Serum inflammatory biomarkers associated with disease severity and response to dupilumab treatment in bullous pemphigoid: A cluster analysis.

BACKGROUND: Dupilumab, a novel therapy targeting the T helper (Th) 2-mediated inflammation, is showing clinical benefits in treating bullous pemphigoid (BP). However, limited research investigated the serum biomarkers that reflect the inflammation alterations throughout the disease course. OBJECTIVES: To explore the changes of the serum inflammatory biomarkers under dupilumab therapy in BP and establish their correlations with disease severity and clinical outcomes. METHODS: This exploratory study evaluated serum samples from 40 patients with BP at baseline, 30 of these patients following 16-week dupilumab therapy, and 20 senior healthy controls. Serum levels of 29 cytokines and chemokines were quantified using the Magnetic Luminex Assay. RESULTS: Two distinct clusters based on serum inflammatory profiles were identified. The first cluster, characterized by elevated levels of inflammatory activation, exhibited worse disease severity and poorer remission outcomes. Following the 16-week dupilumab therapy regimen, a significant suppression of Th2-mediated inflammation in the serum was observed, alongside a relative upregulation of Th1 responses. Patients treated with adjuvant systemic steroids exhibited an enhanced suppression of B cell activating factor compared to those receiving dupilumab alone. Significant correlations were unveiled between Th2 biomarkers and clinical scores, eosinophil counts, and anti-BP180 immunoglobulin G levels. Baseline levels of CCL18, Periostin, interleukin (IL)-6, and IL-16 constitute an optimal combination to distinguish between inflammatory clusters. CONCLUSIONS: Cluster analysis of serum inflammatory biomarkers provided novel insights into the heterogeneity of the inflammation profiles in BP. Baseline levels of CCL18, Periostin, IL-6, IL-16 emerged as effective predictors for disease severity and therapy response to dupilumab.

Autoimmune Retinopathy Following COVID-19: A Case Report.

PURPOSE: To present a presumed case of non-paraneoplastic autoimmune retinopathy (nPAIR) following COVID-19 in a healthy woman. METHODS: A single case was evaluated and followed for 32 months. RESULTS: A healthy 32-year-old woman presented with photopsia and paracentral scotoma (OU) after a recent COVID-19 infection. Past medical history and family history were unremarkable. Her visual acuity was normal (OU). Retinal atrophy, mild disc pallor, and foveal reflex attenuation were observed (OU). Optical coherence tomography (OCT) scans showed outer nuclear layer thinning and ellipsoid zone disruption (OU). The visual field test showed blind spot enlargement and arcuate scotomas (OU). Uveitis workup and underlying malignancy investigations were negative. A diagnosis of nPAIR was presumed. At the time, she refused therapy, and 20 months later, her visual acuity was stable, but there were progressive retinal atrophic changes and visual field constriction. After initiation of glucocorticoids and immunosuppressive therapy, flashing lights completely disappeared, her visual field was stabilized without progression, and OCT scans showed partial recovery of ellipsoid zone. CONCLUSION: SARS-CoV-2 infection may be a trigger for nPAIR in susceptible individuals, but further research is needed to determine this association.

Antiphospholipid Syndrome and Catastrophic Antiphospholipid Syndrome: A Comprehensive Review of Pathogenesis, Clinical Features, and Management Strategies.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs) that predispose individuals to thrombotic events and pregnancy-related complications. APS can occur as a primary condition or in association with other autoimmune diseases, most commonly systemic lupus erythematosus (SLE). Catastrophic APS (CAPS) is a rare, severe variant of APS, marked by rapid-onset, widespread thrombosis leading to multi-organ failure, often triggered by infections, surgical procedures, or cessation of anticoagulation therapy. Both APS and CAPS present significant clinical challenges due to their potential for severe morbidity and mortality. This comprehensive review aims to provide a detailed overview of the pathogenesis, clinical features, diagnostic criteria, and management strategies for APS and CAPS. The review highlights the immunological mechanisms underlying APS, including the role of aPLs, complement system activation, and endothelial cell dysfunction in developing thrombosis. It also outlines the clinical manifestations of APS, such as venous and arterial thrombosis, pregnancy morbidity, and neurological symptoms, along with the diagnostic criteria based on clinical and laboratory findings. The review delves into its pathogenesis, clinical presentation, and diagnostic challenges in the context of CAPS, emphasizing the need for immediate and intensive therapy to manage this life-threatening condition. Current management strategies for APS, including anticoagulant therapy, immunomodulatory treatments, and specific interventions for pregnancy-related complications, are discussed. The review highlights the importance of a multidisciplinary approach for CAPS, combining anticoagulation, high-dose corticosteroids, plasma exchange, and intravenous immunoglobulin. The review also addresses the prognosis and long-term outcomes for patients with APS and CAPS, underlining the necessity for ongoing monitoring and follow-up to prevent recurrent thrombotic events and manage chronic complications. Finally, future directions in research are explored, focusing on emerging therapies, biomarkers for early diagnosis, and the need for clinical trials to advance the understanding and treatment of these complex syndromes. By enhancing the understanding of APS and CAPS, this review aims to improve diagnosis, treatment, and patient care, ultimately leading to better health outcomes for those affected by these conditions.

Nivolumab-Induced Diabetic Ketoacidosis: A Case Report.

Nivolumab, an investigational monoclonal antibody targeting a specific immune pathway, has shown promise in treating various autoimmune diseases. However, like other immunomodulatory agents, it has potential side effects. This case report describes a rare adverse event of nivolumab-induced diabetic ketoacidosis (DKA) in a patient with a history of adrenal insufficiency secondary to nivolumab. The patient presented with symptoms of hyperglycemia, metabolic acidosis, and ketosis after receiving nivolumab therapy for 12 cycles. Prompt recognition and management of nivolumab-induced DKA are crucial to prevent complications and ensure patient safety.

Dupilumab Therapy Modulates Circulating Inflammatory Mediators in Patients with Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by intense pruritus and skin nodules. Beyond the skin, PN involves circulating blood inflammation that may contribute to systemic disease comorbidities. Dupilumab was recently approved for treatment of PN, but its effects on systemic inflammation are unknown. Thus, we aimed to characterize changes in plasma concentrations of inflammatory proteins after dupilumab treatment. In this exploratory study, plasma samples were collected from 3 patients with moderate-to-severe PN before and after ≥6 months of dupilumab treatment. All patients exhibited clinically significant improvements after treatment. Of the 2569 proteins tested, 186 were differentially expressed after treatment (q < 0.1, fold change > 1.3). Downregulated proteins included cytokines associated with T helper (Th) 1 (IFN-γ, TNF-α), Th2 (IL-4, IL-13), and Th17/Th22 (IL-6, IL-22) signaling. Markers of innate immunity (IL-19, toll-like receptor 1, nitric oxide synthase 2), immune cell migration (CCL20, CD177), and fibrosis (IL-11, IL-22) were also decreased (q < 0.1). Gene set variation analysis of Th2, Th17, and epithelial-mesenchymal transition gene sets showed reduced pathway expression in the post-treatment cohort (P < .05). Plasma cytokine levels of IL-11, nitric oxide synthase 2, IL-13, IL-4, and IFNG (R2 > 0.75, q < 0.10) showed the strongest correlations with pruritus severity. Dupilumab may reduce systemic inflammatory proteins associated with multiple immune and fibrosis pathways in patients with PN, potentially modulating the development of systemic disease comorbidities.

T cells and macrophages jointly modulate osteogenesis of mesenchymal stromal cells.

Approximately 5%-10% of fractures go on to delayed healing and nonunion, posing significant clinical, economic, and social challenges. Current treatment methods involving open bone harvesting and grafting are associated with considerable pain and potential morbidity at the donor site. Hence, there is growing interest in minimally invasive approaches such as bone marrow aspirate concentrate (BMAC), which contains mesenchymal stromal cells (MSCs), macrophages (Mφ), and T cells. However, the use of cultured or activated cells for treatment is not yet FDA-approved in the United States, necessitating further exploration of optimal cell types and proportions for effective bone formation. As our understanding of osteoimmunology advances, it has become apparent that factors from anti-inflammatory Mφ (M2) promote bone formation by MSCs. Additionally, M2 Mφ promote T helper 2 (Th2) cells and Treg cells, both of which enhance bone formation. In this study, we investigated the interactions among MSCs, Mφ, and T cells in bone formation and explored the potential of subsets of BMAC. Coculture experiments were conducted using primary MSCs, Mφ, and CD4+ T cells at specific ratios. Our results indicate that nonactivated T cells had no direct influence on osteogenesis by MSCs, while coculturing MSCs with Mφ and T cells at a ratio of 1:5:10 positively impacted bone formation. Furthermore, higher numbers of T cells led to increased M2 polarization and a higher proportion of Th2 cells in the early stages of coculture. These findings suggest the potential for enhancing bone formation by adjusting immune and mesenchymal cell ratios in BMAC. By understanding the interactions and effects of immune cells on bone formation, we can develop more effective strategies and protocols for treating bone defects and nonunions. Further studies are needed to investigate these interactions in vivo and explore additional factors influencing MSC-based therapies.

Network meta-analysis of four common immunomodulatory therapies for the treatment of patients with thin endometrium.

OBEJECTIVE: To compare the effectiveness of endometrial receptivity and pregnancy outcomes of four common immunomodulatory therapies for patients with thin endometrium. METHOD: This systematic review and network meta-analysis using a literature search up to January 2024, to identify relevant trials comparing endometrial receptivity and pregnancy outcomes of human chorionic gonadotropin (hCG), platelet-rich plasma (PRP), infusion of granulocyte colony-stimulating factor (IG-CSF), and peripheral blood mononuclear cell (PBMC) for patients with thin endometrium. We used surface under the cumulative ranking (SUCRA) to ranked four common immunomodulatory therapies on endometrium thickness, implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR). RoB2 and ROBINS-I were used to assess the certainty of evidence. RESULTS: The pooled results of 22 studies showed that hCG (mean difference [MD]: 3.05, 95% confidence interval [CI]: 1.46-4.64) and PRP (MD: 0.98, 95% CI: 0.20-1.76) significantly increase endometrium thickness. The hCG was the best among the IG-CSF (MD = -2.56, 95% CI = -4.30 to -0.82), PBMC (MD = -2.75, 95% CI = -5.49 to -0.01), and PRP (MD = -2.07, 95% CI = -3.84 to -0.30) in increasing endometrium thickness. However, IG-CSF and PRP significantly improved IR (IG-CSF: risk ratio (RR; IG-CSF: RR = 1.33, 95% CI = 1.06-1.67; PRP: RR = 1.63, 95% CI = 1.19-2.23), and LBR (IG-CSF: RR = 1.53, 95% CI = 1.16-2.02; PRP: RR = 1.59, 95% CI = 1.08-2.36). CONCLUSIONS: Available evidence reveals that hCG and subcutaneous or intrauterine CSF (SG-CSF) may be the best treatment options for current thin endometrium patients. However, future high-quality and large-scale studies are necessary to validate our findings.

Spatial transcriptomic brain imaging reveals the effects of immunomodulation therapy on specific regional brain cells in a mouse dementia model.

Increasing evidence of brain-immune crosstalk raises expectations for the efficacy of novel immunotherapies in Alzheimer's disease (AD), but the lack of methods to examine brain tissues makes it difficult to evaluate therapeutics. Here, we investigated the changes in spatial transcriptomic signatures and brain cell types using the 10x Genomics Visium platform in immune-modulated AD models after various treatments. To proceed with an analysis suitable for barcode-based spatial transcriptomics, we first organized a workflow for segmentation of neuroanatomical regions, establishment of appropriate gene combinations, and comprehensive review of altered brain cell signatures. Ultimately, we investigated spatial transcriptomic changes following administration of immunomodulators, NK cell supplements and an anti-CD4 antibody, which ameliorated behavior impairment, and designated brain cells and regions showing probable associations with behavior changes. We provided the customized analytic pipeline into an application named STquantool. Thus, we anticipate that our approach can help researchers interpret the real action of drug candidates by simultaneously investigating the dynamics of all transcripts for the development of novel AD therapeutics.

A Rare Presentation: Bilateral Necrotizing Scleritis in Primary Sjögren's Syndrome.

PURPOSE: We report a rare and challenging case of bilateral necrotizing scleritis in primary Sjögren's syndrome (pSS). METHODS: Retrospective case report. RESULTS: A 72-year-old diabetic, hypertensive female patient presented with sudden onset of painful red left eye and was noted to have a corneal ulcer with severe thinning. She was managed with topical fortified antibiotics and tissue glue and bandage contact lens. During subsequent follow-ups, she developed necrotizing scleral melts in both eyes. On investigations, antinuclear antibodies were positive in a dilution of 1:160 with 2+ speckled pattern, with antinuclear antibody line immunoassay showing anti SS-A/ Ro52 positive. In view of rapidly developing scleral thinning and impending perforation, she was started on intravenous methylprednisolone 1 g/day for 3 days, along with steroid-sparing immunomodulatory therapy (mycophenolate mofetil 500 mg twice a day). She showed a rapid response to therapy and is currently stable on tapering oral steroids and mycophenolate mofetil. CONCLUSION: This case underscores the unique presentation of pSS, characterized by bilateral necrotizing scleritis. The favorable outcome was attained through prompt immunosuppressive intervention and a collaborative, multidisciplinary approach. Further, this case report addresses a gap in the existing literature concerning pSS-related scleritis. It also emphasizes the crucial role of a rheumatologist in the comprehensive management of this condition.

Recent Advances in Immunomodulatory Therapy in Sepsis: A Comprehensive Review.

Sepsis remains a critical healthcare challenge, characterized by dysregulated immune responses to infection, leading to organ dysfunction and high mortality rates. Traditional treatment strategies often fail to address the underlying immune dysregulation, necessitating exploring novel therapeutic approaches. Immunomodulatory therapy holds promise in sepsis management by restoring immune balance and mitigating excessive inflammation. This comprehensive review examines the pathophysiology of sepsis, current challenges in treatment, and recent advancements in immunomodulatory agents, including biologics, immunotherapy, and cellular therapies. Clinical trial outcomes, safety profiles, and future research and clinical practice implications are discussed. While immunomodulatory therapies show considerable potential in improving sepsis outcomes, their successful implementation requires further research, collaboration, and integration into standard clinical protocols.

Rapidly Progressive Dementia Presenting as Schizophrenia Spectrum Disorder: A Diagnostic Dilemma.

Rapidly progressive dementia (RPD) presenting initially as schizophrenia spectrum disorder poses significant diagnostic challenges. We present the case of a 55-year-old woman initially diagnosed with schizophrenia spectrum disorder due to symptoms including social withdrawal, disorganized behavior, and psychosis. However, the rapid progression of cognitive decline and motor dysfunction prompted further investigation, leading to the diagnosis of anti-N-methyl-d-aspartate (NMDA) receptor antibody-mediated encephalitis. Cerebrospinal fluid analysis revealed the presence of anti-NMDA receptor antibodies, guiding targeted immunomodulatory therapy with intravenous immunoglobulin and corticosteroids. This resulted in significant clinical improvement, highlighting the importance of comprehensive diagnostic evaluation and timely initiation of immunomodulatory therapy in autoimmune-mediated RPD. This case underscores the complexities of overlapping psychiatric and neurological conditions and emphasizes the need for a multidisciplinary approach to diagnosis and management.

[The German COVID-19 rheumatism register]. / Das deutsche COVID-19-Rheumaregister.

At the beginning of the coronavirus disease 2019 (COVID-19) pandemic in December 2019 there was no available evidence regarding the management of immunosuppressive or immunomodulatory treatment and the potential outcomes of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections in inflammatory rheumatic diseases (IRD). As a result, the Justus Liebig University of Giessen, Germany, in collaboration with the German Society for Rheumatology, established the German COVID-19 register ( www.covid19-rheuma.de ). The COVID-19 register enabled for the first time a systematic documentation and evaluation of viral infections in patients with IRD. The data collection started as early as March 2020. Currently, the register is one of the largest global registers in the field of COVID-19 and IRD. As of 18 December 2023 the register has recorded more than 7100 cases. The first scientific findings on SARS-CoV­2 infections in IRD patients were generated from the register in 2020, showing an association between disease activity of IRD, certain comorbidities, such as cardiovascular diseases and treatment with rituximab, with an unfavorable course. The contents and construction of the database of the register were designed at the conception to allow collaboration and data exchange with other national and international registers (e.g., EULAR COVID-19 register, COVID-19 global rheumatology alliance and the Lean European open survey on SARS-CoV­2 infected patients). In addition, other registers and surveys were initiated. A vaccination register documents the tolerability and possible adverse reactions to COVID-19 vaccination in IRD patients. The data resulted in numerous publications and formed the basis for national and international recommendations for action in the care and vaccination of IRD patients during the COVID-19 pandemic. In summary, the German COVID-19 register has made a significant contribution to the understanding of the course of COVID-19 in IRD patients and has facilitated international collaboration for a better understanding of COVID-19 and IRD.

Intravenous cyclophosphamide therapy for patients with severe ocular inflammatory diseases who failed other immunomodulatory therapies.

BACKGROUND: Ocular inflammatory diseases, including scleritis and uveitis, have been widely treated with immunomodulatory therapies (IMTs) as a steroid-sparing approach. Such strategy includes conventional therapies (antimetabolites, alkylating agents, and calcineurin inhibitors) as well as biologic agents like adalimumab, infliximab, rituximab, and tocilizumab. Cyclophosphamide (CP) is an alkylating agent and mainly inhibits the functioning of both T and B cells. Though known to have potential adverse events, including bone marrow suppression, hemorrhagic cystitis, and sterility, CP has been shown to be efficacious, especially in recalcitrant cases and when used intravenous (IV) for a limited period. MAIN FINDINGS: We conducted a retrospective case-series to assess the safety and efficacy of CP therapy for patients with severe ocular inflammatory diseases who failed other IMTs. Medical records of 1295 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were reviewed. Seven patients (10 eyes) who received CP therapy for ocular inflammatory diseases with at least one year of follow-up were included. The mean age of the patients (4 males, 3 females) was 61.6 ± 14.9 (43.0-89.0) years. Clinical diagnoses included necrotizing scleritis (5 eyes), peripheral ulcerative keratitis (2 eyes), orbital pseudotumor (1 eye), HLA-B27 associated panuveitis and retinal vasculitis (2 eyes). Ocular disease was idiopathic in 3 patients, and was associated with rheumatoid arthritis, IgG-4 sclerosing disease, dermatomyositis, and ankylosing spondylitis in 1 patient each. All the patients had history of previous IMT use including methotrexate (5), mycophenolate mofetil (3), azathioprine (1), tacrolimus (1), adalimumab (2), infliximab (4), and rituximab (1). The mean follow-up time was 34.4 ± 11.0 (13-45) months, and mean duration of CP therapy was 11.9 ± 8.8 (5-28) months. Remission was achieved in 5 patients (71.4%). Four patients (57.1%) experienced transient leukopenia (white blood cell count < 4000/mL). SHORT CONCLUSION: CP therapy can be considered a potentially effective and relatively safe therapeutic option for patients with severe ocular inflammatory diseases who failed other IMTs including biologics (TNFa and CD20 inhibitors).

Personalized Approach to Chronic Antibiotic-Refractory Pouchitis: A Case Report and Review of the Literature.

Patients who undergo restorative proctocolectomy and ileoanal anastomosis can develop pouchitis as a common chronic complication. A rare subset of patients fails to respond to multiple antibiotic therapies and develop chronic antibiotic-refractory pouchitis (CARP). We present a case of a 45-year-old male with pouchitis refractory to chronic antibiotic therapy and histology demonstrating chronic inflammatory changes. Management involved mesalamine and probiotics, resulting in a positive clinical response and symptom absence on follow-up. This case highlights the intricacies of treating chronic pouchitis post ileoanal anastomosis, showcasing the efficacy of a personalized approach using mesalamine and probiotics. CARP is emerging as an entity associated with poor quality of life and increased healthcare costs. CARP fails to respond to multiple courses of antibiotic therapy. Therefore, the management of CARP is difficult and limited. Current literature on the management of CARP is scarce and mainly involves immunomodulatory therapy and probiotics. It is essential to keep this differential diagnosis in mind in patients with recurrent pouchitis episodes and start them on immunomodulator treatment and probiotics rather than repeated courses of antibiotics.

Suppression of antitumor immune signatures and upregulation of VEGFA as IDH-mutant gliomas progress to higher grade.

OBJECTIVE: Several studies have compared the immune microenvironment of isocitrate dehydrogenase (IDH)-wildtype glioma versus IDH-mutant glioma. The authors sought to determine whether histological tumor progression in a subset of IDH-mutant glioma was associated with concomitant alterations in the intratumoral immune microenvironment. METHODS: The authors performed bulk RNA sequencing on paired and unpaired samples from patients with IDH-mutant glioma who underwent surgery for tumor progression across multiple timepoints. They compared patterns of differential gene expression, overall inflammatory signatures, and transcriptomic measures of relative immune cell proportions. RESULTS: A total of 55 unique IDH-mutant glioma samples were included in the analysis. The authors identified multiple genes associated with progression and higher grade across IDH-mutant oligodendrogliomas and astrocytomas. Compared with lower-grade paired samples, grade 4 IDH-mutant astrocytomas uniquely demonstrated upregulation of VEGFA in addition to counterproductive alterations in inflammatory score reflective of a more hostile immune microenvironment. CONCLUSIONS: Here, the authors have provided a transcriptomic analysis of a progression cohort for IDH-mutant glioma. Compared with lower-grade tumors, grade 4 astrocytomas displayed alterations that may inform the timing of antiangiogenic and immune-based therapy as these tumors progress.

[Pregnancy and breastfeeding in women with multiple sclerosis]. / Schwangerschaft und Stillzeit bei Frauen mit Multipler Sklerose.

The diagnosis of multiple sclerosis (MS) in women of reproductive age is associated with many uncertainties regarding childbearing and lactation. Pregnancies of MS patients are not usually considered high-risk pregnancies per se. The likelihood of pregnancy complications or adverse pregnancy outcomes is not increased by the disease; however, a careful planning of pregnancy is important in order to choose the treatment option with the greatest benefit for the mother and the least possible risk for the baby. For highly active courses of the disease, anti-CD20 antibodies, cladribine, or continued administration of natalizumab show the best data. Patients with MS can be supported in their desire to breastfeed. If women have had a very active disease course, it is recommended that treatment should be started as soon as possible postpartum. Interferon-beta preparations, glatiramer acetate and ofatumumab are also approved for use during breastfeeding but off-label breastfeeding is also possible with other monoclonal antibodies.

The Role of Corticosteroids and Immunomodulatory Therapy in the Management of Infectious Uveitis.

PURPOSE: The index review aims to provide an update on the role of corticosteroids and steroid-sparing immunomodulatory therapy (IMT) in managing patients with infectious uveitis. METHOD: Narrative literature review. RESULTS: Corticosteroids and immunomodulatory therapy (IMT) focus on the host defense system instead of the pathogen, adjusting exaggerated inflammatory reactions to reduce potential harm to ocular tissues. Systemic or local corticosteroids are primarily selected as adjunctive medication for infectious uveitis. Concomitant corticosteroids have also been used in cases of paradoxical worsening in ocular tuberculosis and immune recovery uveitis in cytomegalovirus (CMV) retinitis. While there is no well-established evidence to support the use of IMT in infectious uveitis, it is occasionally used in clinical settings to treat persistent inflammation following resolution of infection such as cases of ocular tuberculosis and ocular syphilis where an insufficient response is observed with corticosteroids. CONCLUSION: There is no consensus on the position of immunomodulatory therapy in the management of infectious uveitis with different etiologies. The index review provides an overview of available adjunctive corticosteroids and IMT options to assist clinicians in managing such disease entities more efficiently.