIN000012987, UMIN000018414.
Immune checkpoint inhibitors (ICIs) can cause severe immune-related adverse events (irAEs), including life-threatening myositis and myocarditis. Characterizing the immunopathological features of these conditions is essential for improving clinical recognition and management. We report a case of a 76-year-old man with metastatic renal cell carcinoma who developed fatigue, elevated creatine kinase, and complete atrioventricular block after receiving nivolumab. Despite pacemaker implantation and plasmapheresis, the patient died of respiratory failure. Notably, serum tests were positive for anti-Kv1.4 and anti-titin antibodies, although typical myasthenia gravis features were absent. Autopsy revealed CD8-positive T-cell and CD163-positive macrophage infiltration in the myocardium and skeletal muscles, while also confirming a pathological complete response of the carcinoma. Spatial analysis using digital pathology demonstrated that Human leukocyte antigen (HLA) class I expression in cardiomyocytes was closely apposed to infiltrating CD8-positiveT cells in a patchy distribution. This observation suggests a potential local feedback loop where activated T cells may induce HLA class I upregulation in adjacent muscle fibers, sustaining focal inflammation. This case provides important insights into the complex pathophysiology of fatal irAEs and underscores the value of postmortem examination in irAEs.
Over the past decade, immune checkpoint inhibitors (ICIs) have moved from the research setting into routine clinical practice. Their use has expanded from single-agent therapy to combination regimens with cytotoxic chemotherapy, targeted agents, and radiotherapy, and more recently being incorporated into neoadjuvant treatment. Although ICIs have improved the outcomes of a subset of patients, this progress has been accompanied by the occurrence of immune-related adverse events (irAEs), which represent an important challenge in daily clinical care. Ongoing research continues to pursue more effective and durable antitumor immune responses. At the same time, enhanced immune activation is associated with an increased risk of unintended tissue injury, suggesting that irAEs are closely linked to the mechanisms underlying therapeutic immune activation. Therefore, the benefits and disadvantages of ICIs should be considered within the same biological framework. This review does not aim to provide a comprehensive catalog of irAEs; instead, we highlight several representative and clinically relevant topics and discuss them from a pathological perspective. By integrating clinicopathological observations across organ systems, we seek to illustrate how tissue-based findings can contribute to the understanding, recognition, and management of irAEs.
Anti-myelin oligodendrocyte glycoprotein antibody-associated cerebral cortical encephalitis (MOG-CCE) occasionally exhibits cerebrospinal fluid (CSF) anti-N-methyl-D-aspartate receptor (NMDAR) antibody co-positivity; however, its clinical relevance remains unclear. This study examined the clinical characteristics of NMDAR antibody-positive and NMDAR antibody-negative MOG-CCE to clarify its clinical implications. Consecutive patients with MOG-CCE admitted to our hospital between January 2015 and July 2025 were included. Clinical, laboratory, and imaging findings, as well as treatments and outcomes, were descriptively analyzed according to the CSF anti-NMDAR antibody status. Ten cases with MOG-CCE were included, with five being NMDAR antibody-positive MOG-CCE. Compared to patients with NMDAR antibody-negative MOG-CCE, patients with NMDAR antibody-positive MOG-CCE appeared to have a higher frequency of psychiatric symptoms (80% vs. 20%), abnormal behavior (80% vs. 0%), and movement disorder (60% vs. 0%). Beyond fluid attenuated inversion recovery hyperintensity and gadolinium enhancement, cerebral perfusion imaging demonstrated regional hyperperfusion in most cases, irrespective of CSF anti-NMDAR antibody status. Functional outcomes were similar (median modified Rankin Scale at final follow-up 0 vs. 0). This study suggests that cases with NMDAR antibody-positive MOG-CCE may represent a synergistic overlap between MOG-CCE and NMDARE, characterized by NMDARE-like symptoms. Cerebral perfusion evaluation may serve as a supportive tool for the assessment of MOG-CCE.
A 59-year-old woman with 45 years history of systemic lupus erythematosus (SLE) and antiphospholipid syndrome was admitted to our hospital with progressive disturbances in consciousness, cognitive impairment and paraparesis following pneumonia and cerebral infarction. Diagnostic workup revealed anti-aquaporin-4 antibody positivity and a longitudinally extensive transverse myelitis lesion, leading to a diagnosis of neuromyelitis optica spectrum disorder (NMOSD). Additionally, ventricular enlargement and cerebrospinal fluid (CSF) findings raised suspicion of normal pressure hydrocephalus (NPH). Treatment with methylprednisolone pulse therapy, hydroxychloroquine, and mycophenolate mofetil resulted in rapid clinical improvement. We propose that systemic inflammation and blood-brain barrier disruption, triggered by infection and infarction, facilitated the entry of autoantibodies and potentially exacerbated CSF dynamics. This case illustrates that neuropsychiatric symptoms in SLE can arise from the convergence of multiple distinct pathologies. Clinicians should maintain a high index of suspicion for overlapping conditions like NMOSD and NPH to ensure appropriate intervention, even when systemic lupus activity is not overtly high.
Estimation of histological cirrhosis on diagnosis is useful for predicting prognosis in patients with primary biliary cholangitis (PBC). The pretreatment GLOBE score is associated with survival, but its relationship with histological cirrhosis remains unknown. We retrospectively investigated the pretreatment GLOBE score in PBC patients who had undergone liver biopsy. We analyzed the association between pretreatment GLOBE score and clinical findings, including histological cirrhosis and liver transplant (LT)-free survival rate. Among 183 patients with PBC, the pretreatment GLOBE score increased significantly with histological stage. The pretreatment GLOBE score demonstrated a high AUROC (0.868) than other noninvasive tools, with a cutoff value of 1.265 (95% CI: 1.195-1.585) for predicting histological cirrhosis. Patients with a pretreatment GLOBE score of < 1.265 had a significantly higher LT-free survival rate than those with a score of ≥ 1.265. A score of ≥ 1.265 was associated with lower LT-free survival rate independent of the presence of histological cirrhosis or GLOBE score 1 year after ursodeoxycholic acid treatment. Assessment of the pretreatment GLOBE score in PBC patients may be useful as a noninvasive prognostic tool.
This study aimed to compare the risk signals of Guillain-Barré syndrome (GBS) associated with recombinant zoster vaccine (RZV) and zoster vaccine live (ZVL) to improve understanding of herpes zoster vaccine safety. Disproportionality analyses were conducted using the Vaccine Adverse Event Reporting System (VAERS) and validated using the EudraVigilance database. Reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) methods were applied, followed by time-to-onset and logistic regression analyses. A total of 482 GBS reports associated with RZV and 85 reports associated with ZVL were identified in VAERS. Significant disproportionality signals were detected for RZV but not for ZVL. Most GBS cases occurred within 30 days after RZV vaccination. Time-to-onset analysis indicated an early-failure pattern. Multivariable analysis showed that male sex and age ≥65 years were associated with an increased reporting risk of GBS following RZV vaccination. Sensitivity analyses restricted to cases occurring within 42 days of vaccination and to vaccines administered alone yielded consistent findings. Similar disproportionality signals for RZV were observed in EudraVigilance. This pharmacovigilance study identified a disproportionate reporting signal of GBS associated with RZV but not with ZVL. Although causality cannot be established, continued post-marketing surveillance of neurological adverse events following herpes zoster vaccination is warranted.
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by harnessing the immune system to target tumors. The introduction of ipilimumab, an anti-CTLA-4 monoclonal antibody, marked a major milestone in immuno-oncology when it was approved by the U.S. Food and Drug Administration (FDA) in 2011 for advanced melanoma. By blocking CTLA-4, ipilimumab enhances T-cell activation and promotes antitumor immunity. Subsequent development and approval of anti-PD-1 and anti-PD-L1 antibodies, such as nivolumab and pembrolizumab, since 2014 have broadened the scope of ICI therapy to various malignancies, often demonstrating improved tolerability relative to CTLA-4 inhibition. While these agents have significantly improved clinical outcomes, they also disrupt immune homeostasis, leading to immune-related adverse events (irAEs), in which healthy tissues are attacked by the immune system. Among these, gastrointestinal irAEs - including hepatitis and colitis - are frequently observed and may require intensive management. These toxicities are immunologically mediated and differ substantially from adverse effects associated with conventional cytotoxic chemotherapy. As ICIs gain broader indications clinicians must be prepared to identify and manage irAEs promptly. This review provides an in-depth discussion of ICI-associated gastrointestinal toxicities, emphasizing their epidemiology, immunopathogenesis, diagnostic strategies, and therapeutic management, in line with the latest clinical guidelines from major oncological societies such as ASCO and ESMO.
Common variable immunodeficiency (CVID) is associated with diverse clinical manifestations. This systematic review aimed to explore associations between disease factors and clinical outcomes in patients with CVID. Eligible studies included patients with CVID and reported associations between disease factors and clinical outcomes (e.g., autoimmune cytopenia, bronchiectasis, infections, lung damage, malignancy, and mortality). Quality assessment was conducted using the Newcastle-Ottawa Scale. Thirty-nine studies met inclusion criteria. The occurrence of lymphadenopathy or splenomegaly was associated with an increased risk of autoimmune cytopenia and lung damage specific to granulomatous-lymphocytic interstitial lung disease; splenomegaly was associated with increased risk of bronchiectasis. Higher levels of switched memory B (smB) cells and marginal zone B cells were associated with reduced risks of lung damage; higher levels of smB cells were associated with a reduced risk of autoimmune cytopenia. Elevated CD21low B cells were associated with increased risks of autoimmune cytopenia, lung damage, and infections. Higher total B cells were associated with lower risk of bronchiectasis and mortality. These findings suggest specific relationships are present between lymphoproliferation markers and B-cell subsets and clinical outcomes in CVID. Limitations including heterogeneity in study designs and low- to moderate-quality evidence underscore the need for additional research to validate these associations.
Immune checkpoint inhibitors (ICI) have transformed cancer therapy but can disrupt immune tolerance, causing immune-related adverse events (irAE) in various organs. ICI-induced neurological irAE encompass a heterogeneous spectrum of central and peripheral nervous system disorders. A recently proposed diagnostic algorithm recommends first excluding alternative etiologies, then confirming neuroinflammation using laboratory or radiological evidence. The clinical presentation of neurological irAE is often atypical and may go unrecognized in routine practice, and the impact of irAE on morbidity and mortality is disproportionately high, particularly in phenotypes with overlapping cardiac or respiratory involvement. These facts, along with the early onset, rapid progression, and frequent corticosteroid-refractoriness characteristic of many neurological irAE, underscore the need for heightened clinical vigilance and rapid initiation of immunomodulatory therapy. Targeted biologics are also under active investigation in response to the growing recognition of corticosteroid-refractory neurological irAE. Triple M syndrome—the concurrent occurrence of ICI-induced myasthenia, myositis, and myocarditis—represents the most severe and life-threatening irAE. Certain high-risk populations, including patients with pre-existing neurological autoimmune diseases, thymoma, or paraneoplastic neurologic syndromes, may be predisposed to this and other severe neurological irAE. Future research should focus on refining predictive biomarkers, including autoantibody profiles, cytokine signatures, and neuro-injury markers.
Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis, whereas antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis that frequently involves the kidneys and lungs. Although an overlap between SSc and AAV has been reported, ANCA-positive IgA nephropathy (IgAN) in SSc has not been described. Clinically, ANCA-positive IgAN resembles AAV, posing challenges for disease classification and management. However, the optimal treatment strategy for such overlapping cases has not yet been established. We report the case of a 73-year-old woman with long-standing SSc and interstitial lung disease who developed rapidly progressive glomerulonephritis. She was positive for myeloperoxidase-ANCA, and renal biopsy demonstrated crescentic glomerulonephritis with mesangial IgA and C3 deposition, raising the possibility of concomitant IgAN. The patient was treated with glucocorticoids (GCs) and rituximab (RTX) as induction therapy, followed by mycophenolate mofetil (MMF) as maintenance therapy, resulting in a marked reduction in proteinuria and stabilization of renal function. This case underscores the importance of considering ANCA-positive IgAN in SSc patients presenting with renal dysfunction and suggests that combination therapy with RTX and MMF may represent a feasible therapeutic option for this rare overlap condition.
Macrophages play a pivotal role in the progression of synovitis and joint destruction in rheumatoid arthritis (RA). MS4A4A, a transmembrane protein, has been linked to RA disease activity, but its role in synovitis remains unclear. The present cross-sectional study analyzed MS4A4A and CX3CR1 expression on monocytes and macrophages from peripheral blood and synovial tissue from 15 RA and 14 osteoarthritis (OA) patients. MS4A4A+ cells were increased in RA compared to OA across all monocyte subsets (p < 0.001). In the synovium, MS4A4A was selectively elevated on infiltrating (CD206-MerTK-) macrophages in RA (p = 0.008), but not on resident macrophages. In RA, MS4A4A+ non-classical monocytes correlated with MS4A4A+ infiltrating macrophages (r = 0.44, p = 0.016), and these infiltrating macrophages correlated with the Clinical Disease Activity Index (CDAI) (r = 0.58, p = 0.024). Across all subsets, MS4A4A+ monocytes expressed higher CX3CR1 than MS4A4A- monocytes (p < 0.001); only MS4A4A+CX3CR1+ non-classical monocytes correlated with MS4A4A+ infiltrating macrophages (r = 0.57, p = 0.026). MS4A4A may therefore link systemic monocyte upregulation to local infiltrating macrophage accumulation and disease activity. Given MS4A4A's reported role in promoting M2 macrophage polarization, its selective upregulation on infiltrating macrophages may indicate a plastic macrophage population and a potential biomarker for predicting therapeutic response in RA.
Alopecia areata (AA) is a common autoimmune, non-scarring hair loss disease in which anagen hair follicles are predominantly affected. Typically, from a single to multiple and round to oval patchy hair loss is observed in AA with a tendency for spontaneous regression; however, total scalp or whole-body hair loss can be seen in severe cases. 'IFN-γ-IL-15 cytokine loop' existing between autoreactive cytotoxic T cells and hair follicle epithelial cells underlies AA intractability, leading to the development of Janus kinase inhibitors (JAKis) inhibiting the downstream signaling pathways as remedies for severe AA. JAKis were shown to be effective and tolerable in clinical studies and now, baricitinib and ritlecitinib have been used for severe AA in Japan. Despite the fact that these medications can achieve clinically meaningful hair regrowth in around 30%-40% of treated patients, nearly 30% of patients have been found to be non-responders both in post-hoc analyses and real-world experience including ours. In addition, relapse can be seen not only in those who are downtitrated or discontinued medication but also in patients under treatment, leaving room for further improvement/development. New medications and/or dosing regimens tested in currently ongoing/planned clinical trials have potential to address JAKi-associated unmet needs in severe AA.
Eosinophilic cholangitis (EC) is a rare, benign disorder characterized by eosinophilic infiltration of the bile ducts, often mimicking cholangiocarcinoma or sclerosing cholangitis. In this report, we present the case of an 84-year-old woman who presented with biliary stricture, peripheral eosinophilia, and elevated serum IgG4 levels. Liver biopsy revealed prominent eosinophilic infiltration without definitive findings of IgG4 sclerosing cholangitis (IgG4-SC). The patient responded promptly to corticosteroid therapy, although biliary abnormalities on magnetic resonance cholangiopancreatography persisted for another 16 months. This case highlights the diagnostic challenge of differentiating EC from IgG4-SC and underscores the importance of considering EC in patients with biliary strictures and eosinophilia.
