Standard Immunosuppressive Agents Research Articles

Rituximab induced remission in systemic lupus erythematosus with lupus nephritis along with nail fold capillaroscopy and trichoscopic findings: a case report

Lupus nephritis is a major cause of mortality and morbidity in patients with systemic lupus erythematosus (SLE). Early diagnosis and treatment are important, as early response to therapy is correlated with better prognosis and quality of life. Here, we report a case of 24-year-old male with SLE along with lupus nephritis. The patient was given 3 cycles of rituximab 1 gm 6 months apart following which the patient went into remission. Thus, Rituximab has been found to be an effective therapeutic modality to induce remission in SLE with Lupus Nephritis and also avoids the potential toxicity associated with standard immunosuppressive agents. Nail fold capillaroscopy (NFC) and trichoscopy were done which helped in the diagnosis of the disease.

Evaluation of the Efficacy and Safety during Treatment with TPO-Ras in 40 SLE-ITP and APS-ITP Patients

Objectives: Thrombopoietin receptor agonists (TPO-RAs) have emerged over the last decade as a therapeutic option in primary immune thrombocytopenia (ITP). TPO-RAs have demonstrated their efficacy in more than 70% of cases and are taking an increasingly important place in second line therapy. However, to date, no prospective cohort has been able to question the efficacy and safety of TPO-RAs in systemic lupus erythematosus (SLE-ITP) and antiphospholipid syndrome (APS-ITP) patients, particularly regarding venous and arterial thrombosis risks in this population. Methods: This multicenter retrospective cohort study was conducted from 2012 to 2023 in seven hospitals belonging to the French national network for adult ITP. We assessed the efficacy and the tolerance of TPO-RAs on a large retrospective cohort with a long follow-up of patients with ITP associated with 1) SLE or 2) primary or secondary APS or 3) with antinuclear antibodies (ANA) and anti-dsDNA or anti-Sm antibodies or 4) with ANA and at least one antiphospholipid antibody (APA) without thrombotic events (TEs). We studied the efficacy according the international criteria of response (Rodeghiero et al, Blood 2009) and the incidence of TEs, the risk factors for the occurrence of thrombosis, the management of TPO-RAs and their combination with antiplatelet agents or anticoagulants. Results: We included 40 ITP patients treated with TPO-RAs; 28 SLE-ITP, four APS-ITP, four with both SLE and APS, and four with significant ANA and APA positivity without definite SLE or APS. Five patients were triple positive for APA. The median duration of follow up was 46 months (1-132). The overall response rate was 84.2% for patients treated with romiplostim and 71% for those treated with eltrombopag after failure of standard treatments such as corticosteroids, intravenous immunoglobulins, rituximab and immunosuppressive agents. Eight TEs occurred in seven (17.5%) patients at a median of 119 days (IQR=171.5) after eltrombopag (n=4) or romiplostim (n=4) initiation with a median exposure duration of 37 days (13-119) for romiplostim and 255 days (30-807) for eltrombopag. Two venous TEs were observed including one cerebral vein thrombosis and one pulmonary embolism. We observed six arterial thrombotic events, such as myocardial infarctions and ischemic strokes including one fatal catastrophic APS. Four of these patients had a history of APS, and most had thrombotic risk factors and positive APA. TPO-RAs were continued after TEs in two patients for a total duration of 20 and 53 months in association with an antiplatelet agent for one patient and a combination of an antiplatelet agent and an anticoagulant for the second one without a new TE thereafter. TPO-RAs were transiently stopped and then reintroduced due to ITP flare in two patients. A new episode of myocardial infarction occurred in one of them despite association with antiplatelet agents requiring TPO-RAs definitive arrest. Conclusion: We confirmed the effectiveness of TPO-RAs in over 70% of SLE-ITP and APS-ITP patients who failed to respond to corticosteroids, intravenous immunoglobulins, rituximab and/or standard immunosuppressive agents. Nevertheless, these findings highlight the need to carefully consider the potential benefits and thrombotic risks before initiating TPO-RAs, especially in elderly patients with thrombotic risk factors and positive APA or a confirmed APS. Further studies are needed to evaluate more precisely the TEs risk factors of these agents in this specific population, in order to better select SLE and APS-ITP patients who could benefit from them.

P157 Potential benefit of intravenous immunoglobulin in connective tissue disease associated interstitial lung diseases

Abstract Background/Aims Intravenous immunoglobulin (IVIg) confers significant benefit in range of connective tissue diseases (CTD) including inflammatory myopathy (IM) of which interstitial lung diseases (ILD) are a major complication. This study aimed to assess the efficacy of IVIg on pulmonary involvement in refractory active CTD including systemic sclerosis (SSc). Methods All patients with CTD-ILD confirmed on HRCT either with IM or SSc overlap myositis who did not achieve satisfactory clinical response to standard immunosuppressive agents and subsequently received regular IVIg infusions for IM were retrospectively identified. Serial lung function tests and immunosuppressive treatment regimen 9-12 months prior and 9-12 months after repeat courses of IVIg were recorded. Progressive ILD was considered when, despite immunosuppressive treatment, a relative FVC decline≥10% and/or relative DLco decline ≥15% were identified during the 9-12 months preceding IVIg treatment. The significance of median DLco and FVC percentage relative change to IVIg treatment was assessed by Wilcoxon signed-rank test. Results 22 patients (mean age 50.5±13.1 years old) with IM-ILD treated with IVIg were identified. ILD occurred in association with IM in 10 patients, overlap SSc myositis in another 11 patients, while one had mixed connective tissue disease with myositis. Lung function results were available for 19/22 (86%). Eight patients (42.1%) were found to have progressive ILD(four with IM and four with overlap SSc-myositis). The median change in FVC% predicted and DLco% predicted in the 9-12 months before and after IVIg treatment is presented in Table 1. There was a significant difference in the DLco% predicted rate of relative change before and after IVIg treatment (p = 0.035) for the overall cohort. However, no differences in lung function were observed in the rate of relative change between patients with IM and patients with SSc myositis overlap. Significant improvement in DLco% predicted values was identified in the subgroup analysis of patients with progressive ILD(p = 0.012). P157 Table 1:The median change in FVC and DLco% predicted values prior and after the IVIg treatmentPatients with myositis related ILD9-12 months before IVIg treatment (relative change)9-12 months after IVIg treatment (relative change)p-valueAll (n = 19)FVC % predicted-3.8 (-54.4 - 14.6)2.1 (-33 - 33.7)0.145DLco % predicted-9.2 (-60.7 - 9.2)-2.3 (-26 - 41.9)0.035PM/DM (n = 10)FVC % predicted-1.8 (-20.2 - 14.6)0.8 (-33 - 30.9)0.401DLco % predicted-9.6 (-60.7 - 9.2)-2.4 (-26 - 41.9)0.093SSc-PM/DM overlap (n = 11)FVC % predicted-6 (-54.4 - 10.6)3.4 (-19.9 - 33.7)0.139DLco % predicted-10.8 (-47.1 - 2.5)4.2 (-22.7 - 16.8)0.173Progressive ILD (n = 8)FVC % predicted-14.5 (-54.4 - 14.6)5.7 (-11.9 - 33.7)0.123DLco % predicted-25.3 (-60.6 - -14.1)12 (-2.3 - 41.9)0.012 Conclusion IVIg may be an effective rescue therapy in the prevention of further lung function decline in refractory myositis and SSc overlap in particular in subgroups with progressive ILD. Future studies to determine its role in CTD-ILD are warranted. Disclosure V. Kouranos: None. L.V. Host: None. C. Campochiaro: None. A. Wells: None. C.P. Denton: None. V.H. Ong: None. E. Renzoni: None.

Lupus Low Disease Activity State and Reduced Direct Health Care Costs in Patients With Systemic Lupus Erythematosus.

Treat-to-target end points for systemic lupus erythematosus (SLE) have been assessed for their impact on damage accrual and flare, but whether they have an impact on the high health care utilization and costs in SLE has not been studied. The purpose of this study was to examine our hypothesis that the recently described lupus low disease activity state (LLDAS) would be associated with reduced health care cost. Data from a single tertiary hospital longitudinal SLE cohort were assessed. Baseline demographics, disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K], physician global assessment [PhGA], and flare index), and medication use were evaluated, and direct health care utilization and cost data were obtained from hospital information systems. LLDAS was defined as previously published: briefly, SLEDAI-2K ≤4 with no new activity, PhGA ≤1, prednisolone ≤7.5 mg/day, and optimal standard immunosuppressive agents. Analysis was performed using multivariable linear regression. Two hundred SLE patients, contributing 357.8 person-years of observation, were included. A history of lupus nephritis was present in 42% of patients, and damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index >0) was present at study commencement in 57.3% of patients. The mean ± SD annual direct medical cost per patient was US$7,413 ± 13,133/year. In multivariable analysis, increased cost was associated with the presence of baseline organ damage (41.7% increase; P = 0.009) and corticosteroid use (>7.5-15 mg/day: 55.7% increase; P = 0.02; and >15 mg/day: 202% increase; P < 0.001). In contrast, spending ≥50% of the observation period in LLDAS was associated with a 25.9% reduction in annual direct medical cost (P = 0.04). Greater time spent in LLDAS was associated with significantly reduced direct hospital health care costs among patients with SLE.

Neuromyelitis optica spectrum disorders: Emerging therapies

AbstractNeuromyelitis optica or neuromyelitis optica spectrum disorders (NMOSD) are autoimmune diseases associated with a disease‐specific autoantibody directed against the water channel protein aquaporin‐4. While almost all patients with NMOSD show a relapsing‐remitting course, just 2% of patients present with a progressive course, suggesting that preventing acute attacks can lead to stable remission and avoid progression of the condition. Standard immunotherapy, immunosuppressive agents, and corticosteroids can prevent acute attacks and maintain remission in the majority of patients with NMOSD. However, there is a strong need for alternative options for patients who are refractory to standard treatments. Emerging therapies targeting specific molecules related to the pathogenicity of NMOSD are currently being developed. In addition to standard intravenous high‐dose corticosteroid and plasma exchange/plasmapheresis, therapies targeted at inhibiting granulocytes, complement, and vascular endothelial growth factor are anticipated for acute attacks. With regard to preventive treatment of NMOSD, randomized clinical trials using monoclonal immunoglobulin G antibody targeting CD19 and CD20 on B cells, interleukin‐6, and complement protein C5 are underway. There are many preclinical therapeutic agents that target aquaporin‐4 and the pathogenic anti‐aquaporin‐4 antibody itself: complement inhibitor and T helper 17 cells based on the specific NMOSD pathology. The future goal of immunotherapies for NMOSD would be to select suitable therapies for the patient's pathological condition among off‐target and molecular‐target agents.

C75 Fatty Acid Synthesis (FAS) Inhibitor Has Potent Immunosuppressive Activity

Fatty acid synthesis (FAS) or oxidation (FAO) are important regulatory pathways in immune response. In fact, FAS plays a pivotal role in antigen presentation and T cells activation and FAO leads to fatty acid degradation which has been previously shown to regulate hematopoietic stem cell maintenance. Here we hypothesized that FAS can be a new target to suppress T cell alloimmune responses in solid organ or stem cell transplantations. Therefore, we tested if the FAS inhibitor C75 could suppress T cell alloreactivity without impairing normal hematopoiesis.The immuno-suppressive (IS) effect of moderate FAS inhibition was demonstrated in mixed leukocyte cultures (MLC) where C75 at 10 mkg/ml significantly reduced T cell proliferation and prevented the expansion of CD3+CD25+ and CD3+CD69+ T cells. In T cells stimulated by alloantigen, C75 also induced the downregulation of NF-kB gene expression and the upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) gene involved in ubiquitination and degradation of NF-kB protein.When compared to other standard IS agents, such as anti-thymocyte globulin (ATG), Cyclosporine A, Rapamycin or inhibitor of FAO Etomoxir, C75 showed similar anti-T cell activity.The same dose of C75 (10 mkg/ml) did not cause apoptotic death of human CD34+ cells in vitro, nor affected CD34+ cell clonogenicity in vitro. In fact, C75 increased the number of BFU-E and CFU-GM colonies (P < 0.05). We observed that the expression of de novo DNA methyltrasferases DNMT3A and DNMT3B, which are important regulators of stem cell renewal, was strongly reduced in CD34+ cells co-cultured for 3 days with allogeneic T cells. On the contrary, in the presence of C75 the expression of DNMT3A and DNMT3B was not different from baseline control. To test the in-vivo effect of C75 we utilized a xenograft model of stem cell rejection where 2 x 105 human CD34+ cells and HLA incompatible T lymphocytes were injected in immunodeficient nonobese diabetic/ltsz-scid/scid - IL2 receptor gamma chain knockout (NSG) mice at 1:1 ratio. Four weeks after transplantation, control NSG mice showed complete rejection of huCD45+CD34+ cells and the expansion of T cells in the marrow and spleen. NSG mice treated with intra-peritoneum injections of C75 every 3 days for 2 weeks, instead, showed 10-15% human CD45+ myeloid cells in the marrow and spleen at week 4 after transplant, suggesting at least a partial effect on preventing rejection of incompatible stem cells.We showed here that moderate FAS inhibition may represent a novel immunosuppressive strategy and our findings will prompt preclinical investigations exploiting the effect of FAS inhibitors alone or in combination with standard IS agents in models of allogeneic transplantation or bone marrow failure. DisclosuresNo relevant conflicts of interest to declare.

CCL8 and the Immune Control of Cytomegalovirus in Organ Transplant Recipients

Monitoring of cytomegalovirus cell-mediated immunity is a promising tool for the refinement of preventative and therapeutic strategies posttransplantation. Typically, the interferon-γ response to T cell stimulation is measured. We evaluated a broad range of cytokine and chemokines to better characterize the ex vivo host-response to CMV peptide stimulation. In a cohort of CMV viremic organ transplant recipients, chemokine expression-specifically CCL8 (AUC 0.849 95% CI 0.721-0.978; p = 0.003) and CXCL10 (AUC 0.841, 95% CI 0.707-0.974; p = 0.004)-was associated with control of viral replication. In a second cohort of transplant recipients at high-risk for CMV, the presence of a polymorphism in the CCL8 promoter conferred an increased risk of viral replication after discontinuation of antiviral prophylaxis (logrank hazard ratio 3.6; 95% CI 2.077-51.88). Using cell-sorting experiments, we determined that the primary cell type producing CCL8 in response to CMV peptide stimulation was the monocyte fraction. Finally, in vitro experiments using standard immunosuppressive agents demonstrated a dose-dependent reduction in CCL8 production. Chemokines appear to be important elements of the cell-mediated response to CMV infection posttransplant, as here suggested for CCL8, and translation of this knowledge may allow for the tailoring and improvement of preventative strategies.

ADALIMUMAB IN TREATMENT OF SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS

A history case of systemic juvenile idiopathic arthritis with early onset and severe clinical case, resistant to treatment with standard immunosuppressive agents is represented in the article. This case demonstrates high clinical efficacy of adalimumab in a patient with severe course of systemic juvenile idiopathic arthritis, prolonged remission of extra-articular involvement and persistent polyarthritis. By the 4 th week of the treatment inflammatory changes in the joints had arrested, range of motions had widened, laboratory markers of activity had normalized and non-active stage of the disease had been established. The duration of the remission of articular syndrome was 2 years, no relapses were observed during the follow-up period.

Adalimumab for the treatment of Behcet's disease: experience in 19 patients

To describe the experience of two tertiary Spanish centres (Hospital Clínico San Cecilio, Granada and Hospital Clínic, Barcelona) with the use of adalimumab for the treatment of severe clinical manifestations in patients with Behçet's disease (BD) in whom immunosuppressive therapy had failed. Retrospective chart review from patients with BD treated with adalimumab in two specialized Spanish centres (Hospital Clínico San Cecilio, Granada and Hospital Clínic, Barcelona). From November 2006 to February 2011, 19 patients with BD were treated with adalimumab. The reason to initiate adalimumab was refractory disease in 17 (89.5%) patients and adverse events to CSA and infliximab in two (10.5%) patients, respectively. The main clinical manifestations leading to adalimumab administration were panuveitis in eight patients, severe bipolar aphthosis in eight, retinal vasculitis in three and severe folliculitis in three. Overall, adalimumab achieved clinical improvement in 17 of the 19 patients. Of note, ocular manifestations (panuveitis and retinal vasculitis) responded rapidly in all cases. In addition to clinical improvement, treatment with adalimumab was associated with reduction in the number and dose of standard immunosuppressive agents. Of interest, seven patients had received TNF-α inhibitors before adalimumab, five infliximab and the remaining two etanercept. Adalimumab was withdrawn in only one patient due to severe infusional reaction in the form of urticaria and angioedema. Adalimumab is a valid option for patients with BD and recalcitrant non-controlling manifestations with good safety profile.

Post-Transplantation Lymphoproliferative Disorders (PTLD) Management in Solid Organ Transplantation (SOT) Recipients

Abstract 4941 Introduction:PTLD are lymphoid proliferations that develop as a consequence of immunosuppression in 1% of SOT recipients. The majority of PTLD are associated with Epstein-Barr virus (EBV) infection, as therapeutic immunosuppression causes decreased T-cell surveillance, increasing the proliferative potential of EBV in latently infected B-cells. PTLD may manifest as early lesions including polyclonal plasmacytic hyperplasia and infectious mononucleosis-like PTLD as well as monoclonal polymorphic PTLD. Patients who develop polymorphic PTLD, universally associated with EBV and occurring early after transplant, usually have good prognosis and respond well to reduction of immunosuppression and antiviral therapy. Monomorphic PTLD is indistinguishable from a subset of B-cell and much less frequently T-cell lymphomas that occur in immunocompetent individuals. Monomorphic PTLD in SOT patients frequently involve extranodal sites as well as the allograft and causes significant morbidity and mortality in this group of patients. There is no universally accepted treatment strategy for monomorphic PTLD as randomized trials are lacking with most of the data coming from prospective and retrospective cohort trials evaluating heterogeneous populations of patients. Standard therapy consists of a stepwise treatment approach, aimed at partially restoring cellular immunity by reduction of immunosuppression (RI) sometimes in combination with or followed by rituximab. If there is no response chemotherapy is initiated. However, this strategy is vague as there are no clear rules for how much and for how long immunosuppression is reduced and may be associated with both graft loss and disease progression. We believe that aggressive monomorphic PTLD patients can be successfully treated by employing aggressive chemo-immunotherapy and withdrawal of standard immunosuppressive agents. We prefer to use “dose dense” administration schedule to 1) provide intensive therapy and 2) provide strong enough immunosuppression to prevent rejection. This retrospective study was designed to assess the outcome of such a strategy in monomorphic PTLD patients treated at the Yale Cancer Center (YCC) over a 15 year period. Patients and Methods:We identified patients with the PTLD after SOT by searching Yale Tumor Registry. Patients were eligible for selection if they were diagnosed with PTLD after SOT between January 1st of 1995 and December 31st of 2009 provided they were 18 years of age or older at the time of diagnosis (diagnosis criteria). We planned to analyze the outcomes among patients treated with combined approach (treatment criteria). Sixteen patients met inclusion criteria. Results:Out of 16 identified patients 11 received kidney, 1 kidney and pancreas, 3 heart and 1 liver transplants. Thirteen patients (81%) were diagnosed with diffuse large B cell lymphoma (DLBCL), 3 with Burkitt or Burkitt-like lymphoma (19%). All patients were treated with a combined approach with most of the patients (n=11, 69%) receiving CHOP-R every 2 weeks (“dose dense”). 10 out of the 16 patients had EBV positive lymphoma (62%). Only one patient had early PTLD (< 1 year after SOT) which was EBV positive. 6 out of 15 patients with late PTLD had EBV negative tumors. 9 (56%) patients had an advanced stage disease and 13 (81%) had extranodal involvement. One patient who developed PTLD after kidney transplantation had graft involvement with PTLD. Complete response (CR) was seen in all but one patient (94%). Median overall survival and median progression free survival were 5.39 years. Only 3 patients died due to PTLD and median cause specific survival time has not been reached. Out of the 16 patients, 4 had graft rejection and graft loss due to PTLD. Both the PTLD related-graft-rejection rate and graft loss rate were 25% with 95% CI (0.07-0.52). Conclusion:Combined therapy approach utilized at the YCC yields excellent results for patients with monomorphic PTLD after SOT. High CR rate, low number of PTLD-related deaths and low graft rejection /graft loss rate make this strategy an appealing option in the treatment armamentarium for this disease. Disclosures:No relevant conflicts of interest to declare.

Have we improved in preventing and treating acute graft-versus-host disease?

Acute graft-versus-host disease (GVHD) is a considerable source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Accordingly, progress in the prevention and primary therapy of this complication is needed to improve patient outcomes. Guided by insights into acute GVHD pathogenesis, investigators have explored novel cellular and pharmacologic approaches to acute GVHD prevention that demonstrates promise. Although pan-T-cell depletion has reduced GVHD, novel strategies that selectively deplete alloreactive T cells or modulate the balance of effector T cells and regulatory T cells offer promise to selectively abrogate acute GVHD while retaining protection from primary disease relapse and infectious complications. Divergent approaches in the primary therapy of acute GVHD have explored both combination approaches with standard dose glucocorticoids and additional immunosuppressive agents and conversely steroid-sparing approaches including topical agents such as beclomethasone or sirolimus as a steroid-free approach to acute GVHD therapy. Mature results of high-quality clinical trials are needed to determine the optimal therapy that results in effective control of the syndrome and limited toxicity. These complementary outcomes represent the therapeutic goal for future investigation in acute GVHD therapy.

Therapiestandard bei Myositiden und Muskeldystrophien

We summarize the current therapeutic strategies and options in inflammatory myositis and the muscular dystrophies. In myositis, the therapeutic options include basic therapy with glucocorticosteroids and other standard immunosuppressive agents, and in individual cases escalating treatment with chemotherapy or monoclonal antibodies. The exact therapeutic sequence should be performed depending on the type of myositis and the response to immunosuppression.At present, there are still no effective causative interventions to significantly alter the progression of the muscular dystrophies. However, first gene therapy clinical studies have been started in some forms of muscular dystrophy which may open a new field of therapeutic options. Most patients with myositis or muscular dystrophy need symptom-oriented therapies which include physical therapy, adequate cardiorespiratory treatment and orthopedic interventions. In the future novel immunosuppressive options may be available in patients with myositis and possibly causative strategies in the muscular dystrophies.

Desensitization: achieving immune detente

Antibodies to donor HLA (human leukocyte antigen) and/or ABO antigens were a contraindication to transplantation of most organs for decades. Desensitization protocols have shown the ability to produce reduction of such antibodies sufficient to achieve a successful transplantation. The two major protocols in use are high-dose IVIg or plasmapheresis with low-dose IVIg. The protocols differ in the basic treatment and, to some degree, in their application, but both use standard immunosuppressive agents as well as more recently developed adjunctive agents such as cell-depleting antibodies. Graft and patient survival with both types of protocol are comparable to that of non-sensitized patients, although desensitized patients do have a higher incidence of antibody-mediated rejection (AMR). Antibodies to donor antigens may persist after transplantation, and while the initial antibody titer represents the level of difficulty for successful desensitization, the strength of antibodies that persist after transplantation reflects the risk of AMR. Current protocols do not eliminate B cell clones specific for donor HLA; therefore, desensitized patients remain at an increased risk of antibody rebound if patients experience pro-inflammatory events. Therefore, ongoing antibody monitoring is crucial for early detection of antibody-mediated graft injury. Importantly, the results of numerous programs show that ABOi- and HLA-positive crossmatch renal transplantation, with proper desensitization, can be performed successfully. Further, in addition to increasing the rate of transplantation among sensitized patients, desensitization is providing insight into immunoregulatory processes and may provide information useful in diseases involving immune dysfunction.

A retrospective review of oral low-dose sirolimus (rapamycin) for the treatment of active uveitis

PurposeThe purpose of this study is to elicit the role of oral low-dose sirolimus as a corticosteriod-sparing agent for active uveitis.MethodsA retrospective, interventional case series was performed by reviewing the clinical records of all patients treated with oral, low-dose sirolimus (1–4 mg daily) for severe uveitis. Data reviewed included symptomatic improvement, Snellen best-corrected visual acuity, corticosteroid requirement, sirolimus levels, intraocular inflammation, spectral-domain optical coherence tomography, and fluorescein angiogram. Primary outcome measures were determined by the ability to decrease the intraocular inflammation, corticosteroid requirement, and frequency of flares.ResultsEight patients with varied diagnoses were treated with oral low-dose sirolimus for severe, chronic uveitis between 2008 and 2010. In four of the eight patients, there was an improvement of all primary outcome measures. While sirolimus monotherapy was successful in only one patient, a sirolimus/methotrexate combination was successful in three patients. Although there was a good initial response in three patients, treatment was a failure after serious side effects forced the cessation of sirolimus therapy. One patient was lost to follow-up.ConclusionSirolimus may have a limited role in severe uveitis as an adjunct corticosteroid-sparing agent in combination with more standard immunosuppressive agents. Oral low-dose sirolimus appeared to be better tolerated than higher doses, but there were a significant number of adverse events, requiring therapy to be stopped.

Update on transplantation tolerance

The induction of transplantation tolerance has become a major goal, because modern immunosuppressive therapy has not improved chronic rejection rates, and is associated with significant side effects. This article aims to explain the principles of immunological tolerance. Mechanisms of central tolerance involve deletion of self-reactive T cells. Mechanisms of peripheral tolerance are reviewed and also the identification of a subset of regulatory T cells which are characterised by the expression of the transcription factor FoxP3. Interesting recent insights on the role of the ‘anti-inflammatory’ cytokine transforming growth factor β which can ultimately lead to the generation of inhibitory Tregs or inflammatory Th17 cells (CD4 helper T cells which secrete the pro-inflammatory cytokine IL17) are discussed. There are many ways to induce experimental tolerance in animals, however these are difficult to translate tolerance into the clinical context. In addition, standard immunosuppressive agents are calcineurin inhibitors which block T cell activation and IL-2 production. These drugs not only inhibit the activation of effector T cells, but also Tregs, therefore inhibiting Treg driven tolerance induction. Other classes of immunosuppressive drugs should be introduced into the clinic to allow for the possibility of tolerance induction. Strategies to modulate immune responses following transplantation and their potential risks are discussed.

Acute Myocardial Infarction due to Polyarteritis Nodosa in a Young Female Patient

Coronary artery aneurysms are uncommon, are usually associated with atherosclerosis, and rarely involve all three major coronary arteries. The present report describes a rare case of a young female patient presenting with acute myocardial infarction (AMI). Coronary angiography revealed multiple severe aneurysmal and stenotic changes. Based on clinical feature and angiographic findings, it was strongly suspected that the patient had polyarteritis nodosa (PAN) complicated by AMI. The patient was treated with standard cardiac medications and immunosuppressive agents and has remained stable without further complications during a follow-up period of 6 months.

UVEITIS INA RHEUMATOLOGISTS PRACTICE: A ROLE OF TUMOR NECROSIS FACTOR-а INHIBITORS

Uveitis frequently develops in patients with ankylosing spondylitis (AS) and other autoimmune diseases. It is occasionally characterized by a severe recurrent course and untreatable with systemic glucocorticoids (GC) and standard immunosuppressive agents. The results of (mainly small) clinical trials, as well as some observations suggest that therapy with tumor necrosis factor-а (TNF-а) inhibitors is effective in such patients. There is the strongest evidence that they are beneficial in treating recurrent uveitis in patients with AS, infliximab having some efficacy advantages over etanercept and adalimumab. Accordingly, chronic uveitis in AS can be considered as an additional argument in favor of the use of TNF-а inhibitors. Furthermore, treatment with drugs of this group is warranted in severe uveitis refractory to GC and immunosuppressants. It is conceivable that in some forms of uveitis, for example, in patients with Behcet's disease, treatment with TNF-а inhibitors should be initiated at an earlier stage as the efficacy of standard immunosuppressants is generally limited

BAFF May Modulate the Rate of B-Cell Repopulation After Rituximab Therapy for Acute Renal Transplant Rejection

BAFF May Modulate the Rate of B-Cell Repopulation After Rituximab Therapy for Acute Renal Transplant Rejection

One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet’s disease refractory to standard immunosuppressive drugs

The aim of the study was to assess the long-term efficacy and safety of Infliximab therapy in the treatment of patients with Behçet's disease refractory to standard immunosuppressive agents. Twenty-one patients that did not respond to corticosteroids and to at least one immunosuppressant (cyclosporin, methotrexate, azathioprine, cyclophosphamide) for the presence of ocular and/or CNS involvement were enrolled. Eighteen patients completed the study up to 54 weeks. Stable doses of prednisone (<10 mg/day) were permitted, immunosuppressants were discontinued at least 4 weeks prior baseline visit. The patients received three infusions of 5 mg/kg Infliximab (at weeks 0, 2 and 6) and then infusions of 5 mg/kg Infliximab every 8 weeks. At each visit data on clinical symptoms, response to therapy and adverse events were collected. The primary outcome of interest was to assess the clinical efficacy (total or partial recovery) of infliximab. Secondary end points were to evaluate quality of life and to monitor the safety of the drug. Eighteen patients achieved a total remission. Two patients achieved a partial remission and relapsed after 3 months from discontinuation of therapy. Infliximab was well tolerated throughout the study. A case of non-Hodgkin lymphoma was observed within 6 months. Minor side effects were headache, dizziness, tachycardia that regressed spontaneously and did not entail interruption. Anti-nuclear antibodies were not detected during the period of observation.

Operational Tolerance in Nonvascularized Transplant Models Induced by AR-C117977, a Monocarboxylate Transporter Inhibitor

AR-C117977, a monocarboxylate transporter inhibitor, reduces immune responses both in vitro and in vivo, maintains long-term graft survival, and induces operational tolerance. To evaluate the immunosuppressive limitations of AR-C117977, this study was performed in nonvascularized transplant models noted for their refractive response to standard immunosuppressive agents. Rat skin was transplanted from DA(RT1avl) into PVG(RT1c) and the reverse. Mouse islet allotransplantation was performed with BALB/c H2d donors and C57Bl/6J H2b recipients. In the skin graft model, AR-C117977 monotherapy was associated with long-term skin graft survival in one rat strain combination. AR-C117977 and cyclosporine A (CsA) in combination resulted in significant prolongation of graft survival in both rat strains. CsA monotherapy did not prevent acute rejection in either strain. Islet allograft survival was moderately prolonged with CsA or AR-C117977. AR-C117977 is an efficient immunosuppressive drug in stringent rodent transplant models and further studies are warranted.