Oral Immunosuppressants Research Articles

Early Rituximab versus Escalating Therapy in Neuromyelitis Optica: A Cost and Quality of Life Analysis

Introduction: Rituximab, an anti-CD20 monoclonal antibody, has shown effectiveness in reducing disease relapses and disability accrual through relapses in patients with neuromyelitis optica spectrum disorders (NMOSD). However, its higher cost compared to oral immunosuppressants raises questions about its cost-effectiveness, particularly in low and middle-income countries. This study aimed to compare the cost-effectiveness of early rituximab treatment versus escalation treatment in NMOSD patients. Methods: We conducted a retrospective study of NMOSD patients treated with rituximab in the first five years of disease at a hospital in São Paulo, Brazil, from 2015 to 2019. The Early Group consisted of NMOSD patients who received rituximab as a first-line treatment. The Escalating Therapy Group included patients who were prescribed rituximab after experiencing disease activity while on oral immunosuppressants, primarily azathioprine. An economic model based on Expanded Disability Status Score (EDSS) transitions was used to assess cost-effectiveness. Cost and utility data were derived from previous studies, and sensitivity analyses for different willingness to pay (WTP) thresholds and percentage of patients upscaling from oral immunossupressants to rituximab were performed. Results: Thirty NMOSD patients were included. In the Early Group, the proportion of patients reaching the highest EDSS states (6.5 or more) decreased over five years compared to baseline. In contrast, the Escalating Therapy Group experienced an increase in this proportion over the same period. Cost-effectiveness was achieved for willingness to pay (WTP) of €20-80,000 in our main analysis, sustained in our sensitivity analysis. Conclusion: Early treatment with rituximab has the potential to lower healthcare costs and enhance quality of life for NMOSD patients, supporting its early prescription for preventive treatment.

Bortezomib for rituximab-refractory immune-mediated thrombotic thrombocytopenic purpura in the caplacizumab era: an Italian multicenter study

BackgroundImmune-mediated thrombotic thrombocytopenic purpura (iTTP) patients are not responsive to standard rituximab in approximately 10-15% of cases, and oral immunosuppressants showed controversial results with significant toxicity. Targeting plasma cells with bortezomib appears promising, but available evidence is scarce and stems only from isolated reports in the pre-caplacizumab era. ObjectivesTo evaluate the safety and efficacy of bortezomib in rituximab-refractory iTTP patients. MethodsWe conducted a retrospective observational multicenter study among 13 Italian iTTP-treating centers, collecting data from May 2017 to May 2023 (caplacizumab licensed in Italy in January 2020). ResultsBortezomib was effective in 10/17 patients (59%). Eleven were treated in the acute phase (9/11 responders, 82%, allowing discontinuation of caplacizumab in 5/6 treated patients), and 7 during clinical remission (2/7 responders, 28%). Responses occurred at a median time of 30 days, but 3 patients responded after 4 months. The median duration of response was 22 months (IQR 10-38), still ongoing in 6 patients at the time of data cut-off. Responders had fewer previous acute iTTP episodes than non-responders [median (IQR) 1 (1-2) vs 5.5 (2-7), p=0.03]. Eight subjects (47%) reported toxicities, mostly in those treated with ≥2 cycles. ConclusionDurable responses to bortezomib were registered in about 60% of multi-refractory iTTP patients, with mild-to-moderate toxicities. The occurrence of late responses (i.e., after 30 days) suggests a “watchful waiting” approach after bortezomib treatment.

Clinical Analysis of Reversible Posterior Encephalopathy Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation in Children

To summarize the clinical features of reversible posterior encephalopathy syndrome (PRES) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. The clinical data of six children who developed PRES after undergoing allo-HSCT in the Department of Hematology of Wuhan Children's Hospital from June 2016 to December 2022 were retrospectively analyzed, and their clinical characteristics, imaging examination, laboratory examination, and treatment regression were summarized. Among 281 children underwent allo-HSCT, 6 cases (2.14%) developed PRES, with a median age of 5.1(1.5-9.7) years old. 4 cases underwent related haploidentical donor transplantation, and 2 cases underwent sibling allografting and unrelated donor allografting donor transplantation, respectively. All six children had an acute onset of illness, with clinical manifestations of nausea and vomiting, seizures, psychiatric disorders, visual disturbances. The five cases elevated blood pressure. All children with PRES were treated with oral immunosuppressive drugs during seizures, and 3 cases were combined with different degrees of graft-versus-host disease. Most of the children showed effective improvement in clinical symptoms and imaging after adjusting/discontinuing suspected medications (cyclosporine, etc.) and symptomatic supportive treatments (oral antihypertensive, diazepam for antispasmodic, mannitol to lower cranial blood pressure), and one of them relapsed more than 8 months after the first seizure. PRES is rare after hematopoietic stem cell transplantation in children, and its onset may be related to hypertension, cytotoxic drugs, graft-versus-host disease, etc. Most of them can be recovered after active treatment, but not completely reversible, and the prognosis of those who combined with TMA is poor.

Effects of oral steroid sparing immunosuppressive drugs in long term maintenance treatment of chronic inflammatory demyelinating polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials.

49906 Drug survival for oral immunosuppressant therapy in a cohort of adult patients with atopic dermatitis

49906 Drug survival for oral immunosuppressant therapy in a cohort of adult patients with atopic dermatitis

Augmentative effects of leukemia inhibitory factor reveal a critical role for TYK2 signaling in vascular calcification

Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD.

Healthcare resource utilization patterns in psoriasis patients using biologic and conventional treatments in Finland.

Psoriasis vulgaris is associated with a significant healthcare burden, which increases over time as the disease progresses. The aim of this retrospective, population-based registry study was to characterize healthcare resource utilization (HCRU) in patients with psoriasis using biologics and oral immunosuppressants (conventionals) in Finland. The study cohort included all patients with a diagnosis of psoriasis vulgaris in the secondary healthcare setting between 2012-2018, who initiated a biologic (n=1,297) or conventional (n=4,753) treatment between 2013-2017. Data on primary and secondary HCRU were collected from nationwide healthcare registries. The results indicated a remarkable decrease in contacts with a dermatologist after the treatment initiation among patients starting biologic (mean annual number of contacts 5.4 per person before and 2.3 after the initiation), but not conventional (3.3 and 3.2) treatment. For conventional starters there was a high level of contacts with a dermatologist surrounding times of treatment switching, which was not observed for biologic starters. Overall, primary and other secondary care contacts did not decrease after the initiation or switch of treatment. The results highlight the importance of thorough consideration of the most optimal treatment alternatives, considering the overall disease burden to patients and healthcare systems.

Response to therapy in patients with chronic inflammatory demyelinating polyradiculoneuropathy: An observational study

Background & Objective: The existing practice in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is to initiate therapy with steroids, intravenous immune globulin (IVIg), or plasma exchange (PLEX) followed by period of immunosuppression. The objective of this study is to assess disability outcomes at 6 months after starting therapy. Methods: Patients who were diagnosed as having CIDP from the Army Hospital of Research and Referral, Delhi; who were initiated and maintained on therapy by treating neurologists with a six month follow up were included in this study. They were retrospectively divided into three groups based on initial therapy received. The primary outcome was comparison of the Inflammatory Neuropathy Cause and Treatment (INCAT) group overall disability sum score (INCAT-ODSS) at 6 months. Secondary outcomes were difference in score at 1 and 3 months, proportion with at least 20% response at 3 and 6 months (“responders”) and proportion who needed “rescue” therapy during the 6 months. Results: Sixty patients (26 retrospective, 34 prospective) were included in this study. They were treated with IVIg (33), steroid (19) and PLEX (8). Baseline INCAT-ODSS score (±SD) was 7.2(2.2), 7.2(1.5) and 7.5(1.9) respectively. All received some form of oral immune suppression during follow up. Twenty one (35%) needed additional rescue therapy. There was an overall significant reduction in the mean INCAT-ODSS disability score from 7.2 to 3.1 (Mean difference 4.2; CI 3.6-4.8); p<0.01). Nearly 88% of patients (51/58) showed at least 20% improvement from baseline. Two were lost to follow up (1 IVIg, 1 steroid). There was no difference in the ODSS at 6 months [2.9(2.4), 3.5(2.7) and 2.7(1.3)] respectively. No difference in ODSS at 1 and 3 months. Proportion of responders at 6 months and proportion who needed rescue therapy were also similar. Conclusion: Irrespective of initial therapy and maintenance oral immunosuppression used, the overall disability reduction in treatment with IVIg, steroid or PLEX is significant; however the three modalities are comparable in terms of disability reduction at 6 months. At least a third may need additional rescue therapy.

Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.

#2748 Combined rituximab and daratumumab treatment in difficult to treat nephrotic syndrome cases

Abstract Background and Aims Common treatments for multidrug-resistant and multidrug-dependent nephrotic syndrome (NS) are inconsistently effective and burdened by long-term toxicities. Moreover, affected patients are at high risk of progression to end-stage kidney failure. Objective To test the safety/efficacy profile of combined single infusion of rituximab and daratumumab in inducing proteinuria remission in multidrug resistant nephrotic syndrome and maintaining drug free disease remission in patients with multidrug-dependent nephrotic syndrome after removal of oral immunosuppression. Method We here present a Phase 2 Proof-of-Concept single-arm clinical trial, that enrolled consecutive participants at the Nephrology Unit of the IRCCS Giannina Gaslini Children's Hospital in Genoa, Italy, between September 2021 and March 2023. Enrolled patients, aged between 3 and 24 years, were multidrug-dependent or multidrug-resistant nephrotic syndrome for at least 12 months before enrolment. Multidrug-dependency was defined by the need of at least 2 oral immunosuppressive drugs (prednisone and/or calcineurin inhibitors and/or mycophenolate mofetil) and by the occurrence of at least two consecutive relapses on two immunosuppressive drugs. Multidrug-resistance nephrotic syndrome was defined by the lack of antiproteinuric effect of a double immunosuppressive therapy. Exclusion criteria included genetic forms of NS and administration of monoclonal therapies in the last 9 months before enrolment. Interventions: Rituximab and daratumumab were administered as single doses at 375 mg/m2 and 16 mg/kg, respectively, 15 days apart. Main Outcomes and Measures:Proteinuria, serum albumin, Immunoglobulin M and G, B and T lymphocyte subsets, safety, Quality of Life. Results A total of 7 consecutive multidrug-resistant and 16 multidrug-dependent NS, respectively, were enrolled. In multidrug-resistant NS, combined rituximab and daratumumab promoted complete or partial remission in 6 patients (Fig. 1A). Five subjects experienced proteinuria relapse, that was effectively treated with a second course of combined treatment. Decreased of I'm, but not IgG, correlated with improvement of proteinuria (Fig. 1B).These treatment allowed to reduce the chronic immunosuppressive treatment daily administered (Fig. 1C). In multidrug-dependent NS, combined rituximab and daratumumab extended the relapse-free time, allowing us to remove oral immunosuppressant (Fig. 1D). Disease relapse was invariably anticipated by a recovery of circulating IgM:patients with IgM levels below median values measured at 3 mo post-treatment had a significantly lower rate of relapse at 9 mo than patients with higher IgM levels at 3 mo (Fig. 1E). Combined treatment induced significative reduction of CD38+ plasma cells (Fig. 1F) and IgM, but not IgG. Treatment was well tolerated and significantly increased quality of life. Conclusion Combined rituximab and daratumumab was safe and effective in the treatment of complicated forms of NS, offering a new therapeutic option for this severe condition.

#2362 Clinical utility Anti-human T-lymphocyte Immunoglobulin (ATLG) as an induction agent in a living donor kidney transplantation: 5-year follow-up data

Abstract Background and Aims The usage of induction agents for living donor kidney transplants in India is varied. Polyclonal antibodies currently in use are anti-thymocyte globulin (ATG) and anti-T-lymphocyte globulin (ATLG). The role and dose of ATLG need to be defined. This study is focused on ATLG usage and the outcome with long-term follow-up. Method This is an analysis of 206 patients who received ATLG as an induction agent from 2017 to 2023. Patients received triple immunosuppression therapy: Tacrolimus, Mycophenolate Mofetil (MMF), and prednisolone for maintenance immunosuppression. Results A total of 206 patients received ATLG as an induction agent for living donor kidney transplants. The mean age of the patients was 39.13 ± 12.56 years. There were 87.3% (n = 180) males and 12.6% (n = 26) females. The majority of transplants in our study were ABO-compatible (94.6%, n = 195) and ABO-incompatible (5.2%, n = 11). The mean age of donors was 41 ± 13.7 years. Males were 38.3% (n = 79), and females were 61.6% (n = 127). Overall survival observed in the current study was 98% (n = 202), Post-transplant, 4 patients died (n = 2 died due to COVID-19, 1 due to Heart failure and 1 was infectious mortality.) The mean cumulative dose of ATLG in the current study was 305.1 ± 61.8 mg, and the mean dose was 5.4 ± 1.4 mg/kg. The baseline etiologies of patients who underwent transplant were chronic glomerulonephritis (47.5% n = 98), diabetic nephropathy (16.9% n = 35), hypertension (29.1% n = 60), CIN, and other GMB diseases. In the current study, the figure shows overall 11.6% (n = 24) rejections and 5-year follow-up data of Serum creatinine within a normal range. Post-transplant BK Virus Nephropathy was observed in 3.39% (n = 7) cases, CMV infection in two cases, TB was observed in three cases and fungal pneumonia in one case. Conclusion Long-term 5 year follow-up of Living donor kidney transplant shows that ATLG is an effective and safe induction agent. Good compliance with Oral immunosuppressant can improve graft survival as per the current study.

Modified platelet rich plasma therapy for alopecia totalis

Abstract Alopecia areata (AA) is an autoimmune disease characterized most commonly by patchy nonscarring hair loss which may progress to alopecia totalis which has poor prognosis. Platelet-rich plasma (PRP) therapy along with intralesional triamcinolone acetonide that is modified PRP proved to be beneficial in the case of alopecia totalis and helps in weaning patient off oral immunosuppression.

An Overview of Contemporary and Future Therapeutic Strategies for Scalp Psoriasis.

Scalp psoriasis is a common manifestation of psoriasis that significantly impacts a patient's quality of life. About 80% of cases of psoriasis involve the scalp, making it the most frequently affected area of the body. The treatment of scalp psoriasis is particularly crucial because of its hard-to-treat nature and substantial adverse impacts on overall well-being. Along with the physical symptoms of discomfort and itching, psoriasis, especially when it affects the scalp, can cause severe psychological damage. Treating scalp psoriasis can be challenging due to its location and associated symptoms, such as scaling and pruritus, which is why various drugs have become widely used for refractory cases. Topical treatments like corticosteroids and vitamin D analogs manage scalp psoriasis by reducing inflammation and regulating skin cell growth. Tar-based shampoos, salicylic acid solutions, and moisturizers control scaling. Phototherapy with UVB light reduces inflammation. Severe cases may require systemic medications such as oral retinoids and immunosuppressants. While various therapies are accessible for scalp psoriasis, concerns arise due to their limited advantages and the absence of controlled studies assessing their effectiveness. Considering these challenges, there is a clear demand for innovative approaches to address this condition effectively. Recent advancements in topical therapies, phototherapy, systemic agents, and complementary therapies have shown promising results in managing scalp psoriasis. Also, the advent of biologics, specifically anti-IL-17 and anti-IL-23 drugs for scalp psoriasis, has seen significant improvements. The review highlights the lack of well-tolerated and effective treatments for scalp psoriasis and underscores the importance of further research in this area. The objective of this review is to clarify the different treatment options currently available or being investigated in clinical trials for managing scalp psoriasis.

Safety of Docetaxel in a Patient with Metastatic Castration-Resistant Prostate Cancer After Kidney Transplantation: A Case Report

There are limitations in treating advanced prostate cancer (PC), especially castration-resistant (CR) cases, in renal transplant recipients (RTRs). We describe the case of RTR with metastatic CRPC (mCRPC) treated with docetaxel. A 60-year-old man with end-stage renal disease due to autosomal-dominant polycystic kidney disease (ADPKD) underwent living-related kidney transplantation. A year later, he was diagnosed with PC (prostate-specific antigen level: 998 ng/mL). Prostate biopsy revealed prostatic adenocarcinoma with a Gleason score of 4 + 4 = 8. Radiographic examination revealed seminal vesicle invasion and multiple bone and lymph node metastases. Combined androgen blockade therapy was initiated; however, the patient was diagnosed with CRPC 6 months later. Triweekly docetaxel therapy was administered 28 months after diagnosis. The patient successfully completed 7 cycles of this therapy without major adverse events. However, after the 7th cycle, he developed a high fever caused by an infection of ADPKD-associated renal cysts. Therefore, docetaxel was discontinued, and enzalutamide was started, followed by abiraterone, but without any effect. We then introduced cabazitaxel but discontinued it because of hepatic dysfunction. Hence, the patient underwent a docetaxel rechallenge. He was administered the PEGylated form of the recombinant human granulocyte colony-stimulating factor for neutropenia prophylaxis. After 6 cycles of rechallenge docetaxel therapy, the patient accidentally fell, resulting in a cervical spine fracture and subsequent death due to respiratory failure. Docetaxel can be safely delivered to patients with CRPC after renal transplantation who are taking oral immunosuppressants. It can be a good treatment option for them.

Comparison of Efficacy of Topical Betamethasone Dipropionate and Topical Minoxidil in Patients With Alopecia Areata.

Background and objective Alopecia areata (AA) is a reiterative and nonscarring type of hair loss that can affect any hairy area of the body, particularly the scalp. It manifests as patchy or confluent hair loss with variations in demographics and ethnicity. There are numerous treatment options available, including topical and systemic steroids, topical minoxidil, dithranol, tacrolimus, psoralen and ultraviolet therapy (PUVA), contact immunotherapy, and oral immunosuppressive drugs. However, no previous contrast for efficacy is present between the topical betamethasone versus topical minoxidil alone in our population. This study aims to compare the efficacy of topical betamethasone dipropionate versus topical minoxidil in patients with AA. Methodology A nonrandomized controlled study was conducted at the Department of Dermatology, Jinnah Hospital Lahore, incorporating the data of patients between July 26, 2016, and January 26, 2017, after obtaining institutional ethical approval. One hundred patients with alopecia, either on the scalp or any other hairy part, from both genders, aged between 18 and 50 years, were included in the study. Two groups were created, and patients were assigned to these groups based on the clinician's choice. Group A patients were administered betamethasone dipropionate (0.05%) lotion twice daily on affected areas for 12 weeks. Group B patients were administered minoxidil (5%) solution twice daily on affected areas for 12 weeks. A four-week follow-up plan was followed. A five-point scale score system was used for alopecia grading. After 12 weeks, the hair regrowth score (RGS) was used to compare the efficacy of treatment between the two groups. Results A total of 100 patients with grades S1 to S3 AA of less than three months duration were enrolled. Two groups were created, with 50 patients in each group. The mean age in Group A was 29.08 ± 6.51 years, while in Group B, it was 29.38 ± 6.62 years. In Group A, there were 76% males and 24% females, while in Group B, there were 74% males and 26% females. Comparison of efficacy of topical betamethasone dipropionate versus topical minoxidil in patients with AA demonstrated a greater efficacy of 74% (Grade 3 and Grade 4 responses) in Group A, while in Group B, only 42% of patients showed efficacy. A statistically significant difference was found, with a P-value of 0.001. No serious side effects were noted. Conclusions Our study concluded that topical betamethasone dipropionate (0.05%) lotion has statistically significantly higher efficacy compared to topical minoxidil (5%) solution in patients with AA.

Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): a prospective cohort study

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment. We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539). Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5-31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13-30]). The mean change in MG-QOL15r was -10·4 (95% CI -18·9 to -1·3) with mycophenolate mofetil and -6·8 (-17·2 to 3·6) with azathioprine (mean difference -3·3, 95% CI -7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI -0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI -4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths. More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis. Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America.

Trends in Integration Between Physician Organizations and Pharmacies for Self-Administered Drugs

Increasing integration across medical services may have important implications for health care quality and spending. One major but poorly understood dimension of integration is between physician organizations and pharmacies for self-administered drugs or in-house pharmacies. To describe trends in the use of in-house pharmacies, associated physician organization characteristics, and associated drug prices. A cross-sectional study was conducted from calendar years 2011 to 2019. Participants included 20% of beneficiaries enrolled in fee-for-service Medicare Parts A, B, and D. Data analysis was performed from September 15, 2020, to December 20, 2023. Prescriptions filled by in-house pharmacies. The share of Medicare Part D spending filled by in-house pharmacies by drug class, costliness, and specialty was evaluated. Growth in the number of physician organizations and physicians in organizations with in-house pharmacies was measured in 5 specialties: medical oncology, urology, infectious disease, gastroenterology, and rheumatology. Characteristics of physician organizations with in-house pharmacies and drug prices at in-house vs other pharmacies are described. Among 8 020 652 patients (median age, 72 [IQR, 66-81] years; 4 570 114 [57.0%] women), there was substantial growth in the share of Medicare Part D spending on high-cost drugs filled at in-house pharmacies from 2011 to 2019, including oral anticancer treatments (from 10% to 34%), antivirals (from 12% to 20%), and immunosuppressants (from 2% to 9%). By 2019, 63% of medical oncologists, 20% of urologists, 29% of infectious disease specialists, 21% of gastroenterologists, and 22% of rheumatologists were in organizations with specialty-relevant in-house pharmacies. Larger organizations had a greater likelihood of having an in-house pharmacy (0.75 percentage point increase [95% CI, 0.56-0.94] per each additional physician), as did organizations owning hospitals enrolled in the 340B Drug Discount Program (10.91 percentage point increased likelihood [95% CI, 6.33-15.48]). Point-of-sale prices for high-cost drugs were 1.76% [95% CI, 1.66%-1.87%] lower at in-house vs other pharmacies. In this cross-sectional study of physician organization-operated pharmacies, in-house pharmacies were increasingly used from 2011 to 2019, especially for high-cost drugs, potentially associated with organizations' financial incentives. In-house pharmacies offered high-cost drugs at lower prices, in contrast to findings of integration in other contexts, but their growth highlights a need to understand implications for patient care.

Unilateral Mooren Ulcer After COVID-19 Vaccination

Introduction: Mooren ulcer is an immune-related corneal pathology of unknown origin, that often occurs following a triggering factor. Case Report: We report the case of a 32-year-old woman who presented with a red painful right eye. The clinical findings were in favor of peripheral ulcerative keratitis. The etiological assessment came back negative. The retained diagnosis was Mooren ulcer. The treatment was based on oral corticosteroid therapy and immunosuppressants prescribed by internists. The evolution was marked by the regression of the pain and the stability of the lesion. Discussion: Currently in the literature, rare cases of corneal ulcers following COVID-19 vaccination have been described. A causal link remains possible but not yet proven. This subject needs more perspective and research. Conclusion: The COVID-19 vaccine has several ocular side effects. The mechanism of triggering a mooren ulcer remains unclear.

Comparative Inhibitory Effects of Tacrolimus, Cyclosporine, and Rapamycin on Human Anti-Pig Xenogeneic Mixed Lymphocyte Reactions.

Long-term immunosuppressive maintenance therapy is necessary to prevent the rejection of xenografts. However, it is still unclear which oral immunosuppressant is most suitable for pig-to-human xenotransplantation . A xenogeneic mixed lymphocyte reaction (MLR) system was established using peripheral blood mononuclear cells (PBMCs) isolated from wildtype (WT) or GTKO/CMAHKO/β4GalNT2KO (TKO) pigs as stimulator cells and human PBMCs as responder cells. Various concentrations of tacrolimus (Tac), cyclosporine (CsA), or rapamycin (Rapa) were added to the MLR system as interventions. The inhibitory effects of the three immunosuppressants on the proliferation and cytokine production of human T cells were studied and compared. The inhibitory effect of anti-CD154 mAb alone or in combination with Tac/CsA/Rapa on xenoreactive MLR was also investigated. PBMCs from both WT and TKO pigs stimulated significant proliferation of human T cells. Tac had a strong inhibitory effect on human T-cell proliferation stimulated by pig PBMCs. CsA inhibited human T-cell proliferation in a typical dose-dependent manner. When Tac and CsA concentrations reached 5 and 200ng/mL, respectively, the proliferation rates of CD3+/CD4+/CD8+ T cells were reduced almost to a negative level. Even at high concentrations, Rapa had only a moderate inhibitory effect on xenogeneic MLR. The inhibitory effects of these three immunosuppressants on xenogeneic T-cell responses were further confirmed by the detection of CD25 expression and supernatant cytokines (IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-10, and IL-17). Although anti-CD154 mAb monotherapy showed only moderate inhibitory effects on xenoreactive T-cell proliferation, low-dose anti-CD154 mAb combined with low-dose Tac, CSA, or Rapa could produce significant synergistic inhibitory effects. Tac is more efficient than CsA or Rapa in inhibiting xenogeneic T-cell responses in vitro. If used in combination with anti-CD154 mAb, all the three immunosuppressants can achieve satisfactory synergistic inhibitory effects.

Real-world outcomes of children treated with dupilumab for moderate-to-severe atopic dermatitis: a single-centre retrospective observational UK study.

Dupilumab is licensed for the treatment of moderate-to-severe atopic dermatitis (AD) in patients aged ≥ 6 months. The aim of this study was to examine real-world outcomes and safety of dupilumab in British children with moderate-to-severe AD attending a tertiary referral paediatric centre. Skin and quality of life scores, adverse events and discontinuation rates were assessed. Patients aged ≤ 18 years with moderate-to-severe AD were included if they had skin scores recorded at baseline and at least one follow-up visit. Efficacy and safety were assessed using descriptive statistics. In this retrospective observational survey, 72 children/teenagers, with a median age of 14 years (range 7-18) were included. Oral systemic immunosuppressants had failed to control AD in 88% of children recruited. All patients commenced on dupilumab had pretreatment eczema skin scores consistent with moderate-to-severe disease, with a median Eczema Area and Severity Index (EASI) score of 25 [interquartile range (IQR) 20-31]. EASI scores decreased by a median of 94% (IQR 82-100) and remained consistently low over 10-52 months of the study, with a median EASI score at final follow-up of 2 (IQR 0-6). Of the 72 children, 8 (11%) were able to discontinue dupilumab as they were in remission. Nineteen (26%) experienced adverse events, most commonly conjunctivitis (12 patients; 17%). Eight (11%) discontinued dupilumab (six with ongoing inflammatory skin flares, one with severe allergic conjunctivitis, one with intercurrent Wilson disease). Dupilumab was highly effective in treating most children with moderate-to-severe AD with good safety outcomes in the real world. However, 10% of children may need alternative therapy because of drug ineffectiveness or side-effects.