Systemic Immunosuppressive Medications Research Articles

Skin allograft and vascularized composite allograft: potential for long-term efficacy in the context of lymphatic modulation.

Tissue transplantation restores form and function in burn patients. The treatment of burn injuries is influenced by severity, location, and the percentage of total body surface area. There have been a number of different techniques developed to temporize and repair the destroyed tissue. However, in patients with large wound burden, sufficient donor site tissue may not be available for autograft harvesting. Such extensive burns necessitate other temporary and permanent options for wound coverage such as skin or vascularized composite allografts (VCA). Rejection of these tissues presents an ongoing problem which is currently managed using a host of systemic immunosuppressive medications. This article discusses the mechanism behind the innate and adaptive immune systems rejection of the allografts. By understanding these pathways, various techniques using immunomodulatory protocols have led to increased allograft survival. However, our primary interest lies in the initial recognition of the graft. We tailor this article to have a specific emphasis on lymphatic modulation as a potential adjunctive therapy. Reviews of the studies evaluating the effect of lymph node modulation on graft survival are described with future implications to allograft transplant research.

Current Perspectives on Ophthalmic Manifestations of Childhood Rheumatic Diseases

Inflammatory eye diseases are an important manifestation of many pediatric rheumatologic conditions. Early screening and diagnosis are imperative as these illnesses can not only result in significant visual morbidity but are also an indicator of systemic inflammation. Time to presentation of ocular inflammation varies significantly and can range from many years prior to the onset of systemic symptoms to well after the diagnosis of the rheumatologic disorder. Due to this variability in presentation, careful monitoring by an ophthalmologist is vital to preventing ocular complications and preserving vision. Both local and systemic immunosuppressive medications have been effective in the management of ocular disease. In this review, we will focus on the known ophthalmologic manifestations of common pediatric rheumatologic diseases and discuss recent advances in therapeutic considerations for these conditions.

Diagnosis and Treatment of Pediatric Psoriasis: Current and Future

Psoriasis is a common yet complex inflammatory dermatosis that may be seen in infants, children, and adolescents. The clinical presentation and course may be quite variable, and while patients with mild disease are often easily managed, those with recalcitrant or more severe disease often present a therapeutic dilemma given the number of therapies available and the relative lack of data on the efficacy and safety of use of these therapies in children. This review presents the reader with an overview of the current understanding of the pathophysiology, diagnosis, and treatment of pediatric psoriasis, with an emphasis on the available data in the literature that pertains to the use in children of currently available topical and systemic therapies, including topical corticosteroids, vitamin D analogs, phototherapy, systemic immunosuppressive medications, and biologic agents.

Visual Outcome, Treatment Results, and Prognostic Factors in Patients with Scleritis

To analyze the visual outcome, systemic associations, effectiveness of treatment, and predicting features of 104 scleritis patients. Retrospective case series. One hundred four patients treated for scleritis at the University Medical Centers of Groningen and Utrecht, The Netherlands. The clinical records of 104 patients diagnosed with scleritis between 1992 and 2011 at the University Medical Centers of Groningen (n = 64) and of Utrecht (n = 40) were analyzed retrospectively. Loss of visual acuity, ocular complications, related systemic disease, type of treatment, time to treatment success, and predictive features. Mean age ± standard deviation (SD) was 51.5 ± 13.6 years, and 63 (60.6 %) patients were female. Mean follow-up ± SD was 38.2 ± 33.8 months. A loss of more than 2 lines of Snellen acuity was observed in 23 patients, 3 of whom had a final visual acuity of no light perception. In general, patients with necrotizing scleritis (n = 15) had a poorer outcome. Ocular complications were observed in 88 (84.6%) patients. Underlying systemic disease was identified in 34 (32.7%) patients. Steroid-sparing immunosuppressive medication was used in 47 patients, 36 of whom were treated with methotrexate (MTX). This treatment was successful in 17 (47.2%) patients over the course of a mean ± SD of 103.7 ± 83.7 weeks. Mycophenolate mofetil was the treatment in 10 patients, and in 5 of these patients, treatment success was achieved in a mean ± SD of 65.3 ± 37.4 weeks. Treatment with tumor necrosis factor α (TNF-α) antagonists led to treatment success in a mean ± SD of 32.6 ± 21.8 weeks in 5 of the 11 treated patients. Patients with loss of visual acuity or those treated with steroid-sparing immunosuppressive drugs more often had an underlying associated disease, bilateral scleritis, and a longer duration of symptoms at presentation. Scleritis is a severe ocular inflammatory disease often associated with ocular complications. In this population, roughly half of the patients were treated with systemic immunosuppressive medication. Mycophenolate mofetil and TNF-α antagonists can be used in case of MTX failure. Tumor necrosis factor α antagonists seemed to be more effective than MTX. Within this group, an underlying associated disease, bilateral scleritis, and a longer duration of symptoms at presentation were predictive features for a more severe disease course.

The clinical course of juvenile idiopathic arthritis-associated uveitis in childhood and puberty

AimThe long-term course of juvenile idiopathic arthritis (JIA)-associated uveitis is not known yet. This study investigates the course and activity of JIA-associated uveitis in childhood and puberty.DesignRetrospective study of the...

Dexamethasone for ocular inflammation

Introduction: Corticosteroids, administered systemically and periocularly, have long been used to treat intermediate and posterior segment noninfectious uveitis. In addition to systemic immunosuppressive medications, these therapies are used to reduce inflammation, prevent structural complications and prevent long-term visual loss in patients with uveitis. While systemic immunosuppressive therapies carry their own set of side effects, treatment with local steroids is associated with the risk of development of cataract and glaucoma.Areas covered: Intravitreal delivery of fluocinolone acetonide via a sustained-release implant (Retisert) was approved by the FDA in 2005 for the treatment of noninfectious intermediate and posterior uveitis. Recently, the FDA also approved the biodegradable dexamethasone implant (Ozurdex) for the treatment of noninfectious uveitis involving the posterior segment.Expert opinion: The single injection, 26-week data indicate that the implant is well tolerated and produces meaningful improvements in intraocular inflammation and visual acuity that persist through 6 months. The available 6-month data also indicate that this implant confers much less of a risk of ocular hypertension than other forms of intraocular steroid therapy. However, future longer-term trials are needed to evaluate the efficacy and safety data in patients who receive multiple injections. The newly approved dexamethasone implant, Ozurdex, is a useful addition to our local armamentarium in the treatment of noninfectious intermediate and posterior uveitis given its efficacy, safety, and ease of use in the outpatient setting.

Pediatric SLE—towards a comprehensive management plan

Systemic lupus erythematosus (SLE) results from complex abnormalities of the innate and acquired immune systems. For reasons that are currently not well understood, the disease course and phenotype associated with SLE, although quite variable, are generally more severe when the diagnosis is made during childhood. Active disease, infections, lupus nephritis, and neuropsychiatric SLE manifestations are associated with higher morbidity and mortality. Unlike in adult-onset SLE, systemic glucocorticoid therapy and immunosuppressive medications are needed for the treatment of the majority of children and adolescents with SLE. The complex nature of childhood-onset SLE demands a comprehensive, multidisciplinary management approach that considers the patients' growth and development, their educational needs, and the unpredictable course of SLE and its complications.

Simultaneous Amniotic Membrane Patch in High-risk Keratoplasty

To analyze the short- and intermediate-term results of simultaneous transplantation of amniotic membrane with high-risk keratoplasty. Between January 2002 and February 2004, a simultaneous amniotic membrane patch was transplanted with penetrating keratoplasty in 16 eyes of 16 patients. In 13 eyes, a soft contact lens was applied afterward. Corneal perforation was present in 10 of 14 eyes with emergency keratoplasty. Five patients received systemic immunosuppressive medication for 4-6 months after penetrating keratoplasty. The amniotic membrane patch fell off after 8 ± 3 (range: 4-14) days without residual tissue except in 1 case. In 15 of 16 eyes, the epithelium was completely closed after 10 ± 8 (range: 4-30) days. In 3 eyes, recurrence of the epithelial defect occurred after 3-6 months. During a follow-up period of 18 ± 6 months, 13 of 16 corneal grafts were clear. Simultaneous amniotic membrane transplantation and penetrating keratoplasty may improve the prognosis of corneal graft in eyes with risk of epithelial healing problems.

The management of mucous membrane pemphigoid and pemphigus

Mucous membrane pemphigoid and pemphigus vulgaris are autoimmune blistering disorders in which many similar drugs and therapeutic strategies are utilized. In general, localized disease can be treated with topical agents. In contrast, patients with more severe and progressive disease usually require a combination of systemic corticosteroids and immunosuppressive medications. Oral corticosteroids, adjuvant immunosuppressive agents, antibiotics such as dapsone and immunomodulatory procedures like intravenous immunoglobulin are the main therapeutic agents used in treating these two disorders. Much of the morbidity and mortality associated with these disorders are related to the sites involved and to the drugs used for therapy. Treatment should be individualized based on severity, extent, and rate of progression of disease, comorbidities, and age of the patient. Serum levels of specific autoantibodies and indirect immunofluorescence titers, in certain cases, can be used to monitor response to therapy.

Perifosine-Related Rapidly Progressive Corneal Ring Infiltrate

To report a case of unilateral rapidly progressing corneal ring infiltration in a patient being treated with the investigational drug perifosine for Waldenström's macroglobulinemia. Interventional case report. A 55-year-old woman who was receiving treatment with perifosine for Waldenström's macroglobulinemia developed a corneal ring infiltrate in her left eye. She was treated with topical antibiotics and systemic antiviral medication, but the ring infiltrate continued to expand, resulting in complete stromal opacification and a total epithelial defect. Repeated microbiologic tests, including corneal biopsy, failed to identify an infectious agent. Weeks after instituting systemic immunosuppressive medications, including corticosteroids and cyclophosphamide, the ocular inflammation gradually resolved with corneal re-epithelialization and severe stromal neovascularization. Patients treated with perifosine should be monitored for ocular adverse events. Perifosine-related corneal infiltration may progress rapidly and, after appropriate microbiologic examination, aggressive anti-inflammatory therapy should be considered.

Surgical interventions and local therapy for Wegener's granulomatosis

This review discusses the use of interventional procedures to treat manifestations of Wegener's granulomatosis caused by tissue damage and scarring. These manifestations include nasal and paranasal sinus disease, middle ear inflammation, nasolacrimal duct obstruction, orbital inflammatory masses, subglottic stenosis, tracheobronchial disease, and end-stage renal disease. Tissue damage caused by inflammation or a cicatricial process represents one of the major sources of morbidity for patients with Wegener's granulomatosis. Some of these manifestations require special interventions used alone or in combination with conventional medical treatment. These interventional procedures may include surgical or endoscopic repair of altered tissue, replacement of damaged organs, or the delivery of topical or injectable medications directly to the site of disease. Distinguishing symptoms caused by active disease from symptoms caused by tissue scarring is challenging and may play a critical role regarding the use of systemic immunosuppressive medications in combination with interventional therapy. Interventional procedures are indicated in certain manifestations of Wegener's granulomatosis. Distinguishing active Wegener's granulomatosis from inactive Wegener's granulomatosis and recognizing disease manifestations that may be amenable to local interventions can greatly improve the quality of life of patients. However, the evidence supporting the use of many of these interventions is based on small case series or individual reports.

Fact or Fiction: Does the Non-HIV/AIDS: Immunosuppressed Patient Need Pneumocystis Jiroveci Pneumonia Prophylaxis? An Updated Literature Review

Pneumocystis jiroveci pneumonia (PJP) is a potentially fatal fungal infection occurring in immunocompromised patients. To determine whether PJP prophylaxis is required in the non-human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) immunocompromised patient and, if so, the optimal prophylactic therapy. A thorough literature review, with the appropriate MeSH terms, was conducted using PubMed, Medline, and The Cochrane Database. A number of cases describing PJP in patients with various systemic diseases and immunosuppressive medications, along with a Cochrane review, were highlighted. Although there are a number of case reports in the literature, the only collagen vascular disease with an increased incidence of PJP is Wegener granulomatosis. Oral trimethoprim-sulfamethoxazole continues to be the prophylaxis of choice for PJP. There is currently no evidence to recommend PJP prophylaxis in the non-HIV/AIDS immunocompromised population. If physicians do decide to use prophylaxis, they should always weigh the benefits with the potential risks. Further studies are needed to better quantify the risks of PJP with immunosuppressive medications.

Intraocular Methotrexate in the Treatment of Uveitis and Uveitic Cystoid Macular Edema

A pilot study to evaluate the use of intravitreal methotrexate (MTX) for the treatment of uveitis and uveitic cystoid macular edema (CME). Prospective, consecutive, interventional case series. Fifteen eyes of 15 patients with a unilateral exacerbation of noninfectious intermediate, posterior uveitis, or panuveitis and/or CME such that visual acuity (VA) was 20/40 or worse, together with a history of increased intraocular pressure (IOP) in response to corticosteroid administration. Intravitreal injection of 400 microg in 0.1 ml MTX. The primary outcome measure was VA (using the Early Treatment Diabetic Retinopathy Study chart). Other outcome measures included ocular inflammation scores, time to relapse, levels of systemic corticosteroid and immunosuppressive therapy, and ocular coherence tomography. Potential complications of intravitreal MTX injection, including cataract progression, vitreous hemorrhage, retinal detachment, and corneal epitheliopathy, were assessed. VA improved at all time points and was statistically significant at the 3- and 6-month follow-up examinations. The mean visual improvement was 4 lines at 3 months and 4.5 lines at 6 months, with no statistical difference between the best VA obtained after MTX injection and after previous corticosteroid treatment, including intravitreal triamcinolone acetate injection. Five patients relapsed after a median of 4 months; a similar improvement was seen after re-injection. Ocular inflammation scores improved at all time points, and systemic immunosuppressive medication was reduced in 3 of 7 patients taking this at the start of the trial. In patients with uveitis and uveitic CME, intravitreal MTX can improve VA and reduce CME and, in some patients, allows the reduction of immunosuppressive therapy. Relapse occurs at a median of 4 months in some patients, but reinjection has similar efficacy.

Ocular manifestations of systemic lupus erythematosus

To describe the ophthalmic manifestations of systemic lupus erythematosus and to review recent advances in our understanding of the pathogenesis and treatment of this condition. Significant vision loss and associated ocular morbidity are possible in systemic lupus erythematosus, particularly in cases of retinal or central nervous system involvement. Considerable progress has been made in our understanding of the immunologic mechanisms of disease. Approaches to treatment include the use of systemic immunosuppressive medications. Biologic agents are being developed to target specific aspects of the immune response. Ocular involvement is not uncommon in systemic lupus erythematosus. Aggressive systemic therapy is often needed to control the disease. Several new immunomodulatory treatment strategies are being developed which may show great promise in the future.

Adenovirus‐mediated interleukin‐13 gene therapy attenuates acute kidney allograft injury

Kidney transplantation is possible by virtue of systemic immunosuppression, which is in turn accompanied by serious side effects. The search for novel therapeutic agents and strategies is ongoing. Here we investigate the effects of adenovirus-mediated gene therapy with interleukin (IL)-13, which is a cytokine with strong immunomodulatory properties, on acute renal allograft injury. In addition, we compare the effects of local (intrarenal) and systemic (intramuscular) IL-13 gene therapy in kidney transplantation. The experiments were performed in a rat Fisher to Lewis acute rejection model of kidney transplantation. An adenovirus-IL-13 or adenovirus-luciferase was injected either into the donor kidney before transplantation (local treatment) or into the hind leg muscle of recipient rats (systemic treatment). A group with no treatment served as control. No additional immunosuppressive therapy was applied. The rats were sacrificed after 8 days and inflammatory markers and renal pre-fibrosis were assessed. Efficient gene transfer was confirmed by ELISA, immunohistochemistry and real-time PCR. IL-13 gene therapy diminished graft infiltration with macrophages and cytotoxic T cells and limited up-regulation of mRNA levels of the adhesion molecule E-selectin and pro-inflammatory cytokines TNF-alpha and IFN-gamma. Moreover, reduced renal interstitial pre-fibrosis was found in the rats receiving IL-13 gene therapy. The effects of local and systemic therapy were similar. This study demonstrates that IL-13 gene therapy in the graft significantly attenuates acute renal allograft damage, suggesting local therapy with IL-13 as a strategy to reduce the need for systemic immunosuppressive medication and thereby its side effects.

Intravenous Immunoglobulin: Properties, Mode of Action and Practical Use in Dermatology

Since they were first administered to patients with antibody deficiency disorders over 50 years ago, human intravenous immunoglobulin preparations have been used successfully to treat a rapidly increasing number of autoimmune and inflammatory disorders, among which are a series of cutaneous autoimmune and inflammatory diseases. These include dermatomyositis, Kawasaki's disease, a number of autoimmune bullous diseases, severe adverse drug reactions, and other autoimmune and/or allergic conditions, such as atopic dermatitis. Although only a minority of these indications (dermatomyositis, Kawasaki's disease) are officially registered or based on double-blind, placebo-controlled clinical studies, the observed efficacy and safety profile of currently available intravenous immunoglobulin sometimes makes this a treatment of choice for initiation of therapy or for replacement of more toxic alternatives, such as systemic immunosuppressive medications. The increasing use of intravenous immunoglobulin has been associated with further understanding of its mechanism(s) of action, clinical manipulation and associated side-effects, as well as the introduction of improved or new types of intravenous immunoglobulin. This paper reviews the current knowledge of the mode of action of intravenous immunoglobulin, its reported therapeutic effects in cutaneous disease, its mode of administration and safety profile, and compares the currently available intravenous immunoglobulin preparations.

A Double-masked, Randomized Study to Investigate the Safety and Efficacy of Daclizumab to Treat the Ocular Complications Related to Behçet's Disease

Purpose: To investigate the safety and efficacy of daclizumab (Zenapax, humanized anti-Tac, HAT) in controlling the ocular manifestations of Behçet's disease. Design: Randomized, placebo-controlled, double-masked clinical trial. Participants: Seventeen participants with Behçet's disease experiencing at least two prior ocular attacks and requiring treatment with immunosuppressive agents for the ocular complications of Behçet's disease. Methods: Participants received either intravenous placebo or daclizumab (1 mg/kg) infusions every two weeks for six weeks, then every four weeks while continuing their standard immunosuppressive regimens. If clinically indicated, tapering of the standard immunosuppressive medications was allowed after six months of study enrollment. Complete ocular and physical examinations and an adverse event assessment were performed at baseline and prior to each study infusion. Main Outcome Measures: Primary safety endpoints were the development of a life-threatening complication or a severe opportunistic infection. Primary efficacy outcomes were the number of ocular attacks and an assessment of systemic immunosuppressive medications required during the study, including the ability to taper concomitant immunosuppressive therapy. Results: Nine participants randomized to daclizumab and eight to placebo were followed monthly. Follow-up ranged from one to 34 months, with a median follow-up of 15 months. Two participants randomized to daclizumab discontinued study therapy prior to the end of the study for personal reasons. No participant experienced a safety endpoint, and visual acuity remained stable in all participants during the course of the study. Ten participants (six daclizumab, four placebo) experienced ocular attacks requiring therapy. The median ocular attack rate during the study was greater in the daclizumab arm than the placebo arm (median 1.27 vs. 0.17 attacks/year, respectively). Participants in the placebo arm also experienced a greater reduction in the immunosuppressive medication score compared to participants receiving daclizumab (median –4.0 vs. –1.0, respectively). Conclusions: The observed results in the placebo group demonstrate that careful follow-up and treatment with standard combination immunosuppressive therapy can be effective for the management of the ocular complications of Behçet's disease. In our small study, there was no suggestion that daclizumab was beneficial in comparison with placebo. However, the low observed attack rate limited our ability to make a definitive treatment group comparison.

Differential Effectiveness of Etanercept and Infliximab in the Treatment of Ocular Inflammation

Anti-tumor necrosis factor alpha (anti-TNF-alpha) agents are being used increasingly in refractory inflammatory eye diseases. We reviewed our patients on etanercept and infliximab to determine whether these medications are equally efficacious in controlling ocular inflammation. Exploratory retrospective analysis. Patients with ocular inflammatory disease on an anti-TNF-alpha agent (etanercept, infliximab). Case records of 22 patients treated with anti-TNF-alpha therapy were reviewed for demographic information, ocular and systemic diagnosis, duration and dose of anti-TNF-alpha treatment, concomitant ocular and systemic immunosuppressive medications, and treatment response. Uveitis recurrence rate, initial treatment response, treatment response, and medication use at 6 months, 1 year, and last visit. Patients treated with infliximab had a significant decrease in uveitis recurrences after starting therapy compared with those treated with etanercept (59% vs. 0%, P = 0.004). One year after treatment initiation and at final visit, more infliximab-treated patients had an improvement in their ocular inflammation (100% vs. 33%, P = 0.002, and 94% vs. 0%, P<0.001, respectively) and a decreased requirement for topical prednisolone acetate 1% (94% vs. 33%, P = 0.009, and 89% vs. 29%, P = 0.007, respectively) compared with those treated with etanercept. No significant differences in the use of oral corticosteroids and immunosuppressive agents were noted between the 2 groups at 6 months, 1 year, and final visit. Infliximab was more effective than etanercept in the treatment of recalcitrant uveitis and decreased the use of topical steroids.

Immunoadsorption in pemphigus

The principle of extracorporal immunoadsorption (IA) is based on affinity adsorption of pathogenic (auto-)antibodies and circulating immune complexes (CIC) which reversibly bind to an immobilized ligand of the adsorber. In pemphigus, a blistering autoimmune disease affecting skin and mucous membranes, autoantibodies, mainly of the IgG subclass are directed against desmosomal adhesion molecules and other non-desmosomal antigens on the surface of epidermal keratinocytes, such as acetylcholine receptors. The pathogenicity of these autoantibodies has been shown in various in vitro and in vivo systems. Recently, IA was applied in severe pemphigus demonstrating that a rapid and dramatic decline in desmoglein (Dsg)-reactive autoantibodies is accompanied by clinical remission of mucocutaneous blisters and erosions. As an adjuvant treatment, IA was combined with systemic immunosuppressive medication and current protocols initially apply treatment cycles of 3–4 IAs on consecutive days followed by immunoapheresis once a week or repeating the initial cycle in 4 week intervals depending on the disease activity. IA in pemphigus is generally safe and well tolerated.

Immunosuppression with Cyclosporine A and Mycophenolate Mofetil After Penetrating High-Risk Keratoplasty: A Retrospective Study

Graft-prognosis after penetrating high-risk keratoplasty has improved considerably with the use of systemic immunosuppressive medications. In this retrospective investigation we analyzed the long-term results of 417 high-risk keratoplasties with systemic immunosuppression (cyclosporine A [CsA] or mycophenolate mofetil [MMF]). A total of 417 high-risk keratoplasties with postoperative systemic immunosuppression were evaluated retrospectively: CsA has been given in 252 keratoplasties since 1987, aiming at blood trough levels of 120 to 150 ng/mL. Systemic MMF at a daily dose of 2 x 1 g was administered in 149 surgical procedures. After 16 high-risk keratoplasties, combined systemic immunosuppression with CsA and MMF was administered. Systemic immunosuppression was scheduled for 6 to 12 months. All patients received fluocortolone 1 mg/kg body weight per day, tapered over 3 weeks, and topical prednisolone acetate 1%, tapered over 5 months. Rejection-free graft survival after 1 year was 75% in the CsA group and 89% in the MMF group; 60% of the grafts in the CsA group and 72% of the grafts in the MMF group were rejection-free 3 years postoperatively (Kaplan-Meier log-rank test P=0.03). Clear graft survival after 1 and 3 years was 92% and 77% (CsA) and 96% and 87% (MMF), respectively. The MMF-treated patients showed fewer side effects than the CsA-treated patients. The side effects attributable to both drugs were reversible. We found a statistically significant, stronger effect of MMF compared with CsA in preventing immune reactions after high-risk keratoplasty, despite a shorter MMF administration compared with CsA. Both systemic immunosuppressants were shown to have comparable potency regarding clear graft survival and were well tolerated.