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Evaluation of effect of empirical attack-preventive immunotherapies in neuromyelitis optica spectrum disorders: An update systematic review and meta -analysis.
Ma, J, Yu, H, Wang, H, Zhang, X, Feng, K
Journal of neuroimmunology. 2022;:577790
Abstract
BACKGROUND Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system, which mainly involves the optic nerve and spinal cord. Frequent relapse can accumulate the degree of disability. At present, the main treatment options are immunosuppressants and blood purification. The first-line immunosuppressants for NMOSD are mainly rituximab (RTX), mycophenolate mofetil (MMF) and azathioprine (AZA). Therefore, we designed this systematic review and meta-analysis to evaluate the safety and effect of the above three drugs in the treatment of NMOSD patients. METHODS The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Rituximab or Azathioprine or Mycophenolate Mofetil; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic's Disease, Devic Syndrome, Devic's Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, CD20 Antibody, Rituximab CD20 Antibody, Mabthera, IDEC-C2B8 Antibody, GP2013, Rituxan, Mycophenolate Mofetil, Mofetil, Mycophenolate, Mycophenolic Acid, Morpholinoethyl Ester, Cellcept, Mycophenolate Sodium, Myfortic, Mycophenolate Mofetil Hydrochloride, Mofetil Hydrochloride, Mycophenolate, RS 61443, RS-61443, RS61443, azathioprine sodium, azathioprine sulfate (note: literature retrieval operators "AND" "OR" "NOT" are used to link MeSH with Entry Terms.) The literature search found a total of 3058 articles about rituximab, mycophenolate mofetil and azathioprine in the treatment of NMOSD, 63 of which were included in this study after a series of screening. RESULTS 930,933,732 patients with NMOSD were enrolled, who had been treated with MMF, AZA and RTX, respectively. The pooled standardized mean difference (SMD) of EDSS before and after RTX treated was -0.58 (95%CI: -0.72, -0.44) (I2 = 0%, p = 0.477), before and after MMF treated was -0.47 (95%CI: -0.73, -0.21) (I2 = 85.6%, p<0.001), before and after AZA treated was -0.41 (95%CI: -0.60, -0.23) (I2 = 65.4%, p<0.001). there was no significant difference in the effect of the three drugs on reducing EDSS scores (RTX vs MMF, p = 0.522; RTX vs AZA, p = 0.214; MMF vs AZA, p = 0.732). The pooled standardized mean difference (SMD) of ARR before and after RTX treated was -1.45 (95%CI: -1.72, -1.18) (I2 = 72.4%, p<0.001), before and after MMF treated was -1.14 (95%CI: -1.31, -0.97) (I2 = 54.5%, p<0.001), before and after AZA treated was -1.11 (95%CI: -1.39, -0.83) (I2 = 83.4%, p<0.001). RTX significantly reduced ARR compared with the other two drugs (RTX vs MMF, p = 0.039; RTX vs AZA, p = 0.049; MMF vs AZA, p = 0.436). CONCLUSION The results of this systematic review and meta-analysis showed that the treatment of NMOSD patients with RTX, MMF and AZA is associated with decreased number of relapses and disability improvement as well, and there was no significant difference in the effect of the three drugs on reducing EDSS scores, but RTX significantly reduced ARR compared with the other two drugs.
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Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions.
Zinger, N, Ponath, G, Sweeney, E, Nguyen, TD, Lo, CH, Diaz, I, Dimov, A, Teng, L, Zexter, L, Comunale, J, et al
Neurology(R) neuroimmunology & neuroinflammation. 2022;(2)
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Abstract
BACKGROUND AND OBJECTIVES To determine the effects of dimethyl fumarate (DMF) and glatiramer acetate on iron content in chronic active lesions in patients with multiple sclerosis (MS) and in human microglia in vitro. METHODS This was a retrospective observational study of 34 patients with relapsing-remitting MS and clinically isolated syndrome treated with DMF or glatiramer acetate. Patients had lesions with hyperintense rims on quantitative susceptibility mapping, were treated with DMF or glatiramer acetate (GA), and had a minimum of 2 on-treatment scans. Changes in susceptibility in rim lesions were compared among treatment groups in a linear mixed effects model. In a separate in vitro study, induced pluripotent stem cell-derived human microglia were treated with DMF or GA, and treatment-induced changes in iron content and activation state of microglia were compared. RESULTS Rim lesions in patients treated with DMF had on average a 2.77-unit reduction in susceptibility per year over rim lesions in patients treated with GA (bootstrapped 95% CI -5.87 to -0.01), holding all other variables constant. Moreover, DMF but not GA reduced inflammatory activation and concomitantly iron content in human microglia in vitro. DISCUSSION Together, our data indicate that DMF-induced reduction of susceptibility in MS lesions is associated with a decreased activation state in microglial cells. We have demonstrated that a specific disease modifying therapy, DMF, decreases glial activity in chronic active lesions. Susceptibility changes in rim lesions provide an in vivo biomarker for the effect of DMF on microglial activity. CLASSIFICATION OF EVIDENCE This study provided Class III evidence that DMF is superior to GA in the presence of iron as a marker of inflammation as measured by MRI quantitative susceptibility mapping.
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Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoring.
Waldman, M, Soler, MJ, García-Carro, C, Lightstone, L, Turner-Stokes, T, Griffith, M, Torras, J, Valenzuela, LM, Bestard, O, Geddes, C, et al
Kidney international. 2021;(1):227-237
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Abstract
The effects of SARS-CoV-2 infection on individuals with immune-mediated glomerulonephritis, who are often undergoing immunosuppressive treatments, are unknown. Therefore, we created the International Registry of COVID infection in glomerulonephritis (IRoc-GN) and identified 40 patients with glomerulonephritis and COVID-19 followed in centers in North America and Europe. Detailed information on glomerulonephritis diagnosis, kidney parameters, and baseline immunosuppression prior to infection were recorded, as well as clinical presentation, laboratory values, treatment, complications, and outcomes of COVID-19. This cohort was compared to 80 COVID-positive control cases from the general population without glomerulonephritis matched for the time of infection. The majority (70%) of the patients with glomerulonephritis and all the controls were hospitalized. Patients with glomerulonephritis had significantly higher mortality (15% vs. 5%, respectively) and acute kidney injury (39% vs. 14%) than controls, while the need for kidney replacement therapy was not statistically different between the two groups. Receiving immunosuppression or renin-angiotensin-aldosterone system inhibitors at presentation did not increase the risk of death or acute kidney injury in the glomerulonephritis cohort. In the cohort with glomerulonephritis, lower serum albumin at presentation and shorter duration of glomerular disease were associated with greater risk of acute kidney injury and need for kidney replacement therapy. No differences in outcomes occurred between patients with primary glomerulonephritis versus glomerulonephritis associated with a systemic autoimmune disease (lupus or vasculitis). Thus, due to the higher mortality and risk of acute kidney injury than in the general population without glomerulonephritis, patients with glomerulonephritis and COVID-19 should be carefully monitored, especially when they present with low serum albumin levels.
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Invasive pulmonary aspergillosis associated with COVID-19 in a kidney transplant recipient.
Trujillo, H, Fernández-Ruiz, M, Gutiérrez, E, Sevillano, Á, Caravaca-Fontán, F, Morales, E, López-Medrano, F, Aguado, JM, Praga, M, Andrés, A
Transplant infectious disease : an official journal of the Transplantation Society. 2021;(2):e13501
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in the general population, scarce information is available regarding coronavirus disease 2019 (COVID-19)-associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID-19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 → 3)-β-d-glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.
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Post-renal transplant malignancies: Opportunities for prevention and early screening.
Turshudzhyan, A
Cancer treatment and research communications. 2021;:100283
Abstract
GOAL OF THE REVIEW While transplant recipients are aware of increased malignancy risk, there is little consensus on the preventative measures. The goal of this review is to bring available preventative measures to light and prompt more research to be done with ultimate goal of developing an individualized prevention plan for each patient based on risk factors and available screening tools. INTRODUCTION Transplant surgery offers patients with end-stage renal disease a longer life expectancy with help of immunosuppressive therapies. Nonetheless, life-long immunosuppression comes at a cost of post-renal transplant malignancies, which have become the leading cause of morbidity in this patient group. DISCUSSION Post-renal transplant cancers can develop through either de novo, by donor-related transmission, or recurrence of recipient's pre-transplant cancer. While immunosuppressive therapy is considered to be the leading cause, weakened immunosurveillance of neoplastic cells and inadequate immune response against oncogenic viruses also plays an important role. The most common cancers seen in renal transplant patients are skin cancers and post-transplant lymphoproliferative disorder (PTLD). Risk factors for skin cancers have are ultraviolet light, human papilloma virus infection, and use of cyclosporin and azathioprine. Numerous viral infections have been associated with transplant-related malignancies post-transplant. CONCLUSION While lowering of immunosuppressive therapy remains the treatment of choice, it may lead to graft failure. Given some of the presented malignancies have modifiable risk factors and options for screening, clinical outcomes can be improved. Limiting skin exposure, dermatologic screening, and prophylactic retinoids can help lower the incidence rate of skin malignancy. Endoscopic screening for renal transplant patients can help identify gastric adenocarcinoma early and improve survival rates. Some of the post-transplant malignancies have been responsive to anti-viral treatment.
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Pure red cell aplasia in systemic lupus erythematosus, a nationwide retrospective cohort and review of the literature.
Lobbes, H, Mahévas, M, Alviset, S, Galicier, L, Costedoat-Chalumeau, N, Amoura, Z, Alric, L, Hot, A, Durupt, S, Michel, M, et al
Rheumatology (Oxford, England). 2021;(1):355-366
Abstract
OBJECTIVES To characterize the clinical and biological course, management and response to treatment in SLE-associated pure red cell aplasia (PRCA). METHODS This was a nationwide, multicentre, retrospective cohort study. From 2006 to 2018, we included adults with a diagnosis of PRCA supported by bone marrow examination and SLE or biologic manifestations of SLE after ruling out parvovirus B19 infection. RESULTS We enrolled 24 patients (20 women). SLE was diagnosed before PRCA for 14 patients (median delay 81 months). At PRCA diagnosis, mean age, haemoglobin level, and reticulocyte and differential erythroblast count were 39.2 (13.2) years, 62 ( 20) g/l, 9.1 (7.6) × 109/l and 2.8 ( 2.5)%, respectively. Eleven (45%) patients experienced multiple PRCA flares (median 6, range 2-11). CS therapy resulted in only three complete sustained responses, and 19 (79%) patients required immunosuppressive agents with highly variable regimens. After a median follow-up of 76 months (range 13-173), 17 (71%) patients showed complete response for PRCA, 5 (21%) partial response and 2 (8%) treatment failure. In total, 21 (87%) patients required red blood cell transfusion; 5 had a diagnosis of transfusion-related iron overload. Eighteen (75%) patients experienced severe infectious events requiring hospitalization. CONCLUSION SLE-associated PRCA is a severe condition. Repeated red blood cell transfusions and several lines of immunosuppressant therapy are mostly required, with high risk of severe infectious events and iron overload. Despite sustained response for PRCA and SLE obtained in most patients, the best therapeutic strategy remains to be determined.
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Cyclosporine Anionic and Cationic Ophthalmic Emulsions in Dry Eye Disease: A Literature Review.
Tong, L, Sun, CC, Yoon, KC, Lim Bon Siong, R, Puangsricharern, V, Baudouin, C
Ocular immunology and inflammation. 2021;(7-8):1606-1615
Abstract
Purpose: There are no clinical studies directly comparing anionic and cationic emulsions of cyclosporine for the treatment of dry eye disease (DED). We therefore conducted a literature review to evaluate the efficacy and safety of these different formulations.Methods: A literature search was performed in Embase and Medline from January 1999 to May 2019 to identify publications that evaluated clinical outcomes with either cyclosporine anionic or cationic emulsion in patients with moderate-to-severe or severe DED.Results: Thirteen publications met criteria. In patients with moderate-to-severe disease, evidence demonstrated improvement in the signs of DED with both formulations. However, improvement in symptoms was not consistently demonstrated. Studies specifically in severe DED were only identified with the cationic emulsion and showed improvement in the objective signs of DED. There were no obvious differences in tolerability between products.Conclusions: Both formulations are effective for the treatment of moderate-to-severe DED and are well tolerated.
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Important considerations for drugs, nutritional, and herbal supplements in pediatric solid organ transplant recipients.
Pilch, NA, Sell, ML, McGhee, W, Venkataramanan, R
Pediatric transplantation. 2021;(1):e13881
Abstract
Pediatric transplant recipients are on multiple prescription and non-prescription drugs. Many patients also use dietary, nutritional, and herbal supplements. This manuscript researched formulations of immunosuppressive drugs currently available and presents information on generic immunosuppressive drugs, commonly used non-prescription medications, dietary supplements, and herbal supplements. Immunosuppressive drugs are available in various formulations. Not all formulations are interchangeable. A number of FDA-approved generic formulations are available commercially in the United States. Generally generic formulations produce similar blood concentration vs time profiles compared to brand name products in adults and are considered to be bioequivalent. NSAID should be avoided in transplant patients due to potential drug interactions and increased risk associated with NSAID use; and appropriate doses of acetaminophen should be used for treatment of pain. Over-the-counter medications, such as guaifenesin and dextromethorphan, antihistamine medications, including diphenhydramine, loratadine, cetirizine, and fexofenadine, can be safely used in pediatric solid organ transplant population. Many safe and effective over-the-counter options exist for stool softening and as laxative. Diarrhea can lead to an increase in calcineurin inhibitor levels. Food can alter the absorption of immunosuppressive drugs. Several herbal products can alter immune status of the patients or alter the blood concentration of immunosuppressive drugs or may produce renal or hepatic toxicities and should be avoided in pediatric transplant recipients. It is important to educate pediatric transplant recipients and their families about not only immunosuppressive drug therapy but also about non-prescription drugs, dietary, and herbal supplement use.
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Exposure-response modeling of peficitinib efficacy in patients with rheumatoid arthritis.
Toyoshima, J, Kaibara, A, Shibata, M, Kaneko, Y, Izutsu, H, Nishimura, T
Pharmacology research & perspectives. 2021;(3):e00744
Abstract
The aim was to analyze the relationship between peficitinib exposure and efficacy response according to American College of Rheumatology (ACR) 20 criteria and 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in rheumatoid arthritis (RA) patients, and to identify relevant covariates by developing exposure-response models. The analysis incorporated results from three multicenter, placebo-controlled, double-blind studies. As an exposure parameter, individual post hoc pharmacokinetic (PK) parameters were obtained from a previously constructed population PK model. Longitudinal ACR20 response rate and individual longitudinal DAS28-CRP measurements were modeled by a non-linear mixed effect model. Influential covariates were explored, and their effects on efficacy were quantitatively assessed and compared. The exposure-response models of effect of peficitinib on duration-dependent increase in ACR20 response rate and decrease in DAS28-CRP were adequately described by a continuous time Markov model and an indirect response model, respectively, with a sigmoidal Emax saturable of drug exposure in RA patients. The significant covariates were DAS28-CRP and total bilirubin at baseline for the ACR20 response model, and CRP at baseline and concomitant methotrexate treatment for the DAS28-CRP model. The covariate effects were highly consistent between the two models. Our exposure-response models of peficitinib in RA patients satisfactorily described duration-dependent improvements in ACR20 response rates and DAS28-CRP measurements, and provided consistent covariate effects. Only the ACR20 model incorporated a patient's subjective high expectations just after the start of the treatment. Therefore, due to their similarities and differences, both models may have relevant applications in the development of RA treatment. CLINICAL TRIAL REGISTRATION NCT01649999 (RAJ1), NCT02308163 (RAJ3), NCT02305849 (RAJ4).
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Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.
Jones, JL, Tse, F, Carroll, MW, deBruyn, JC, McNeil, SA, Pham-Huy, A, Seow, CH, Barrett, LL, Bessissow, T, Carman, N, et al
Gastroenterology. 2021;(2):681-700
Abstract
BACKGROUND AND AIMS The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.