Treatment Of Refractory Autoimmune Diseases Research Articles

Hematopoietic Stem Cell Transplantation in Refractory Crohn's Disease: Should It Be Considered?

Hematopoietic stem cell transplantation (HSCT) is widely used in benign and malignant hematological diseases. During the last decade, HSCT, mainly autologous, also gained increasing attention in the treatment of refractory autoimmune diseases. Crohn's disease (CD) is an inflammatory bowel disease leading to transmural inflammation potentially affecting all parts of the luminal gastrointestinal tract. Despite improving therapeutic options, including various biologics, some patients are refractory to all lines of available conservative therapy, leading to increased morbidity and reduced quality of life. Apart from surgery, HSCT might be a reasonable treatment alternative for refractory CD patients. This review aims to describe the current role of HSCT in CD and discusses the procedure, the correct patient selection, the clinical efficacy from initial remission to following relapse rates, and complications of this treatment.

LB935 Psoriasis association with stem cell transplantation for cancer treatment: A retrospective cohort and literature review

Background: Hematopoietic stem-cell transplantation (SCT) is a form of immunotherapy for leukemia, multiple myeloma, and relapsed lymphoma treatment. Given substantial advances in safety since its introduction, SCT is increasingly studied as treatment for refractory autoimmune diseases like psoriasis. Psoriasis is a multifactorial autoimmune disease mediated by T-helper type 1 cell response to an unidentified antigen. Anecdotal reports describe the impact of SCT for cancer treatment in triggering new-onset psoriasis or psoriasis resolution.

Haematopoietic Stem Cell Transplantation for Multiple Sclerosis: Current Status.

Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for aggressive forms of multiple sclerosis (MS) that has been derived from haematological indications and repurposed for treatment of refractory autoimmune diseases. In the present review, a search for clinical studies on AHSCT was performed on the PubMed website and ClinicalTrials.gov databases. Papers were selected according to the following criteria: text written in English language, publication date between 2014 and August 2019, and reports including more than five patients. Prospective randomised and uncontrolled trials and retrospective case series were reviewed to examine the safety and efficacy of the procedure. Treatment protocols, pathological data and economic aspects of AHSCT were also succinctly covered. Growing evidence suggests that long-term suppression of inflammatory activity with stabilization or improvement of disability can be achieved in a high proportion of properly selected patients. More sophisticated outcome measures recently adopted, including effect on brain atrophy and disease biomarkers, are giving further insight into the effectiveness of transplant. The risks of the procedure have decreased to levels that can be considered acceptable for treatment of individuals with aggressive forms of MS. Careful selection of patients with an expected good benefit/risk profile, which is maximal when AHSCT is performed in early phases of the disease, and the expertise of transplant centres are critical to the success of treatment. Higher efficacy of AHSCT than with conventional treatments has recently been demonstrated by one randomised trial and further evidence is awaited from ongoing and planned trials comparing AHSCT with the most effective disease-modifying therapeutic agents.

Allogeneic HSCT for autoimmune disease: a shared decision.

Autologous haematopoietic stem cell transplantation (HSCT) can be an effective treatment for refractory autoimmune diseases. With reports of the use of allogeneic HSCT emerging, how do these two very different types of stem cell transplantation compare and is allogeneic HSCT advisable?

OP0093 Comparison of CD34-Selected and Unmanipulated Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: Four-Year Follow-Up Results

BackgroundThe superior efficacy of autologous hematopoietic stem cell transplantation (auto-HSCT) versus intravenous pulses cyclophosphamide was demonstrated in a randomized phase II trial in 19 severe systemic sclerosis (SSc) patients and...

THU0256 Effectiveness of autologous hematopoietic stem cell transplantation for interstitial lung diseases in patients with systemic sclerosis

BackgroundInterstitial lung disease (ILD) is a major source of mortality in systemic sclerosis (SSc). Autologous hematopoietic stem cell transplantation (HSCT) is employed as a new therapeutic strategy in patients with...

FRI0406 Seven-year follow-up of autologous hematopoietic stem cell transplantation for severe systemic sclerosis

BackgroundAutologous stem cell transplantation for international scleroderma (ASTIS) trial demonstrated that autologous hematopoietic stem cell transplantation (auto-HSCT) is more effective than conventional intravenous cyclophosphamide in the treatment of severe systemic...

THU0238 Long-term follow-up of autologous hematopoietic stem cell transplantation for severe systemic sclerosis

BackgroundRecent phase II study demonstrated that autologous hematopoietic stem cell transplantation (auto-HSCT) is more effective than conventional intravenous cyclophosphamide in the treatment of severe systemic sclerosis (SSc). However, the long-term...

Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T cells

AbstractAutologous hematopoietic stem cell transplantation (ASCT) is an increasingly accepted treatment for refractory autoimmune diseases. Refractory celiac disease with aberrant T cells (RCD type II) is unresponsive to available therapies and carries a high risk of transition into enteropathy associated T-cell lymphoma (EATL). This study reports on the feasibility, safety, and efficacy of ASCT in patients with RCD type II. Thirteen patients with RCD type II were evaluated. Seven patients (4 men, 3 women, mean age 61.5 years [range, 51-69 years]) underwent transplantation. After conditioning with fludarabine and melphalan, ASCT was performed. Patients were monitored for response, adverse effects, and hematopoietic reconstitution. All 7 patients completed the mobilization and leukapheresis procedures successfully and subsequently underwent conditioning and transplantation. Engraftment occurred in all patients. No major nonhematologic toxicity or transplantation-related mortality was observed. There was a significant reduction in the aberrant T cells in duodenal biopsies associated with improvement in clinical well-being and normalization of hematologic and biochemical markers (mean follow-up, 15.5 months; range, 7-30 months). One patient died 8 months after transplantation from progressive neuroceliac disease. These preliminary results showed that high-dose chemotherapy followed by ASCT seems feasible and safe and might result in long-term improvement of patients with RCD type II whose condition did not respond promptly to available drugs.

Viral infections during CD34+ cells purified autologous peripheral blood stem cell transplantation for the treatment of refractory autoimmune diseases

Aims: We retrospectively analyzed viral infections during CD34+ cells autologous peripheral blood stem cell transplantation (PBSCT) for the treatment of refractory autoimmune diseases (AD). Materials and Methods: 9 cases of systemic sclerosis (SSc) with interstitial pneumonia(IP),1 case of amyopathic dermatomyositis (ADM) with IP, 1 case of Wegener granulomatosis (WG) with exophthalmous. Except one SSc patient No. 9, all patients had been treated with steroid, and were administered with steroid during peri-transplant period.

Treatment of refractory autoimmune diseases with autologous stem cell transplantation: focus on juvenile idiopathic arthritis

Autologous stem cell transplantation (ASCT) can be performed in a variety of refractory autoimmune diseases. A retrospective multicenter analysis is presented to evaluate safety and efficacy of ASCT for refractory juvenile idiopathic arthritis. In all, 18 of the 34 patients (53%) with a follow-up of 12 to 60 months achieved a drug-free complete remission. There were three cases (9%) of transplant-related mortality and two cases of disease-related mortality (6%). Infectious complications were seen frequently. We propose adjustments in future protocols to reduce this mortality in this high-risk patient group.

CD34+ cells purified autologous peripheral blood stem cell transplantation for the treatment of refractory autoimmune diseases

The aim of this study was to evaluate the safety and efficacy of CD34+ cells in autologous peripheral blood stem cell transplantation (PBSCT) for the treatment of refractory autoimmune diseases (AD). Methods: Six cases of systemic sclerosis (SSc) with interstitial pneumonia (IP), one case of amyopathic dermatomyositis (ADM) with IP, and one case of Wegener’s granulomatosis with exophthalmous. PBSCs were mobilized with CY 4 g/m2+ G-CSF, and CD34+ cells were purified with CliniMACS. Pretransplantation conditioning consisted of CY 200 mg/kg.

Transcriptional regulation of multidrug resistance‐1 gene by interleukin‐2 in lymphocytes

P-glycoprotein, encoded by the multidrug resistance (MDR)-1 gene, expels various drugs from cells resulting in drug resistance. However, its functional relevance to lymphocytes and the regulatory mechanism remain unclear. Although MDR-1 is known to be induced by various cytotoxic stimuli, it is poorly understood whether the activation stimuli such as cytokines induce MDR-1 transcription. We investigated the transcriptional regulation of MDR-1 in lymphocytes by activation stimuli, particularly by interleukin (IL)-2. IL-2 induced translocation of YB-1, a specific transcriptional factor for MDR-1, from the cytoplasm into nucleus of lymphocytes in a dose-dependent manner and resulted in the sequential events; transcription of MDR-1, expression of P-glycoprotein on the cell surface, and excretion of the intracellular dexamethasone added in vitro. Transfection of YB-1 anti-sense oligonucleotides inhibited P-glycoprotein expression induced by IL-2. Cyclosporin A, a competitive inhibitor of P-glycoprotein, recovered intracellular dexamethasone levels in lymphocytes. We provide the first evidence that IL-2, a representative lymphocyte-activation stimulus, induces YB-1 activation followed by P-glycoprotein expression in lymphocytes. Our findings imply that lymphocytes activation by IL-2 in vivo, in the context of the pathogenesis of autoimmune diseases, results in P-glycoprotein-mediated multidrug resistance, and that P-glycoprotein could be an important target for the treatment of refractory autoimmune diseases.

Treatment of refractory autoimmune diseases with ablative immunotherapy

Immunological manipulations are the basis of modern therapy for refractory autoimmune diseases (AID). Ablative chemotherapy with stem cell support (autotransplant) as well as targeted immunotherapy using specific monoclonal antibodies, such as rituximab (R) and campath 1-H have become acceptable second line therapy for severe refractory AID. Until now, more than 500 autotransplants have been performed worldwide for various autoimmune disorders, including multiple sclerosis (MS), systemic sclerosis (SSc), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA) with encouraging results, although transplant related mortality (TRM) in the range between 2 and 17% still remains one of the major limitations of the procedure. Immunotherapy is a relatively safe approach associating with sustained remissions in a considerable proportion of treated patients. Better selection of patients and earlier immunotherapy, preceded an irreversible organ damage might further improve the clinical outcome of patients with AID.

Treatment of refractory autoimmune diseases with ablative immunotherapy using monoclonal antibodies and/or high dose chemotherapy with hematopoietic stem cell support.

Immunological manipulations are the basis for modern treatments of autoimmune diseases (AID). Targeted immune suppression with lymphopenic based chemotherapy, and monoclonal anti B or T lymphocytic antibodies, are integral part of the conditioning for stem cell transplantation (SCT). Immune manipulation by Cyclophosphamide (Cy), ATG, Campath and recently rituximab (RI), with or without stem cell support are the basis for emerging therapeutic modalities aiming to eradicate the autoreactive clone in various autoimmune disorders. Couple of hundreds of SCTs have been recently performed in various autoimmune disorders, mainly multiple sclerosis (MS), progressive systemic sclerosis (PSS), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA). Preliminary results are encouraging. Better selection of patients and earlier treatment, before irreversible organ failure develops will probably improve results. Current ongoing multicenter studies are evaluating the role of SCT in MS, RA, SLE, and PSS.

Protection of glomerular filtration rate by the thromboxane receptor antagonist L655,240 during low dose cyclosporine administration

Cyclosporin A (CsA) alters the production of prostaglandins (PG) by the kidney. CsA causes an increase in renal vascular resistance, a decrease in renal blood flow, a decrease in glomerular filtration rate (GFR), and increases the renal production of the vasoconstrictor thromboxane. Recently, low dose CsA has been utilized in the treatment of refractory autoimmune diseases. To determine if low dose CsA administration could produce renal hemodynamic alterations and to determine if the thromboxane receptor antagonist L655,240 could prevent these alterations, we administered groups of rats either CsA, 5 mg/kg, subcutaneously and the L655,240 vehicle NaHCO 3 (CsA-NaHCO 3), or CsA and L655,240 (CsA-L655,240), or CsA vehicle and L655,240. The rats were administered the drugs for 7 days and then subjected to inulin and PAH clearances or kidneys were harvested for prostaglandin production studies. CsA significantly depressed GFR and renal plasma flow when compared to the L655,240 treated groups. There was no difference in inulin or PAH clearance between the CsA-L655,240 and CsA vehicle L655,240 groups. Glomerular prostaglandin production including thromboxane was depressed by CsA administration. No histologic alterations were noted in the glomeruli or the medullary portions of the kidney. We conclude that administration of low dose CsA, 5 mg/kg, for 7 days results in a decrease in renal blood flow and GFR without histologic alterations. Administration of the thromboxane receptor antagonist L655,240 prevents the renal hemodynamic alterations induced by CsA in this rat model.

Relationship of chemical structures of anthraquinones with their effects on the suppression of immune responses

A series of 37 anthraquinones were evaluated for their ability to inhibit the induction of cytolytic T-lymphocytes in a mixed lymphocyte culture system, useful as a preliminary screen for immunosuppressive agents. These compounds were also tested for their ability to prevent the production of antibody in mice. It was demonstrated that 1,4- bis [(2-aminoethyl)amino]-5, 8-dihydroxy-9,10-anthracenedione dihydrochloride (AEAD, 2) derived from mitoxantrone (MX, 1) by removing hydroxyethyl groups from both side chains was extremely active in depressing immune responses in vitro and in vivo. Four additional anthraquinones related to AEAD were also identified to share similar suppressive activity. They include a Schiff base, 1,4-dihydroxy-5,8- bis[[2-[3-pyridinylmethylene)amino]ethyl]amino]-9,10-antracenedione ( 25); a dimer with N-terminals methylated, 1,1-[ethylenebis (iminoethyleneimino)]- bis[5,8-dihydroxy-4-[(2-methylamino-ethyl)amino] anthraquinone tetrahydrochloride (35); an oxazolidine, 1,4-dihydroxy-5,8- dis [[2-(2-propyl-3-oxazolidinyl)ethyl]amino] anthraquinone (10); and its polymeric oxazolidine, poly [5,8-dihydroxy-1,4-anthraquinonyleneiminoethylene-3,2-oxazolidine-diyltrimethylene-2,3-oxazolidinediylethyleneimino] (36). These compounds may warrant further consideration as candidates for the treatment of refractory autoimmune diseases and in organ transplantation.