Immunomodulatory Drugs Research Articles

Link Between PTSD and Autoimmune Diseases: A Path to Effective Treatment. Literature review

Introduction and Objective: PTSD is a psychiatric disorder associated with the experience of a traumatic event in the past. Changes in the immune system are presented as one of the mechanisms involved in its pathophysiology. The purpose of this review is to investigate the potential link between PTSD and autoimmune diseases, as well as to highlight the therapeutic implications. Review methods: The review is based on scientific publications in PubMed, Science Direct and NCBI databases. After an initial evaluation of the articles, primarily observational studies and meta-analyses on the relationship between PTSD and autoimmune diseases, the underlying pathophysiology, and new potential therapeutic options were selected. Abbreviated description of the state of knowledge: PTSD is associated with numerous changes in the immune and neuroendocrine systems. As a result, patients affected by the disorder are susceptible to developing somatic diseases, including autoimmune diseases. Numerous studies indicate a reciprocal effect on the increased risk and aggravation of symptoms for PTSD and autoimmune diseases due to certain similarities in pathophysiology. New treatment options for PTSD targeting the immune system with anti-inflammatory and immunomodulatory drugs are currently being explored. Summary: This review article highlights the existing reciprocal relationship between PTSD and autoimmune diseases, which carries important clinical implications. The authors of the review emphasize the importance of better understanding the pathophysiology of PTSD and the early diagnosis and treatment of people with PTSD, as well as the need to develop new effective treatments for PTSD that can help reduce the risk of developing autoimmune diseases in people with the disorder. As suggested, treatment targeting the immune system may be an effective therapeutic option for patients with PTSD.

Changes in serum levels of pro- and anti-inflammatory cytokines in women with papillomavirus infection before and after therapy”

Papillomavirus infections (PVI) are among the most common sexually transmitted diseases in the young population. A long, sluggish inflammatory process sufficiently worsens adequate preparation for normal pregnancy. Herpesvirus and Chlamydia infections are the most frequent associations with papillomavirus infection. Many authors believe that PVI may cause dysregulation of pro- and anti-inflammatory cytokines revealed in blood serum. Currently, there are no uniform standards for management and treatment of women with papillomavirus infection without pronounced clinical manifestations, in order to prevent morphofunctional disorders of genitourinary system leading to reproductive disorders. However, most authors believe that antiviral and immunomodulatory drugs are the main tool of therapy against expansion of pathogens in the body. The aim of our study was to compare changes in the levels of IL-17, IL-12 p70, IL-12 p40, IL-13 and TGF-p1 in blood serum of women with papillomavirus infection before and after therapy with Inosine pranobex (IP) and Solanum tuberosum (ST). We conducted a survey of 137 patients with papillomavirus infection treated with drugs containing Inosine pranobex and Solanum tuberosum as active substances. The levels of IL-17, IL-12 p70, IL-12 p40, IL-13, and TGF-p1 in blood serum were determined using specific reagents from RD Diagnostics Inc. (USA). Changes in pro- and anti-inflammatory cytokines before therapy were as follows: decreased levels were found for IL-12 p70, p40; increased values were revealed for IL-13, IL-17, and TGF-p1. After the courses of therapy, we have registered the following changes in PVI-infected patients treated with synthetic drug Inosine pranobex (IP): the levels of IL-12 p70, IL-12 p40 were increased, along with decrease in IL-13 and TGF-p1. Meanwhile, ST therapy was associated with increase in IL-12 p70, IL-12 p40, and a decrease in IL-13 and TGF-p 1. With IP therapy, patients with combined HPV + HV infection showed an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13, while TGF-p1 did not change. Following ST therapy, these patients exhibited higher IL-12 p70, IL-12 p40, decreased IL-13, whereas TGF-p 1 remained unchanged. In the group of women with HPV + Chlamydia infection, an increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TGF-p1 was associated with IP therapy. An increase in IL-12 p70, IL-12 p40 and a decrease in IL-13 and TGF-p 1 were shown after ST therapy. In all groups of patients, IL-17 remained at high levels after therapy without significant differences between the mentioned subgroups. In the groups of patients treated with IP. we have recorded a general normalization of immune disorders.

Use of Glucagon-like peptide 2 (GLP-2) analogs in inflammatory bowel disease

Introduction: Inflammatory bowel disease (IBD) is a chronic condition that involves long-term treatment and chronic idiopathic inflammation within the gastrointestinal tract. The predominant forms of IBD are: Crohn's disease and ulcerative colitis. These diseases cause significant physical as well as psychological dysfunction - patients with this condition are thought to have an increased risk of depression as well as anxiety. Standard treatment for IBD most commonly includes aminosalicylates, corticosteroids, immunomodulatory drugs, and biologic therapy. In some cases, particularly when it comes to Crohn's disease, it is necessary to remove a portion of the inflamed bowel. Multiple segmental bowel resections can result in the rare but serious complication of short bowel syndrome, which leads to intestinal failure and necessitates parenteral nutrition. Glucagon-like peptide-2 exhibits intestinotropic properties and also acts as a growth factor in the gastrointestinal tract, thereby increasing intestinal perfusion, causing increased absorption of nutrients, and enhancing proliferative mechanisms while inhibiting apoptotic processes. Methods: We carefully reviewed the medical literature on inflammatory bowel disease, short bowel syndrome and the potential treatment of this condition with GLP-2 and its analogs. The materials for the analysis we presented came from the PubMed database. Conclusions: Glucagon-like peptide 2 (GLP-2) analogs may prove to be new treatments for short bowel syndrome (SBS). They exhibit growth-stimulating effects on the intestinal membrane and promote normal function.

New views on the complex interplay between degeneration and autoimmunity in multiple sclerosis.

Multiple sclerosis (MS) is a frequently disabling neurological disorder characterized by symptoms, clinical signs and imaging abnormalities that typically fluctuate over time, affecting any level of the CNS. Prominent lymphocytic inflammation, many genetic susceptibility variants involving immune pathways, as well as potent responses of the neuroinflammatory component to immunomodulating drugs, have led to the natural conclusion that this disease is driven by a primary autoimmune process. In this Hypothesis and Theory article, we discuss emerging data that cast doubt on this assumption. After three decades of therapeutic experience, what has become clear is that potent immune modulators are highly effective at suppressing inflammatory relapses, yet exhibit very limited effects on the later progressive phase of MS. Moreover, neuropathological examination of MS tissue indicates that degeneration, CNS atrophy, and myelin loss are most prominent in the progressive stage, when lymphocytic inflammation paradoxically wanes. Finally, emerging clinical observations such as "progression independent of relapse activity" and "silent progression," now thought to take hold very early in the course, together argue that an underlying "cytodegenerative" process, likely targeting the myelinating unit, may in fact represent the most proximal step in a complex pathophysiological cascade exacerbated by an autoimmune inflammatory overlay. Parallels are drawn with more traditional neurodegenerative disorders, where a progressive proteopathy with prion-like propagation of toxic misfolded species is now known to play a key role. A potentially pivotal contribution of the Epstein-Barr virus and B cells in this process is also discussed.

From Triple- to Penta-Exposed Multiple Myeloma: A Real-World Study in a Medicare Population.

Treatment of multiple myeloma (MM) has been transformed by novel therapies, including CD38 monoclonal antibodies (mAbs), immunomodulatory drugs (IMiDs), and proteasome inhibitors (PIs), resulting in increasing numbers of patients who are triple-class exposed (TCE; exposed to ≥ 1 drug in each class). Many patients are penta-exposed (PE; ≥ 2 IMiDs, ≥ 2 PIs, and a CD38 mAb), some are triple-class refractory (TCR), and some are PE and TCR (PE-TCR). Data on real-world outcomes in elderly patients with MM across this spectrum of exposure are limited. Data from the Medicare Chronic Conditions Warehouse Database from November 2006-December 2020 were used to examine cohorts of TCE, TCR, PE, and PE-TCR patients. Outcomes were assessed from the start of the index line of therapy (LOT), defined as the first LOT after becoming TCE or PE. A total of 2830 TCE, 1371 TCR, 1121 PE, and 774 PE-TCR patients were identified. Pomalidomide was the most frequently used medication for the index LOT in all cohorts (32.6% [PE-TCR] to 43.3% [TCR]). The most frequently used regimens for the index LOT were pomalidomide plus daratumumab for TCE (17.2%) and PE (7.0%), pomalidomide plus carfilzomib for TCR (10.3%), and pomalidomide plus elotuzumab for PE-TCR (7.4%). Median time to discontinuation (TTD) ranged from 4.2 (PE-TCR) to 6.9 (TCE) months, and overall survival (OS) ranged from 13.0 (TCR) to 15.9 (PE) months. Healthcare resource utilization (HRU) was lowest for TCE and highest for PE-TCR patients. Mean monthly healthcare costs (HCC) ranged from $23,091 (TCE) to $24,412 (PE-TCR). MM medications represented 66.2% (PE-TCR) to 72.8% (TCE) of costs. In this study across a spectrum of Medicare TCE patients, there was heterogeneity in treatment regimens, suggesting no standard of care. TTD and OS were short, and HRU and HCC were high. These results underscore the potential for new therapies in this population.

CAR-T Therapy in Relapsed Refractory Multiple Myeloma.

Multiple myeloma is a plasma cell neoplasm. The emergence of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies has improved the prognosis of multiple myeloma patients. However, some patients are still insensitive to conventional therapy or frequently relapse after remission. Chemotherapy based on proteasome inhibitors or immunomodulatory drugs is ineffective in controlling the progression of relapsed refractory multiple myeloma. No consensus has been reached on treating relapsed refractory multiple myeloma to date. Recently chimeric antigen receptor T cells therapy has shown promising results that could achieve rapid remissions of patients and improve their prognoses. Additionally, most patients in chimeric antigen receptor T cell clinical trials were triple-refractory multiple myeloma patients, indicating that chimeric antigen receptor T cell immunotherapy could overcome drug resistance to new drugs. Since single immunotherapies are prone to acquired resistance, combination immunotherapies based on emerging immunotherapies may solve this issue. Achieving complete remission and minimal residual disease negative status as soon as possible is beneficial to patients. This paper reviewed the main chimeric antigen receptor T cell products in relapsed refractory multiple myeloma, and it explained the drug resistance mechanism and improvement methods of chimeric antigen receptor T cells therapy. This review summarized the best beneficiaries of chimeric antigen receptor T cell therapy and the salvage treatment of disease recurrence after chimeric antigen receptor T cell therapy, providing some ideas for the clinical application of chimeric antigen receptor T cells.

Safety and efficacy of belantamab mafodotin with pembrolizumab in patients with relapsed or refractory multiple myeloma.

Belantamab mafodotin (belamaf) has shown promising antimyeloma activity in relapsed or refractory multiple myeloma (RRMM) as a single agent. It was hypothesized that its multimodal activity may be enhanced by programmed cell death protein 1 pathway inhibition and activation of T cell-mediated antitumor responses. This study investigated the efficacy and safety of belamaf with pembrolizumab in patients with RRMM. DREAMM-4 (NCT03848845) was an open-label, single-arm, phase 1/2 study divided into dose-escalation (part 1) and dose-expansion (part 2) phases. Patients were ≥18 years old with ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 agent. Patients received belamaf (2.5 or 3.4 mg/kg, part 1; 2.5 mg/kg, part 2) and 200 mg pembrolizumab for ≤35 cycles. Of 41 enrolled patients, 34 (n=6 part 1, n=28 part 2) who received 2.5 mg/kg belamaf plus pembrolizumab were included in this final analysis. Sixteen patients (47%) achieved an overall response. Minimal residual disease negativity was achieved in three of 10 patients who had very good partial response or better. Five of eight patients who had prior anti-B-cell maturation antigen therapy achieved partial response or better, including two who had B-cell maturation antigen-refractory disease. Common grade ≥3 adverse events were keratopathy (38%) and thrombocytopenia (29%). Despite belamaf-related ocular events, quality-of-life measures remained stable over time. No new safety signals were observed. The results of DREAMM-4 demonstrated clinical activity and a favorable safety profile of belamaf plus pembrolizumab in patients with RRMM. This trial is registered at www. gov as NCT03848845.

CiRS-7 circular RNA overexpression in plasma cells is a promising molecular biomarker of unfavorable prognosis in multiple myeloma.

Several non-coding RNAs are known to be associated with the pathobiology and progression of multiple myeloma (MM). ciRS-7 (also known as CDR1-AS), a key oncogenic circular RNA (circRNA) that sponges miR-7-5p and other cancer-related microRNAs, was recently found to be downregulated in malignant plasma cells resistant to immunomodulatory drugs. Considering that various circRNAs have a strong potential as molecular biomarkers, we aimed to investigate the expression of ciRS-7 in plasma cell disorders, assess its prognostic importance in MM, and compare these findings with those of individuals with smoldering MM (SMM) and monoclonal gammopathy of unknown significance (MGUS). This study included 171 patients (110 newly diagnosed MM, 34 SMM, and 27 MGUS cases), from which bone marrow aspirate samples were collected for CD138+ plasma cell selection. Total RNA was reversely transcribed using random hexamer primers, and the expression levels of ciRS-7 were quantified using an in-house-developed protocol that includes pre-amplification and real-time quantitative polymerase chain reaction. ciRS-7 levels were found to significantly differ among CD138+ plasma cells of MM, SMM, and MGUS patients. ROC analysis indicated that ciRS-7 expression effectively distinguishes between MM and SMM patients. Moreover, high levels of ciRS-7 were associated with unfavorable prognosis in MM, independently of MM patients' age and Revised International Staging System stage. Additionally, in silico analysis predicted the binding of 85 microRNAs to ciRS-7. In conclusion, this study provides novel insights into the role of ciRS-7 as a promising molecular marker able to distinguish MM from SMM and predict prognosis in MM.

IgA Nephropathy – Current and Future Perspectives in Treatment

Abstract Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy in our adult population and is associated with a high lifetime risk of kidney failure. Recent years have succeeded in describing the pathogenesis of IgAN at the molecular level, where immune complexes containing specific galactose deficient IgA1 play an essential role. The gold standard in the diagnosis of IgAN remains renal biopsy followed by determination of a prognostic score using the Oxford classification. A fundamental goal in the management of patients with IgAN is to optimize supportive therapy involving active lifestyle modification and renoprotective medications. The reno-protective drug menu has recently been expanded to include effective sodium-glucose cotransporter 2 inhibitors (SGLT2i), and additional agents are on the way. However, despite maximal supportive therapy, a wide range of patients remain at high risk of disease progression and require the deployment of immunomodulatory drugs. To date, however, we do not have high potency agents that are well tolerated and safe. This has led to the initiation of many studies to target the inflammatory process at different pathogenetic levels. In this article, we summarize the current standards in the treatment of IgAN and present new promising options in the management of this disease.

The Clinical Approach to Interstitial Lung Disease in Childhood: A Narrative Review Article.

Interstitial lung disease (ILD) comprises a group of respiratory diseases affecting the interstitium of the lungs, which occur when a lung injury triggers an abnormal healing response, and an inflammatory process leads to altered diffusion and restrictive respiratory dysfunction. The term "interstitial" may be misleading, as other components of the lungs are usually also involved (epithelium, airways, endothelium, and so on). Pediatric conditions (childhood interstitial lung disease, chILD) are different from adult forms, as growing and developing lungs are affected and more diverse and less prevalent diseases are seen in childhood. Diffuse parenchymal lung disease (DPLD) and diffuse lung disease (DLD) can be used interchangeably with ILD. Known etiologies of chILD include chronic infections, bronchopulmonary dysplasia, aspiration, genetic mutations leading to surfactant dysfunction, and hypersensitivity pneumonitis due to drugs or environmental exposures. Many forms are seen in disorders with pulmonary involvement (connective tissue disorders, storage diseases, malignancies, and so on), but several conditions have unknown origins (desquamative pneumonitis, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia in infancy, and so on). Currently, there is no consensus on pediatric classification; however, age grouping is proposed as some specific forms are more prevalent in infancy (developmental and growth abnormalities, surfactant dysfunction mutations, etc.) and others are usually seen in older cohorts (disorders in normal or immunocompromised hosts, systemic diseases, etc.). Clinical manifestations vary from mild nonspecific symptoms (recurrent respiratory infections, exercise intolerance, failure to thrive, dry cough, etc.) to a severe clinical picture (respiratory distress) and presentation related to the child's age. The diagnostic approach relies on imaging techniques (CT), but further investigations including genetic tests, BAL, and lung biopsy (VATS) are needed in uncertain cases. Pharmacological treatment is mostly empiric and based on anti-inflammatory and immunomodulatory drugs. Lung transplantation for selected cases in a pediatric transplantation center could be an option; however, limited data and evidence are available regarding long-term survival. International collaboration is warranted to understand chILD entities better and improve the outcomes of these patients.

Liver involvement with Langerhans cell histiocytosis in adults.

Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

Oral Neuropathy Associated with Commonly used Chemotherapeutic Agents: A Narrative Review.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication of cytotoxic chemotherapeutic agents; its incidence largely varies, depending on type, dose, agent and preexisting risk factors. Oral-and-perioral-CIPN (OCIPN) is underreported. Neurotoxic agents can cause jaw pain or numbness. This review aims to present available data on OCIPN RECENT FINDINGS: A narrative literature review, following SANRA guidelines was conducted. PubMed and Cochrane databases were searched until September 2023. Articles referring to neuropathy or neuropathic pain due to head and neck cancer, head and neck radiotherapy, oropharyngeal mucositis, infection or post-surgical pain were excluded. Platinum-based chemotherapeutics, taxanes, vinca alkaloids, immunomodulatory and alkylating agents can cause OCIPN. Platinum-based chemotherapeutics can cause orofacial cold sensitivity, orofacial and jaw pain, oral cavity tingling and teeth hypersensitivity. Taxanes may induce oral cavity and tongue numbness and tingling as well as hot hypersensitivity. Vinca alkaloids may cause jaw, teeth and lips pain and oral mucosa hyperalgesia. Immunomodulatory drugs can cause lips, tongue and perioral numbness, while alkylating agents induce tongue and lips tingling and teeth cold-hypersensitivity. Chemotherapy may cause OCIPN due to changes in cellular structure and function, like alterations in membrane receptors and neurotransmission. OCIPN should be documented and physicians, dentists and health care providers should be alerted.

Efficacy of rituximab in the treatment of epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous disease that is mediated by antibodies that bind collagen VII. The treatment of EBA can be challenging and often multiple immunomodulatory drugs are required. Rituximab has been reported to be an effective treatment for recalcitrant EBA, although its evidence base is limited to case reports and case series. This study therefore aimed to evaluate the efficacy of rituximab in patients with EBA. EBA patients treated with rituximab were identified by searching electronic medical records. Diagnostic criteria for EBA were as follows; mechanobullous skin lesions and / or mucosal ulceration, indirect immunofluorescence localising to the base of salt split skin and positive collagen VII antibodies. Clinical disease activity, collagen VII antibody levels and serum immunoglobulins were recorded at each follow up visit over 600 day period. Treatment responses were classified as follows; complete remission (CR) as the absence of new or established lesions on minimal therapy for 2 months, partial remission (PR) as transient lesions that heal within 1 week on minimal therapy and active disease (AD) as the development of new lesions. 14 patients with EBA were treated with rituximab. CR or PR was observed in 11 patients, and the duration of response varied between 4 and 24 months. A reduction in collagen VII antibody levels was observed in all patients. No significant adverse events were reported. Rituximab is a safe and effective treatment for patients with recalcitrant EBA although there was significant heterogeneity in the disease response.

The evolution of cyclosporine treatments for treatment of ocular surface diseases.

Cyclosporine is a versatile immunomodulatory drug commonly employed in modern medicine. Although cyclosporine was initially used to prevent solid organ transplant rejection, its indications have extended to treat many inflammatory or autoimmune diseases. Cyclosporin is available for use in oral, intravenous, and topical forms, including eye drops to treat corneal and ocular surface conditions. It is naturally advantageous to administer cyclosporin directly into the eye, avoiding potential and dose limiting systemic adverse effects. However, the transition from systemic to topical administration has been a challenging one. This report reviews the evolution of ophthalmic cyclosporine treatment and explores its clinical impacts and future research directions. Latest advancements in formulations - from oil-based solutions to nanomicelle and gel systems and waterless formulations - have improved the therapeutic efficacy and tolerability of topically applied cyclosporine, demonstrating greater effectiveness in treating ocular surface parameters compared to oil-based solution. Cyclosporine continues to be a safe and effective immunomodulatory drug in the field of ophthalmology to treat various chronic inflammatory ocular surface diseases and dry eye. Currently, there are several commercially available topical preparations available for ophthalmic use each with unique formulation and clinical outcomes.

Recent Updates in the Diagnosis and Management of Kidney Diseases in Multiple Myeloma

Multiple myeloma (MM) represents a difficult-to-treat plasma cell malignancy and the second most common hematologic malignancy in adults, significantly impacting kidney function. The spectrum of kidney involvement in MM is broad, encompassing electrolyte imbalances, tubular injury, and even rare glomerular diseases. The evolution of MM treatment modalities has led to notable improvements in the long-term survival of patients experiencing kidney-related complications. Over the past decade, groundbreaking therapeutic agents have emerged, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export, and antibody-drug conjugates. These novel therapies have revolutionized the landscape of MM management, offering new hope for patients and challenging the traditional treatment paradigms. This comprehensive review explores recent advances in the diagnosis and management of MM, emphasizing the pivotal role of these innovative therapeutic agents in improving patient outcomes. We delve into the intricacies of diagnosing MM, highlighting the significance of early detection and precise diagnostic tools. We elucidate the evolving treatment strategies, emphasizing the mechanisms of action and clinical efficacy of the latest agents. This manuscript provides valuable insights into the ever-evolving field of MM management, shedding light on the remarkable progress achieved in enhancing the prognosis and quality of life of MM patients.

Anti-B-Cell-Activating Factor (BAFF) Therapy: A Novel Addition to Autoimmune Disease Management and Potential for Immunomodulatory Therapy in Warm Autoimmune Hemolytic Anemia.

Although rituximab is not specifically approved for the treatment of warm autoimmune hemolytic anemia (WAIHA), the First International Consensus Group recommends considering its use as part of the initial therapy for patients with severe disease and as a second-line therapy for primary WAIHA. Some patients do not respond to rituximab, and relapses are common. These relapses are associated with elevated B-cell-activating factor (BAFF) levels and the presence of quiescent long-lived plasma cells (LLPCs) in the spleen. A new group of immunomodulatory drugs, B-cell-activating factor inhibitors (BAFF-i), demonstrated efficacy in multiple autoimmune diseases and have the potential to improve WAIHA treatment outcomes by targeting B-cells and LLPCs. This article reviews the role of BAFF in autoimmune disorders and the currently available literature on the use of BAFF-directed therapies in various immunologic disorders, including WAIHA. Collectively, the clinical data thus far shows robust potential for targeting BAFF in WAIHA therapy.

Pneumocystis jirovecii pneumonia secondary to chronic steroid use: An uncommon cause of pneumocystis pneumonia

Patients on long-term immunosuppression, including corticosteroids or immunomodulatory drugs, are susceptible to opportunistic infections, such as like Pneumocystis jirovecii pneumonia (PJP). Corticosteroid use can increase the frequency of fungal infection, mask symptoms, and delay the diagnosis, and thus warrant preventive measures. Maintaining a high index of suspicion is important, and prophylactic antibiotics, particularly trimethoprim-sulfamethoxazole, should be considered for high-risk patients. This case underscores the diagnosis of PJP in a patient with interstitial lung disease receiving prolonged steroid therapy, despite lacking HIV and conventional risk factors for this infection. Notably, PJP can present as a more severe infection in non-HIV patients, leading to higher mortality rates and stressing the need for swift and effective diagnosis and treatment by healthcare providers. Keywords: Pneumocystis jirovecii; pneumonia; chronic corticosteroid treatment use; fungal pneumonia; interstitial lung disease

Mantle Cell Lymphoma- A Rare Occurrence: Case Report

Mantle Cell Lymphoma (MCL) is a relatively uncommon yet distinct type of malignant lymphoma whose clinical and pathological characterization has been limited by the small numbers of cases published to date. It comprises 3-7% of all Hodgkin’s lymphoma cases, with a median diagnosis age of 68 years. Based on immunophenotypic and molecular data, MCL is a neoplasm composed of cells resembling those residing in follicular mantle zones. Although MCL usually presents as advanced disease some patients may present with more limited (stages I-I) disease. We present the case of a 41-year-old male who exhibited generalized lymphadenopathy and hepatosplenomegaly. Peripheral smear showed absolute lymphocytosis and the bone marrow biopsy and flow cytometry identified the condition as mantle cell lymphoma. The patient’s management required a multidisciplinary approach, incorporating haematological, molecular, and genetic evaluations. Treatment included hyper-CVAD chemotherapy. Proteasome inhibitors (Bortezomib), mTOR inhibitors (Temsirolimus), and immunomodulatory drugs (Lenalidomide) have recently been added to the treatment options in MCL.This case underscores the significance of comprehensive evaluation and customized therapeutic strategies and re looking an old diagnosis in managing complex haematological disorders.

Uncovering the Molecular Pathways Implicated in the Anti-Cancer Activity of the Imidazoquinoxaline Derivative EAPB02303 Using a Caenorhabditis elegans Model.

Imiqualines are analogues of the immunomodulatory drug imiquimod. EAPB02303, the lead of the second-generation imiqualines, is characterized by significant anti-tumor effects with IC50s in the nanomolar range. We used Caenorhabditis elegans transgenic and mutant strains of two key signaling pathways (PI3K-Akt and Ras-MAPK) disrupted in human cancers to investigate the mode of action of EAPB02303. The ability of this imiqualine to inhibit the insulin/IGF1 signaling (IIS) pathway via the PI3K-Akt kinase cascade was explored through assessing the lifespan of wild-type worms. Micromolar doses of EAPB02303 significantly enhanced longevity of N2 strain and led to the nuclear translocation and subsequent activation of transcription factor DAF-16, the only forkhead box transcription factor class O (Fox O) homolog in C. elegans. Moreover, EAPB02303 significantly reduced the multivulva phenotype in let-60/Ras mutant strains MT2124 and MT4698, indicative of its mode of action through the Ras pathway. In summary, we showed that EAPB02303 potently reduced the activity of IIS and Ras-MAPK signaling in C. elegans. Our results revealed the mechanism of action of EAPB02303 against human cancers associated with hyperactivated IIS pathway and oncogenic Ras mutations.

Integrated clustering of multiple immune marker trajectories reveals different immunotypes in severely injured patients

BackgroundThe immune response of critically ill patients, such as those with sepsis, severe trauma, or major surgery, is heterogeneous and dynamic, but its characterization and impact on outcomes are poorly understood. Until now, the primary challenge in advancing our understanding of the disease has been to concurrently address both multiparametric and temporal aspects.MethodsWe used a clustering method to identify distinct groups of patients, based on various immune marker trajectories during the first week after admission to ICU. In 339 severely injured patients, we initially longitudinally clustered common biomarkers (both soluble and cellular parameters), whose variations are well-established during the immunosuppressive phase of sepsis. We then applied this multi-trajectory clustering using markers composed of whole blood immune-related mRNA.ResultsWe found that both sets of markers revealed two immunotypes, one of which was associated with worse outcomes, such as increased risk of hospital-acquired infection and mortality, and prolonged hospital stays. This immunotype showed signs of both hyperinflammation and immunosuppression, which persisted over time.ConclusionOur study suggest that the immune system of critically ill patients can be characterized by two distinct longitudinal immunotypes, one of which included patients with a persistently dysregulated and impaired immune response. This work confirms the relevance of such methodology to stratify patients and pave the way for further studies using markers indicative of potential immunomodulatory drug targets.Graphical