Nonsteroidal Immunosuppressive Agents Research Articles

Advancements in Targeted Therapies for Generalized Acetylcholine Receptor Antibody Positive Myasthenia Gravis: Beginnings of a Paradigm Shift.

In recent years, a new era of biologic therapeutics has emerged for the treatment of generalized myasthenia gravis (gMG). Compared to traditional immune modulatory therapies (steroids, non-steroidal immunosuppressive agents), these agents have more specific target engagement via inhibition of complement activation (eculizumab, ravulizumab, zilucoplan) or blockade of IgG recycling via the neonatal Fc receptor (FcRn; efgartigimod, rozanolixizumab). Phase 3 trials with each of these agents have shown rapid clinical improvement and good safety and tolerability. B-cell targeting with rituximab was safe and well-tolerated but with less impressive efficacy in two phase 2 studies. As a result, four new therapies are now approved for use (eculizumab, ravulizumab, efgartigimod, rozanolixizumab), another (zilucoplan) is in regulatory approval process and several others are in pivotal trials. A paradigm shift is afoot. The challenge is figuring out where these therapies may fit in gMG treatment algorithms.

Outcomes after thymectomy in non-thymomatous myasthenia gravis.

Guidelines by the myasthenia gravis (MG) Foundation of America suggest patients aged 18 to 50 years with non-thymomatous myasthenia gravis (NTMG) benefit from thymectomy. Our objective was to investigate utilization of thymectomy in NTMG patients outside the confines of a clinical trial. From the Optum de-identified Clinformatics Data Mart Claims Database (2007 to 2021), we identified patients diagnosed with MG between 18-50 years old. We then selected patients who received a thymectomy within 12 months of MG diagnosis. Outcomes included use of steroids, non-steroidal immunosuppressive agents (NSIS), and rescue therapy (plasmapheresis or intravenous immunoglobulin), as well as NTMG-related emergency department (ED) visits and hospital admissions. These outcomes were compared in the 6-months before and after thymectomy. A total of 1,298 patients met our inclusion criteria, of whom 45 (3.47%) received a thymectomy, performed via minimally invasive surgery in 53.3% of cases (n=24). In comparing the pre- to post-operative period, we noted that steroid use increased (53.33% to 66.67%, P=0.034), NSIS use remained stable, and use of rescue therapy decreased (44.44% to 24.44%, P=0.007). Costs associated with steroid and NSIS use remained stable. However, the mean costs of rescue therapy decreased (from $13,243.98 to $8,486.26, P=0.035). Hospital admissions and ED visits related to NTMG remained stable. There were 2 readmissions within 90 days (4.44%) associated with thymectomy. Patients with NTMG undergoing thymectomy experienced less need for rescue therapy following resection, albeit with increased rates of steroid prescriptions. Thymectomy is infrequently performed in this patient population despite acceptable postsurgical outcomes.

367 Entropion repair outcomes in ocular cicatricial pemphigoid versus other cicatricial etiologies: A retrospective study

Mucous membrane pemphigoid with ocular involvement or ocular cicatricial pemphigoid (OCP) can lead to severe eyelid disease, including entropion. Surgical repair outcomes of OCP-related entropion compared to other cicatricial entropion has yet to be elucidated. This study aims to understand the association between entropion recurrence and diagnosis of OCP. Entropion repair of OCP patients were compared to patients with entropion of other cicatrizing etiology from January 2010 to June 2020. A generalized estimating equation with binomial likelihood and logit link was used to analyze the association between a diagnosis of OCP and failure of the first entropion repair, determined by recurrence or repair noted. Patient ID was used as the clustering variable with exchangeable correlation structure.19 OCP patients and 60 patients with entropion secondary to other etiologies received 38 and 75 entropion repairs, respectively. The unadjusted odds of failure did not significantly differ between groups (odds ratio (OR) 2.66, 95% confidence interval (CI) 0.92-7.69). No significant effect of OCP diagnosis was found (OR: 2.43, 95% CI: 0.75-7.87) when adjusting for age at repair, sex, repair approach, ophthalmologic steroids, and non-steroidal ophthalmologic immunosuppressants (systemic steroids and non-steroidal immunosuppressive agents were highly correlated with OCP diagnosis and removed from the model). Age at first repair was positively associated with failure (p=0.026). Ophthalmic steroids use decreased the odds offailure (OR: 0.27 95% CI: 0.07-0.96). This study provides evidence that in a population of OCP patients where the majority were systemically immunosuppressed, the likelihood of entropion failure was no different than that for repair of entropion secondary to other cicatrizing etiologies.

Efficacy and safety of immunosuppressive treatment in IgA nephropathy: a meta-analysis of randomized controlled trials

BackgroundImmunosuppressive agents have been widely used in the treatment of IgA nephropathy (IgAN), but the efficacy and safety remain controversial. The recent STOP-IgAN and TESTING studies have again focused attention on the application of immunosuppressive agents in IgAN. This study investigated the benefits and risks of immunosuppressive agents in IgAN.MethodsMEDLINE, EMBASE, the Cochrane Library, and article reference lists were searched for randomized controlled trials (RCTs) comparing immunosuppressive agents with any other non-immunosuppressive agents for treating IgAN. A meta-analysis was performed on the outcomes of proteinuria, creatinine (Cr), estimated glomerular filtration rate (eGFR), and adverse events in patients with IgAN, and trial sequential analyses were also performed for outcomes.ResultsTwenty-nine RCTs (1957 patients) that met our inclusion criteria were identified. Steroids (weighted mean difference [WMD] –0.70, 95% confidence interval [CI] –1.2 to − 0.20), non-steroidal immunosuppressive agents (NSI) (WMD –0. 43, 95% CI − 0.55 to − 0.31), and combined steroidal and non-steroidal immunosuppressive agents (S&NSI) (WMD –1.46, 95% CI − 2.13 to − 0.79) therapy significantly reduced proteinuria levels compared with the the control group. Steroid treatment significantly reduced the risk of end-stage renal disease (ESRD) (relative risk [RR] 0.39, CI 0.19 to 0.79) compared with the control group. The immunosuppressive therapy group showed significant increases in gastrointestinal, hematological, dermatological, and genitourinary side effects, as well as impaired glucose tolerance or diabetes. Hyperkalemia was more common in the control group.ConclusionImmunosuppressive therapy can significantly reduce proteinuria and ESRD risk in patients with IgAN, but with a concomitant increase in adverse reactions. Therefore, care is required in the application of immunosuppressive agents in IgAN.

Features of Microscopic Colitis in Cancer Patients Receiving Immune Checkpoint Inhibitors

Introduction: Microscopic colitis (MC) has been described as one pattern of injury in immune checkpoint inhibitor (ICPI)-induced colitis. However, very little information is available in the medical literature regarding MC characteristics in patients receiving ICPI. We aimed to characterize ICPI-induced MC by exploring risk factors, colitis treatment, endoscopic features, and clinical outcomes and comparing them with those of patients who had MC without ICPI exposure. Methods: We studied consecutive patients with MC from January 2012 to January 2018. Patients were grouped as cancer patients with or without ICPI exposure or non-cancer patients. Medical charts were reviewed to collect risk factors, colitis treatment, endoscopic features, and clinical outcomes. Continuous variables were compared between the three groups using Wilcoxon rank-sum test. Categorical variables were compared using chi-square test. Results: Total of 65 patients with MC were included; 15 patients had cancer and received ICPI, 39 patients had cancer without exposure to ICPI, and 11 had no cancer diagnosis. Most were Caucasian (88%), female (63%) with mean age of 62 years. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040; Table 1). Mucosal abnormality (i.e. erythema, edema and altered vascularity) was the most common endoscopic feature in patients with ICPI-induced MC compared to normal findings in the non-ICPI-induced MC groups (P = 0.106; Table 2). Budesonide was used less frequently for patients with ICPI-induced MC than other groups (P = 0.008). Instead, patients with ICPI-induced MC required treatment with oral and intravenous steroids, and nonsteroidal immunosuppressive agents more than other groups (P < 0.001 for all). Higher number of hospitalizations was required for patients with ICPI-induced MC compared to those without ICPI exposure (P < 0.001). The recurrence rate for the three entities was comparable (P = 0.502). In the ICPIinduced MC group, 13 patients had histological features of lymphocytic colitis whereas 2 had features of collagenous colitis (Table 3). Conclusion: This study suggests that despite the similarities in histological features between MC with and without ICPI exposure, MC in patients receiving ICPI treatment was more frequently associated with abnormal mucosal injury and aggressive disease course that requires potent immunosuppressive therapy and hospitalization.123_A Figure 1 No Caption available.123_B Figure 2 No Caption available.123_C Figure 3 No Caption available.

Can Immune Checkpoint Inhibitors Induce Microscopic Colitis or a Brand New Entity?

Microscopic colitis (MC) has been described as 1 pattern of injury in immune checkpoint inhibitor (ICPI)-induced colitis. The main objective of this study was to characterize ICPI-induced MC by exploring the differences in risk factors, colitis treatments, endoscopic features, and clinical outcomes between cancer and noncancer patients with MC with and without exposure to ICPIs. A retrospective chart review was conducted among patients diagnosed with MC from our institutional pathology database from January 2012 to January 2018. Patients were categorized into MC in cancer patients with or without ICPI exposure and in noncancer patients. Risk factors (use of tobacco and certain medications), colitis treatments (antidiarrheals and immunosuppressants), endoscopic features (with or without mucosal abnormality), and clinical outcomes (diarrhea recurrence, hospitalization, mortality) were collected and compared among the 3 groups. Of the 65 eligible patients with MC, 15 cancer patients had exposure to ICPI, 39 cancer patients had no exposure to ICPI, and 11 had no cancer diagnosis. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040). Furthermore, in this population, mucosal abnormality was the most common endoscopic feature compared with normal findings in the non-ICPI-induced MC groups (P = 0.106). Patients with ICPI-induced MC required more treatments with oral and intravenous steroids and nonsteroidal immunosuppressive agents (all P < 0.001) and had a higher rate of hospitalization (P < 0.001). This study suggests that despite some similarities between MC with and without exposure to ICPIs, ICPI-induced MC has a more aggressive disease course that requires more potent immunosuppressive treatment regimens and greater need for hospitalization. 10.1093/ibd/izy240_video1izy240.video15828223597001.

Evidence-based clinical practice guidelines for IgA nephropathy 2014.

1. Definition and background IgA nephropathy (IgAN, also known as Berger’s disease) is a disease characterized by urinary findings suggesting glomerulonephritis; predominantly, IgA is deposited in the glomeruli, with no evidence of other underlying disease. Glomerular hematuria and proteinuria are urinary findings that suggest glomerulonephritis. Renal biopsy findings, which are required for confirming the diagnosis of glomerulonephritis, include IgA deposits mainly in the glomerular mesangium and occasionally in the capillary loops. In many cases, C3 is also co-deposited. The rate of progression to end-stage renal disease (ESRD) is approximately 40 % at 20 years after diagnosis. Treatment may include therapy with renin-angiotensin system (RAS) blockers, antiplatelet agents, oral corticosteroids, fish oil, or non-steroidal immunosuppressive agents; steroid pulse therapy; or tonsillectomy. The therapeutic effects of each have been examined, but an effective treatment regimen is yet to be established.

Analysis of rituximab’s usage for the treatment of pediatric systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by chronic inflammation that potentially leads to organ damage. Severe manifestations make the management of SLE difficult and challenging. Nonsteroidal antiinflammatory drugs (NSAIDs), antimalarial drugs, glucocorticoids, immunosuppressive and citotoxic agents are the mainstays of treatment. Unfortunately, these agents are related to a vast toxicity. For an amount of patients, these approaches arent enough to achieve disease activity control, especially in those with cytopenia, nephritis and neuropsychiatric lupus. For these cases, Rituximab (RTX) – a chimeric mouse/human monoclonal antibody specific for human CD20 B-cell – has been widely prescribed. It is known that B-cells have a central role in SLE pathogenesis, being precursors of plasma cells production autoantibodies, precipitating inflammation by producing cytokines, activation T-cells by presentation of self-antigens, and regulating T-cells activity via co-stimulatory molecules. Although the clinical trials of RTX in SLE had controversial results, RTX seems to be a valuable option as an off-label drug for refractory patients.

A Case of Relapsing Polychondritis with Sequentially Bilateral Sudden Sensory Neural Hearing Loss

Relapsing polychondritis is a relatively rare systemic disease of unknown etiology. The disease is considered as an autoimmune disorder and characterized by episodic recurrent inflamma tion of cartilage and connective tissue, most often of the ears, nose, eyes, joints, respiratory tract, cardiovascular system and audiovestibular system. Treatment plans involve suppression of the immune system with corticosteroid. However, steroid therapy is associated with a number of adverse effects, and non-steroidal anti-inflammatory agents and immunosuppressive agents are helpful in treating the disease. Authors have recently experienced a case of relapsing polychondritis in a 24-year-old man who had both auricular chondritis and bilateral sudden hearing loss with vertigo. The patient showed a significant hearing improvement with the treatment using steroid and immunosuppressive agents. We report this case with a review of the literature.

Recurrent Posterior Scleritis—Report of a Case

Posterior scleritis is a serious ocular inflammatory and potentially blinding disorder. It is uncommon and often under-recognized due to its varied presentations, and general ophthalmologists are not familiar with it. Posterior scleritis may be idiopathic or associated with systemic diseases. Visual disturbances such as blurring or distortion are the commonest symptoms. There may be pain, tenderness, and deep-seated discomfort in and around the orbit. One study reported a 49% recurrence rate of posterior scleritis. Posterior scleritis responds well to systemic nonsteroidal anti-inflammatory agents, systemic steroids, and immunosuppressive agents. Recurrences are known to occur despite therapy. However, multiple recurrences in posterior scleritis are uncommon. We report a patient with posterior scleritis who had one episode in the right eye and four episodes in the left eye over a 35-month period.

Immunosuppressive Agents and Nonsteroidal Anti-inflammatory Drugs for Ocular Immune and Inflammatory Disorders

We now have at our disposal several nonsteroidal immunosuppressive and anti-inflammatory agents that may be used in addition to or instead of corticosteroids to treat ocular diseases. This article discusses some of the nonsteroidal immunosuppressive and anti-inflammatory agents available to the ophthalmologist.

Reasons why some children receiving tacrolimus therapy require steroids more than 5 years post liver transplantation

Tacrolimus is a potent immunosuppressive agent and has been used in liver transplantation (LTx) for nearly a decade. More than 70% of children can be maintained on tacrolimus monotherapy, without steroids, by the end of 1 yr post-Tx. This freedom from steroids does not appear to change significantly in subsequent years. The use of steroids has obvious metabolic and cosmetic disadvantages, besides affecting linear growth in children. The present study identifies why some children still require steroid therapy after successful LTx. One hundred and sixty-six consecutive pediatric patients who had undergone primary LTx between October 1989 and December 1992, were included in this study. Follow-up ranged from 6 to 9 yr (mean 7.5 +/- 0.8 yr). One hundred and forty-one children were alive in November 1998 and these patients constituted the study group. Their current rate of prednisone use, reason for prednisone use, and prednisone dose were examined retrospectively. Of the 141 patients, 139 (98.5%) had stopped taking steroids at some time-point after LTx. Thirteen patients (9%) were off immunosuppression altogether (group I), 97 were undergoing tacrolimus monotherapy (group II), and the remaining 31 were receiving therapy with steroids and tacrolimus (group III). The mean prednisone dose at the last follow-up was 6.5 +/- 4.9 mg/day (median 5.0 mg/day). In group III, two children were never weaned off steroids because of inadequate follow-up (both lived outside the country), and the remaining 29 children completely stopped steroid therapy at some time-point after LTx; however, prednisone was re-introduced for clinically suspected or biopsy-proven rejection in 24. Seven children in group III had completely stopped immunosuppressive therapy either as part of an immunosuppression reduction protocol (n = 3) or for suspected or proven post-transplant lymphoproliferative disorder (PTLD) (n = 4). In eleven of the 18 children in group III, requirement of steroid for rejection was thought to be related, in part, to non-compliance. In three children in group III, steroids were re-introduced for renal dysfunction, and two of these patients subsequently received a kidney Tx. In one child with cerebral ischemia, steroids were used to reduce brain edema, and another child had features of auto-immune hepatitis. Hence, almost all children can be weaned off steroids when tacrolimus is used as primary immunosuppression after primary LTx. However, approximately 22% of children may need re-institution of steroids because of late acute rejection or renal dysfunction. The concomitant use of other non-steroidal immunosuppressive agents with tacrolimus may further reduce the dose and rate of steroid use.

Fluocinolone acetonide sustained drug delivery device to treat severe uveitis

Purpose Uveitis is often a chronic disease requiring long-term medical therapy. In this report, we describe a pilot safety and efficacy trial of a novel sustained drug delivery system containing fluocinolone acetonide to treat patients with severe uveitis. Design Prospective, noncomparative, interventional case series Participants Patients with severe uveitis. Methods Sustained drug delivery devices designed to release fluocinolone acetonide for at least 2.5 years were implanted through the pars plana into the vitreous cavity of seven eyes of five patients. All patients had severe uveitis not well controlled with, or intolerant to, repeated periocular corticosteroid injections, systemic corticosteroids, nonsteroidal immunosuppressive agents, or a combination thereof at the time of device implantation. Before device implantation, patients underwent complete evaluation including history, ophthalmologic examination, fluorescein angiography, visual field testing, and electroretinography. After surgery, patients were reexamined at 1 week, 2 weeks, 4 weeks, and at 1- to 3-month intervals. Visual fields, electroretinograms, and fluorescein angiography were repeated at 3- to 6-month intervals. Main outcome measures Preoperative and postoperative visual acuity, ocular inflammation, anti-inflammatory medication use, and intraocular pressure. Results Patients had a diagnosis of Behçet’s syndrome (two eyes), or idiopathic panuveitis (five eyes, including two with necrotizing retinitis, two with progressive chorioretinitis, and one with iridocyclitis and intermediate uveitis). Patients were observed an average of 10 months (range, 5–19 months). All eyes had stabilized or improved visual acuity after device implantation, and four of seven eyes had an improvement of three lines or more. The mean initial visual acuity, measured by Snellen chart, was 20/207, and the mean final visual acuity was 20/57 ( P = 0.02). After surgery, at the final visit, no eye had clinically detectable inflammation, and all seven eyes had a marked reduction in systemic, topical, and periocular anti-inflammatory medication use. Four eyes had increased intraocular pressure 6 weeks to 6 months after device implantation. Intraocular pressure has been controlled on topical medications. No patient experienced intraoperative complications. Conclusions A fluocinolone acetonide sustained drug delivery device is a promising new therapy for the treatment of severe uveitis. Intraocular pressure must be carefully monitored long after device implantation. Based on these data, a randomized study of a larger group of patients is warranted.

Connective tissue diseases

Connective tissue diseases are a source of frustration for both patients and their families. Short-term treatment is aimed at the presenting syndrome, and a specific diagnosis is not needed. Long-term treatment attempts to provide an acceptable quality of life while avoiding complications and disability. Drug therapy includes nonsteroidal antiinflammatory drugs, antimalarial drugs, corticosteroids, and immunosuppressive agents. Joint-protection measures and physical therapy help prevent specific complications. Exacerbations of disease can be traced to several common aggravating factors. Because of the nature of connective tissue diseases, psychosocial problems among patients and their families are common. Physicians who anticipate these problems can help patients learn to cope with a chronic, painful condition.

Virus myocarditis

Concurrent viral infection and myocarditis presumably indicate viral myocarditis. The electrocardiographic and pathologic changes developing during acute infection may, however, result from changes not produced by the infection itself, eg, fever, tachycardia, ischemia, potassium depletion, vitamin deficiencies, drugs. This qualification should be remembered in the evaluation of all alleged virus myocarditis. Viral infection seems to prefer the very young. Its localization in the heart is favored by general or local hypoxia, perhaps thus explaining a predilection for the subendocardium. It may be influenced by the strain of the organism or by the hormonal or immunologic state of the host. Intrauterine infection of the fetus with rubella, mumps, and perhaps coxsackievirus can induce congenital cardiac defects. The role of virus infection in precipitating acute myocardial infarction deserves further study. The value of treatment, including steroids, nonsteroidal immunosuppressive agents, and "antiviral" agents is not yet established.

Treatment of Idiopathic Thrombocytopenic Purpura (ITP)

In summary, idiopathic thrombocytopenic purpura (as defined here) should be treated initially with glucocorticoids unless there is life-threatening hemorrhage (such as intracranial bleeding), in which case emergency splenectomy is indicated, since it generally gives the most prompt improvement in platelet count of all modes of the disease and to better define the cause of the thrombocytopenia. A complete, sustained remission following treatment with steroids may occasionally be obtained. In most cases the steroid response is transient, and splenectomy is the most definitive measure with respect to a lifelong cure. Complete clinical cure is obtained in 70-80% of instances following splenectomy, with a very low operative risk. The remainder either fail to respond or experience relapse. In this group of patients steroids should again be tried; if a good response is obtained, steroids should be given every second or third day to lessen long-term side effects. If these measures fail, the use of immunosuppressive agents is justified. Both vinca alkaloids and cyclophosphamide are especially useful. Vinca alkaloids act more promptly, but cyclophosphamide may have a more lasting effect. Azathioprine may also be used; however, it appears to yield a lower remission rate. Nonsteroidal immunosuppressive agents should not be used as the primary modality of therapy. And, due to their carcinogenic and teratogenic potential, they should be avoided, if possible, especially in children and in women during their childbearing years.