Traditional Immunosuppressants Research Articles

Rituximab treatment in resistant lupusnephritis: A single-center prospective study.

Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE) and failure to respond to traditional immunosuppression increases morbidity and mortality. Rituximab has been considered a novel therapeutic option for the management of SLE. We conducted a single-center, prospective, observational study from July 2018 to June 2019 to evaluate the effectiveness of rituximab in patients with resistant LN. Resistant LN was defined as the failure to respond to conventional immunosuppressive therapy including both cyclophosphamide and mycophenolate mofetil. All adult patients (>18 years) with biopsy-proven class III/IV LN were included in the study. Four doses of intravenous rituximab (375 mg/m2) on 0, 1, 2, 3 weeks were administered. Patients were followed for 6months, and the rates of complete renal response (CRR), partial renal response (PRR), or no renal response (NRR) were measured. The change in baseline 24-hour urine protein, mean serum creatinine levels, and mean serum CD-19 levels at 24 weeks were also measured. Six months after rituximab therapy, total sustained renal response (CRR+PRR) was observed in 52% cases of resistant LN (CRR was achieved in 24% of patients and PRR in 28%, respectively). Rituximab was associated with a significant decline in the 24-hour urine protein, even in non-responders. However, the improvement in eGFR and serum creatinine was not statistically significant. The mean absolute CD-19 count was significantly low in responders compared to the non-responder group. Rituximab is a safe and effective therapeutic strategy for patients with resistant LN.

Targeted treatments for immune dysregulation in inborn errors of immunity

Primary immune regulatory disorders (PIRDs) constitute a subset of inborn errors of immunity and are characterized by lymphoproliferation, autoimmunity, malignancy, and infection. Unlike classical primary immune deficiencies, initial symptoms of PIRDs can manifest as autoimmunity such as cytopenias or enteropathy, which can often prove resistant to conventional treatments and occur years prior to the onset of infectious complications. Raising awareness about PIRDs among specialists and adopting a multidisciplinary approach is crucial for early diagnosis, intervention, and potential prevention of severe organ damage. Significant progress has been made in identifying several PIRDs, which has contributed to a more comprehensive comprehension of their underlying immunological mechanisms. This knowledge has paved the way for targeted therapies focusing on specific molecules, which tend to offer superior disease control compared to traditional immunosuppressants. This review, informed by the latest literature, explores prevalent PIRDs, detailing their clinical manifestations and recent advancements in treatment modalities.

Dawn of CAR-T cell therapy in autoimmune diseases.

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies. Based on the immunomodulatory capability of CAR-T cells, efforts have turned toward exploring their potential in treating autoimmune diseases. Bibliometric analysis of 210 records from 128 academic journals published by 372 institutions in 40 countries/regions indicates a growing number of publications on CAR-T therapy for autoimmune diseases, covering a range of subtypes such as systemic lupus erythematosus, multiple sclerosis, among others. CAR-T therapy holds promise in mitigating several shortcomings, including the indiscriminate suppression of the immune system by traditional immunosuppressants, and non-sustaining therapeutic levels of monoclonal antibodies due to inherent pharmacokinetic constraints. By persisting and proliferating in vivo, CAR-T cells can offer a tailored and precise therapeutics. This paper reviewed preclinical experiments and clinical trials involving CAR-T and CAR-related therapies in various autoimmune diseases, incorporating innovations well-studied in the field of hematological tumors, aiming to explore a safe and effective therapeutic option for relapsed/refractory autoimmune diseases.

Data mining and safety analysis of traditional immunosuppressive drugs: a pharmacovigilance investigation based on the FAERS database

ABSTRACT Objective The purpose of this study aimed to explore the new and serious adverse events(AEs) of Tacrolimus(FK506), cyclosporine(CsA), azathioprine(AZA), mycophenolate mofetil(MMF), cyclophosphamide(CTX) and methotrexate(MTX), which have not been concerned. Methods The FAERS data from January 2016 and December 2022 were selected for disproportionality analysis to discover the potential risks of traditional immunosuppressive drugs. Results Compared with CsA, FK506 has more frequent transplant rejection, and is more related to renal impairment, COVID-19, cytomegalovirus infection and aspergillus infection. However, CsA has a high infection-related fatality rate. In addition, we also found some serious and rare AE in other drugs which were rarely reported in previous studies. For example, AZA is closely related to hepatosplenic T-cell lymphoma with high fatality rate and MTX is strongly related to hypofibrinogenemia. Conclusion The AEs report on this study confirmed that the results were basically consistent with the previous studies, but there were also some important safety signals that were inconsistent with or not mentioned in previous published studies. Expert opinion The opinion section discusses some of the limitations and shortcomings, proposing the areas where more effort should be invested in order to improve the safety of immunosuppressive drugs.

Optimizing Behçet Uveitis Management: A Review of Personalized Immunosuppressive Strategies.

Behçet uveitis poses significant management challenges, owing to its intricate pathogenesis and the severe prognosis it harbors, frequently culminating in irreversible visual impairment and an elevated risk of blindness. This review synthesizes contemporary insights into personalized immunosuppressive strategies for Behçet uveitis, emphasizing the necessity for a customized approach in recognition of the disease's heterogeneity and the variable responsiveness to treatment. This discourse elaborates on the application, efficacy, and safety profiles of traditional immunosuppressants, highlighting a paradigm shift toward integrative combination therapies aimed at diminishing reliance on glucocorticoids and mitigating their associated adverse effects. This thorough evaluation seeks to enlighten clinical practices and spearhead future investigations aimed at refining the management of Behçet uveitis, championing a personalized, multidisciplinary strategy to amplify therapeutic efficacy and enhance patient quality of life.

P19 Our experience diagnosing and treating deficiency of adenine deaminase 2 (DADA2) vasculitis

Abstract Introduction Deficiency of adenine deaminase 2 (DADA2) is caused by biallelic pathogenic variants in the gene on chromosome 22q11. It is autosomal recessive with incomplete penetrance, and a variable presentation. It typically manifests as a systemic vasculopathy with early onset strokes, cutaneous manifestations, immunodeficiency and cytopenia. Traditional immunosuppressants have limited efficacy, but vasculitic manifestations have been reported to respond to biologic TNF-inhibitors. We report a patient with confirmed ADA2 deficiency whose cutaneous manifestations were previously classified as Sneddon syndrome. After a period of stability on adalimumab she developed marked cutaneous ulceration that healed following a therapy switch to intravenous infliximab. Case description We report a 39-year-old female with a long clinical history that started in childhood when she developed Diamond-Blackfan anaemia that went into remission following corticosteroid treatment and transfusions. In 2006, she suddenly had two thalamic infarcts and was thoroughly investigated but was found to have unremarkable vascular imaging, a negative antiphospholipid syndrome and autoantibody testing, a modestly elevated CRP (5-15 mg/L) and a notably persistent low serum IgM. She continued to experience frequent migraines associated with transient sensorimotor symptoms. Subsequently, she developed recurrent botchy, polymorphic macular eruptions on the lower limbs. A deep cutaneous biopsy demonstrated lymphocytic predominant perivascular inflammation of deep dermal vessels associated with thrombus formation and endothelial proliferation. A putative diagnosis of Sneddon’s syndrome was made. However, after the subsequent identification of ADA2-deficiency vasculitis, the patient underwent genetic screening which identified a compound heterozygosity for two novel ADA2 mutations (c6634_636, delTTC (p.Phe212del) and c.1225C>T (p.Pro409Ser)). Her mother was as a carrier. She was started on adalimumab injections to which she had a good clinical response with improved cutaneous disease and no further neurological symptoms. However, after two years of disease stability, she then developed a significant ‘punched out’ ulcer on the mid-calf which was painful and increasing in size to a maximum of 2 x 3 cm. Dermatology colleagues were reluctant to re-biopsy due to a high likelihood of non-specific appearances and increased risk of poor healing leading to worsening ulceration. Drawing on experience from rheumatoid arthritis that a switch in anti-TNF biological will often restore efficacy following secondary non-response to adalimumab; we empirically switched treatment to intravenous infliximab, with a reducing course of prednisolone (40mg per day tapering to 5mg after 12 weeks). This was associated with a notable improvement within one month and a complete healing of the ulcer within 4 months. Discussion DADA2 remains a rare condition with a carrier frequency estimated at 1 in 236 persons worldwide and a predicted disease prevalence of approximately 1 in 222,000 persons. Patients with DADA2 who have haematological manifestations tend to present during early infancy, whereas delayed presentation is common in patients with vasculitis and systemic inflammation. It should be suspected in patients with early onset strokes, livedo and other haematological and immunological features. Additionally, many previously diagnosed cases of Sneddon syndrome may in fact have DADA2, with a low IgM level favouring the later. Diagnosis can be confirmed by genetic studies or by a biochemical assay that demonstrates near-absent levels of ADA2 activity in the plasma or serum. Interestingly, on screening of adult patients with polyarteritis nodosa (PAN) 3.4% possessed biallelic pathogenic ADA2 variants and similarly, in genomic survey of patients with Diamond-Blackfan anaemia 2% possessed biallelic pathogenic ADA2 variants in the absence of the ribosomal protein gene mutations associated with it. Treatment is phenotype based with a preference for lifelong TNF inhibitor and biosimilar use in those with vasculitis and/or systemic inflammation, though not currently commissioned for this indication. Glucocorticoids, disease-modifying antirheumatic drugs, and other biologic agents may partially ameliorate systemic inflammation. Unfortunately, they are all ineffective for severe hematologic manifestations and hematopoietic cell transplantation (HCT) is currently the only treatment option. Treating asymptomatic patients and mildly symptomatic patients picked up on screening remains senior clinician led on a risk benefit basis. Disease activity is clinically monitored with an overall mortality rate estimated at 8%. Key learning points The main learning points for me included an increased awareness of this syndrome, its variable presentation, association with other autoimmune illnesses, diagnosis, and treatment initiation. In addition, I learnt about screening of family members, weighing the benefits versus risks when considering treating mildly symptomatic and asymptomatic patients, clinical monitoring for response, and when to switch to other anti-TNFs and biosimilars. From this conference, I would like to explore the experience of our rheumatology colleagues with similar cases.

Janus kinase inhibitors in autoimmune bullous diseases.

Autoimmune bullous disease (AIBD) is a severe skin disorder caused by autoantibodies that target intercellular or cell-matrix adhesion proteins. Currently, the preferred treatment for AIBD involves the use of glucocorticoids or traditional immunosuppressants. Additionally, the utilization of biological agents such as rituximab, omalizumab, and dupilumab is on the rise. However, effectively managing AIBD remains a challenge. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway has been implicated in various inflammatory diseases. In recent years, a range of drugs known as JAK inhibitors, which target this pathway, have been developed. Several studies have explored the efficacy and safety of JAK inhibitors for treating AIBD. Consequently, this review begins by examining the role of the JAK/STAT pathway in AIBD, summarizing the application of different JAK inhibitors in AIBD treatment, and emphasizing the importance of disease management in treating AIBD with JAK inhibitors. Furthermore, it highlights the need for a better understanding of the JAK/STAT pathway's role in AIBD, as well as the effectiveness and safety of JAK inhibitors for treating this disease.

Efficacy and Safety of Abrocitinib in Patients with Severe and/or Difficult-to-Treat Atopic Dermatitis: A Post Hoc Analysis of the Randomized Phase 3 JADE COMPARE Trial.

Traditional systemic immunosuppressants and advanced therapies improve signs and symptoms of moderate-to-severe atopic dermatitis (AD). However, data are limited in severe and/or difficult-to-treat AD. In the phase 3 JADE COMPARE trial of patients with moderate-to-severe AD receiving background topical therapy, once-daily abrocitinib 200mg and 100mg showed significantly greater reductions in the symptoms of AD than placebo and significantly greater improvement in itch response (with abrocitinib 200mg) than dupilumab at week2. This study assessed the efficacy and safety of abrocitinib and dupilumab in a subset of patients with severe and/or difficult-to-treat AD in a posthoc analysis of the JADE COMPARE trial. Adults with moderate-to-severe AD received once-daily oral abrocitinib 200mg or 100mg, dupilumab 300mg subcutaneous injection every 2weeks, or placebo with concomitant medicated topical therapy. Severe and/or difficult-to-treat AD subgroups were classified by baseline characteristics [Investigator's Global Assessment (IGA) 4, Eczema Area and Severity Index (EASI) > 21, failure or intolerance to prior systemic agents (excluding patients who took only corticosteroids), percentage of body surface area (%BSA) > 50, upper quartiles of EASI (EASI > 38) and %BSA (%BSA > 65), and combined subgroup of IGA 4, EASI > 21, and %BSA > 50, and failure or intolerance to prior systemic agents (excluding patients who took only corticosteroids)]. Assessments included IGA score of 0 (clear) or 1 (almost clear) and a ≥2-point improvement from baseline, ≥75% and ≥90% improvement from baseline in EASI (EASI-75 and EASI-90), ≥4-point improvement from baseline in Peak Pruritus-Numerical Rating Scale (PP-NRS4), time to PP-NRS4, least squares mean (LSM) change from baseline in 14-day PP-NRS (days2-15), Patient-Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI) up to week16. The proportion of patients achieving IGA 0/1, EASI-75, and EASI-90 responses was significantly greater with abrocitinib 200mg than placebo (nominal p <0.05) across all subgroups with severe and/or difficult-to-treat AD. Across most subgroups, PP-NRS4 response was significantly greater with abrocitinib 200mg than placebo (nominal p <0.01); the time to achieve this response was shorter with abrocitinib 200mg (range 4.5-6.0days) than abrocitinib 100mg (range 5.0-17.0days), dupilumab (range 8.0-11.0 days), and placebo (range 3.0-11.5days). LSM change from baseline in POEM and DLQI was significantly greater with abrocitinib 200mg than placebo (nominal p <0.001) across all subgroups. Clinically meaningful differences were observed between abrocitinib and dupilumab for most evaluated endpoints across several subgroups, including in patients who failed or were intolerant to prior systemic therapy. Abrocitinib provided rapid and substantially greater improvements in skin clearance and quality of life compared with placebo and dupilumab in subgroups of patients with severe and/or difficult-to-treat AD. These findings support the use of abrocitinib for severe and/or difficult-to-treat AD. ClinicalTrials.gov, NCT03720470.

Pulmonary and central nervous system nocardiosis: Alcoholism as an immunocompromising factor

Nocardiosis is a disease with worldwide distribution. It is usually found in tropical areas and mainly affects immunocompromised patients, however, there are also cases where its infection has been reported in immunocompetent patients. This pathology is caused by bacteria known as Nocardia spp., which are gram-positive microorganisms and environmental saprophytes, and although exposure to Nocardia spp. is almost universal, only a small fraction of exposed people develops the disease. We present the case of a 47-year-old man, with no evidence of immunosuppression, from a rural area of Boyacá, who was admitted due to intense and intermittent headache accompanied by paresthesia and, finally, a decrease in consciousness. A brain magnetic resonance was performed and evidenced a fronto-temporo- occipital space-occupying lesion in the cortico-subcortical region with a compressive effect and displacement of the ventricular system cavities. It was suspected at first a neoplastic lesion or a brain abscess. The lesion was surgically resected, and its culture showed Nocardia africana/nova. In later studies a possible primary pulmonary focus was evidenced. Alcoholism was the only risk factor documented. The patient completed 6 weeks of hospital antibiotic treatment with favorable clinical and radiological evolution and was discharged with a 1-year plan of outpatient antibiotic therapy. Although Nocardia spp. mainly affects immunocompromised patients, evidence shows that this microorganism can also be a threat to individuals without traditional immunosuppression risk factors.

Takayasu arteritis and large-vessel giant cell arteritis in Italian population. Comprehensive analysis from a single institutional cohort of 184 cases

ObjectiveTo compare clinical and imaging characteristics in patients with Takayasu arteritis (TAK) and large vessel-giant cell arteritis (LV-GCA) in an Italian population. MethodsWe conducted a retrospective monocenter study comparing characteristics and outcomes of a cohort of 59 patients with TAK and a cohort of 127 patients with LV-GCA diagnosed between 1996 and 2016. Most of them (92%) were followed up for at least 24 months at Reggio Emilia Hospital (Italy). We also reviewed the literature discussing the results of the published manuscripts comparing LV-GCA to TAK ResultsLV-GCA patients had a higher prevalence of males (p = 0.003), and more frequently presented with cranial symptoms (p = 0.001), fever ≥38 °C (p = 0.007), polymyalgia rheumatica (p = 0.001), and hypertension (p = 0.001), and they had higher ESR levels at diagnosis (p = 0.0001). Differently, TAK patients had longer delay to diagnosis from the beginning of symptoms (p = 0.048), they presented more frequently with loss of pulses of large arteries (p = 0.0001), vascular bruits (p = 0.001), limb claudication (p = 0.003), myocardial infarction/angina (p = 0.03), and hypertension induced by renal artery stenosis (p = 0.001). Regarding treatment, TAK patients received a higher total and at 1 year cumulative prednisone doses (p = 0.0001 and p = 0.001, respectively), they had a longer duration of prednisone therapy (p = 0.008), and received during follow-up more frequently traditional immunosuppressants (p = 0.0001) and biological agents (p = 0.0001). Flares were more frequently observed in TAK patient (p = 0.001), while no differences were observed for long-term remission. New vascular procedures during the follow-up were more frequently performed in TAK patients (p = 0.0001). Regarding imaging at diagnosis, TAK patients had more frequently vascular stenosis/occlusion (p = 0.0001) and a higher number of vessels with structural damage per person (p = 0.0001), while LV-GCA patients had a higher number of inflamed vessels per person (p = 0.0001).Comparing the involved vascular districts at diagnosis for the presence of vessel inflammation and/or arterial damage, patients with LV-GCA had a more frequent involvement of thoracic and abdominal aorta (p = 0.024 and p = 0.007, respectively), and axillary, iliac and femoral arteries (p = 0.018, p = 0.002, and p = 0.0001. respectively), while in TAK patients, brachiocephalic, celiac, mesenteric and renal arteries were more frequently involved (p = 0.011, p = 0.019, p = 0.019, and p = 0.005, respectively). At imaging arterial damage at diagnosis was more frequently observed in TAK patients, specifically at common carotid, brachiocephalic, and subclavian arteries (p = 0.0001, p = 0.006, p = 0.0001, respectively) and descending aorta (p = 0.022). Regarding imaging during the follow-up, TAK patients developed more frequently new vascular stenosis/occlusion (p = 0.0001) and new vascular thickening (p = 0.002), no differences were observed for the development of new dilatation/aneurysm between the two vasculitides. ConclusionPatients with TAK and LV-GCA show a number of similarities and also differences. Indeed, it is unclear whether they are part of the same disease spectrum or they are different conditions. As more information regarding the pathogenesis and etiology becomes known, answers to these questions are like to be forthcoming.

Review of an Anti-CD20 Monoclonal Antibody for the Treatment of Autoimmune Diseases of the Skin.

Biologic therapies targeting B-cells are emerging as an effective strategy to treat a variety of immune-mediated diseases. One of the most studied B-cell-targeted therapies is rituximab, an anti-CD20 monoclonal antibody that exemplifies B-cell depletion therapy and has served as the prototype for other anti-CD20 monoclonal antibodies and the development of biosimilars. While there are multiple studies on the use of rituximab in dermatology, a comprehensive review of rituximab therapy in autoimmune skin conditions is lacking. In this literature review, we summarize indications, treatment efficacy, and safety of rituximab among common autoimmune diseases of the skin: pemphigus vulgaris, cutaneous lupus erythematous, dermatomyositis, systemic sclerosis, thyroid dermopathy, autoimmune pemphigoid diseases, and cutaneous vasculitis diseases. Existing data on rituximab support the approach of rituximab, biosimilars, and newer B-cell-targeting therapies in immune-mediated cutaneous diseases. Overall, rituximab, which targets CD20, provides an effective alternative or concomitant option to traditional immunosuppressants in the management of various autoimmune diseases of the skin. Further studies are necessary to expand the understanding and possible utility of B-cell-targeted therapies among autoimmune skin diseases.

Efficacy and safety of belimumab treatment in childhood-onset systemic lupus erythematosus

Objective: To evaluate the efficacy and safety of belimumab in children with systemic lupus erythematosus (cSLE). Methods: The clinical data of 49 cSLE patients admitted into the Department of Rheumatology and Immunology, Children's Hospital affiliated to the Capital Institute of Pediatrics, from August 2018 to December 2021 were collected. They were divided into the belimumab treatment group (18 cases) and the traditional treatment group (31 cases) according to whether they received belimumab treatment. The cSLE patients in the traditional group had similar baseline SLEDAI scores with the belimumab group and were treated with traditional immunosuppressive drugs. The clinical symptoms and improvements before and after treatment, as well as the differences in adverse events during follow-up were compared between the two groups. Results: In belimumab group, the age was (11.9±1.8) years old, the median (Q1, Q3) of disease duration was 7.5 (2.0, 16.8) months, 3 patients were male, and 15 patients completed 24 weeks of treatment. In the traditional treatment group, 31 patients with cSLE were enrolled, with an average age of (11.3±2.4) years, a median (Q1, Q3) of disease duration of 7.0 (2.5, 10.5) months, among whom 6 patients were male, and 25 patients completed 24 weeks of treatment. At baseline, the belimumab treatment group had a significantly lower oral prednisone dose than the conventional treatment group [(29.58±12.43) mg/d vs (38.20±14.11) mg/d, P=0.037]. After 24 weeks of treatment, the dosage of prednisone in both groups was reduced, and the dosage of prednisone in the belimumab group was (14.12±5.86) mg/d, which was lower than that in the traditional treatment group [(23.51±9.79) mg/d] (P=0.002). After 24 weeks of treatment, the levels of complement C3 and C4 increased, the dsDNA levels and SLEDAI score decreased in both groups (all P>0.05). The incidence of adverse events in belimumab group (3/15, 3 cases) was lower than that in traditional treatment group (32.0%, 8/25) (P>0.05). Conclusions: Belimumab in the treatment of cSLE can reduce the initial dose of prednisone and facilitate the reduction of prednisone dose, significantly improve the clinical symptoms and organ involvement, and reduce the disease activity. The incidence of adverse events was low during belimumab treatment.

Efficacy and safety of rituximab treatment in patients with idiopathic inflammatory myopathies: A systematic review and meta-analysis.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases with various subtypes, myositis-specific antibodies, and affect multiple systems. The treatment of IIMs remains challenging, especially for refractory myositis. In addition to steroids and traditional immunosuppressants, rituximab (RTX), a B cell-depleting monoclonal antibody, is emerging as an alternative treatment for refractory myositis. However, the therapeutic response to RTX remains controversial. This meta-analysis aimed to systematically evaluate the efficacy and safety of RTX in patients with IIMs, excluding sporadic inclusion body myositis. PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and WanFang Data were searched for relevant studies. The overall effective rate, complete response rate, and partial response rate were calculated to assess the efficacy of RTX. The incidences of adverse events, infection, severe adverse events, severe infection, and infusion reactions were collected to evaluate the safety of RTX. Subgroup analyses were performed using IIM subtypes, affected organs, continents, and countries. We also performed a sensitivity analysis to identify the sources of heterogeneity. A total of 26 studies were included in the quantitative analysis, which showed that 65% (95% confidence interval [CI]: 54%, 75%) of patients with IIMs responded to RTX, 45% (95% CI: 22%, 70%) of patients achieved a complete response, and 39% (95% CI: 26%, 53%) achieved a partial response. Subgroup analyses indicated that the overall efficacy rates in patients with refractory IIMs, dermatomyositis and polymyositis, as well as anti-synthetase syndrome were 62%, 68%, and 62%, respectively. The overall efficacy rates for muscle, lungs, and skin involvement were 59%, 65%, and 81%, respectively. In addition, studies conducted in Germany and the United States showed that patients with IIMs had an excellent response to RTX, with an effective rate of 90% and 77%, respectively. The incidence of severe adverse events and infections was 8% and 2%, respectively. RTX may be an effective and relatively safe treatment choice in patients with IIMs, especially for refractory cases. However, further verification via randomized controlled trials is warranted.

Knowledge mapping of targeted immunotherapy for myasthenia gravis from 1998 to 2022: Abibliometricanalysis.

BackgroundThe treatment of myasthenia gravis (MG) has advanced from steroids and traditional immunosuppressants to targeted immunotherapy. Targeted immunotherapy has been successfully employed in clinical practice in recent years. This study aimed to explore the emerging trend of targeted immunotherapy in MG and summarize the knowledge structure through bibliometric methods.MethodsThe Web of Science Core Collection database (WoSCC) was chosen to retrieve the literature on targeted immunotherapy for MG. Two bibliometric analysis software, VOSviewer and CiteSpace, and bibliometric online platform were mainly used to evaluate the contributions from countries/regions, institutions, journals, and authors through the construction and visualization of bibliometric networks. By systematically reviewing a knowledge domain, future research developments were determined. The R version 4.1.2 and Microsoft Excel 365 were used for statistical analysis.ResultsA total of 562 original articles and 262 reviews relevant to MG targeted immunotherapy were included. The number of publications on targeted immunotherapy for MG exhibited a two-phase advancement. The first stage showed a steady growth trend from 1998 to 2016, with an annual number of no more than 35 publications. The second stage revealed an explosive growth trend from 2017, reaching a peak number of publications in 2020. The United States ranked first in the number of publications, citations, and h-index. The author with the highest citation and h-index was Vincent A. And 28.03% of the articles were published in the top 10 journals. In addition to “myasthenia gravis”, the keyword with the highest consideration was “rituximab”, followed by “double-blind”, which indicate research hotspots gradually from basic research to clinical research over time, especially in the field of targeted immunotherapy. The MG treatment has entered a personalized precision treatment phase. Exploration into new target molecules and conducting high-quality randomized controlled trials on existing biological agents are the further research direction.ConclusionThe current study summarized the global research trends concerning targeted immunotherapy for MG. Research interests gradually advanced from basic research to clinical research. MG treatment has entered a personalized precision treatment phase. Further investigations into new target molecules and high-quality randomized controlled trials on existing biological agents are required urgently to direct future immunotherapy research.

Short-term effectiveness of baricitinib in children with refractory and/or severe juvenile dermatomyositis.

ObjectiveTo determine the short-term effectiveness safety of baricitinib in children with refractory and/or severe juvenile dermatomyositis (rsJDM) in a real-world setting.MethodsThis was a single-center retrospective study, including 20 children with rsJDM. They were all treated using baricitinib combined with steroids and other immunosuppressive agents. The childhood myositis assessment scale (CMAS) and PRINTO remission criteria were used to evaluate the disease severity and treatment outcome at 0, 4, 12, and 24 weeks after initiation of baricitinib.ResultsThe skin rash improved in 95% of patients (19/20) at week 24, with a significant decrease of skin-DAS at weeks 12 (6.0 vs. 2.0, p < 0.05] and week 24 [6.0 vs. 1.0, p < 0.05) by median statistics. The CMAS score increased significantly at week 12 (41.0 [29.0, 44.0] vs. 46.0 [42.0, 52.0], p < 0.05) and week 24 (41.0 [29.0, 44.0] vs. 50.0 [45.0, 52.0], p < 0.05), as did the manual muscle testing (MMT)-8 score at week 24 (73.0 [610, 76.0] vs. 79.0 [77.0, 80.0], p < 0.05). At 24 weeks, the complete response (CR) and partial response (PR) were achieved in 75% (15/20) and 15% (3/20), respectively. The dose of corticosteroids (CS) decreased by 37% from the baseline (0.53 [0.42, 1.00] mg/kg) to week 12 (0.33 [0.18, 0.40] mg/kg) (p < 0.05), and by 49% at week 24 (p < 0.05). No serious side effects were observed.ConclusionBaricitinib combined with traditional immunosuppressants treatment was efficacious in rsJDM. Add-on therapy of baricitinib was helpful for tapering CS dose. No serious side effects were observed in this study.

Advancements in the Treatment of Cutaneous Lupus Erythematosus and Dermatomyositis: A Review of the Literature.

BackgroundCutaneous lupus erythematosus (CLE) and dermatomyositis (DM) are autoimmune diseases that present with a wide variety of cutaneous manifestations. In both cases, first-line therapy includes topical corticosteroids. Patients may present with more widespread disease requiring systemic treatments, including corticosteroids, traditional immunosuppressants, or antimalarials. Due to their complex nature, both CLE and DM remain difficult to treat and continue to cause significant distress to patients.ObjectiveTo summarize the most recent literature on the safety and efficacy of novel treatment modalities for CLE and DM.MethodsA literature search was conducted on PubMed using search terms “(dermatomyositis) AND (treatment)” and “(cutaneous lupus) AND (treatment)”. Additional search terms included specific names of biologic agents, phosphodiesterase inhibitors (apremilast), and JAK inhibitors.ResultsJAK inhibitors, PDE-4 inhibitors, and biologics have shown promise in reducing cutaneous symptoms of both CLE and DM, including reduction in SLE Disease Activity Index 2000 (SLEDAI-2K), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), British Isles Lupus Assessment Group (BILAG), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), and Disease Activity Score (DAS).ConclusionWhile there have been recent advancements in the treatment for CLE and DM, further research and clinical trials are required to better elucidate which therapy is best for individual patients.

Monoclonal antibody-mediated immunosuppression enables long-term survival of transplanted human neural stem cells in mouse brain.

BackgroundAs the field of stem cell therapy advances, it is important to develop reliable methods to overcome host immune responses in animal models. This ensures survival of transplanted human stem cell grafts and enables predictive efficacy testing. Immunosuppressive drugs derived from clinical protocols are frequently used but are often inconsistent and associated with toxic side effects. Here, using a molecular imaging approach, we show that immunosuppression targeting costimulatory molecules CD4 and CD40L enables robust survival of human xenografts in mouse brain, as compared to conventional tacrolimus and mycophenolate mofetil.MethodsHuman neural stem cells were modified to express green fluorescent protein and firefly luciferase. Cells were implanted in the fimbria fornix of the hippocampus and viability assessed by non‐invasive bioluminescent imaging. Cell survival was assessed using traditional pharmacologic immunosuppression as compared to monoclonal antibodies directed against CD4 and CD40L. This paradigm was also implemented in a transgenic Alzheimer's disease mouse model.ResultsGraft rejection occurs within 7 days in non‐immunosuppressed mice and within 14 days in mice on a traditional regimen. The addition of dual monoclonal antibody immunosuppression extends graft survival past 7 weeks (p < .001) on initial studies. We confirm dual monoclonal antibody treatment is superior to either antibody alone (p < .001). Finally, we demonstrate robust xenograft survival at multiple cell doses up to 6 months in both C57BL/6J mice and a transgenic Alzheimer's disease model (p < .001). The dual monoclonal antibody protocol demonstrated no significant adverse effects, as determined by complete blood counts and toxicity screen.ConclusionsThis study demonstrates an effective immunosuppression protocol for preclinical testing of stem cell therapies. A transition towards antibody‐based strategies may be advantageous by enabling stem cell survival in preclinical studies that could inform future clinical trials.

Opportunities and challenges for synthetic biology in the therapy of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a complex, chronic intestinal inflammatory disorder that primarily includes Crohn’s disease (CD) and ulcerative colitis (UC). Although traditional antibiotics and immunosuppressants are known as the most effective and commonly used treatments, some limitations may be expected, such as limited efficacy in a small number of patients and gut flora disruption. A great many research studies have been done with respect to the etiology of IBD, while the composition of the gut microbiota is suggested as one of the most influential factors. Along with the development of synthetic biology and the continuing clarification of IBD etiology, broader prospects for novel approaches to IBD therapy could be obtained. This study presents an overview of the currently existing treatment options and possible therapeutic targets at the preclinical stage with respect to microbial synthesis technology in biological therapy. This study is highly correlated to the following topics: microbiota-derived metabolites, microRNAs, cell therapy, calreticulin, live biotherapeutic products (LBP), fecal microbiota transplantation (FMT), bacteriophages, engineered bacteria, and their functional secreted synthetic products for IBD medical implementation. Considering microorganisms as the main therapeutic component, as a result, the related clinical trial stability, effectiveness, and safety analysis may be the major challenges for upcoming research. This article strives to provide pharmaceutical researchers and developers with the most up-to-date information for adjuvant medicinal therapies based on synthetic biology.

The Combination of Rhodosin and MMF Prolongs Cardiac Allograft Survival by Inhibiting DC Maturation by Promoting Mitochondrial Fusion.

Despite being the gold-standard treatment for end-stage heart disease, heart transplantation is associated with acute cardiac rejection within 1 year of transplantation. The continuous application of immunosuppressants may cause side effects such as hepatic and renal toxicity, infection, and malignancy. Developing new pharmaceutical strategies to alleviate acute rejection after heart transplantation effectively and safely is of critical importance. In this study, we performed a murine model of MHC-full mismatch cardiac transplantation and showed that the combination of Rhodosin (Rho) and mycophenolate mofetil (MMF) could prevent acute rejection and oxidative stress injury and prolong the survival time of murine heart transplants. The use of Rho plus MMF in allografts improved the balance of Tregs/Teff cells, which had a protective effect on allotransplantation. We also isolated bone marrow-derived dendritic cells (BMDCs) and determined that Rho inhibited DC maturation by promoting mitochondrial fusion mainly through the mitochondrial fusion-related protein MFN1. Herein, we demonstrated that Rho, an active ingredient isolated from the plant Rhodiola rosea with antioxidant and anti-inflammatory activities, could efficiently alleviate acute rejection and significantly prolong murine heart allograft survival when used with a low dose of MMF. More importantly, we found that Rho restrained DC maturation by promoting mitochondrial fusion and decreasing reactive oxygen species (ROS) levels, which then alleviated acute rejection in murine cardiac transplantation. Interestingly, as a novel immunosuppressant, Rho has almost no side effects compared with other traditional immunosuppressants. Taken together, these results suggest that Rho has good clinical auxiliary applications as an effective immunosuppressant and antioxidant, and this study provides an efficient strategy to overcome the side effects of immunosuppressive agents that are currently used in organ transplantation.

Impact of Covid-19 on Mental Health and Treatment Compliance in Psoriasis Patients

Objective: This study was designed to determine the impact of COVID-19 on treatment compliance and mental health (anxiety and depression) in psoriasis patients. Methods: A descriptive cross-sectional study was undertaken in the Department of Dermatology at York teaching Hospital from April to August 2020. One hundred and eleven patients diagnosed with psoriasis were asked to complete a questionnaire (HADS). Patients were also asked about their compliance or self-modifications in their treatment regime due to fear of Covid-19. Using SPSS version 26.0 all of the collected data was analysed together. Results: 40 patients (36.03%) had depression and 52 patients (46.84%) anxiety on the basis of their HADS score. Twenty patients (18.01%) stopped treatment due to concerns regarding COVID-19. Prevalence of anxiety was more in female patients and those on traditional immuno-suppressants as compared to biological treatment or those receiving topical treatment only. Conclusion: Depression and anxiety are common in patients with psoriasis. Female patients and those on systemic medications are worse affected compared to patients on topical treatment or those receiving phototherapy. Fear of COVID-19 has led to 18% of patients self-stopping their treatment altogether. Keywords: Psoriasis, Mental Health, Covid-19, Compliance