Novel TNF antagonists for the treatment of rheumatoid arthritis.

IMPORTANCE OF THE FIELD: TNF antagonists have become an integral part of the standard of care for patients with rheumatoid arthritis (RA). Two additional TNF antagonists have recently been approved in the US for this indication, and clinicians will need to understand the data on the efficacy and safety of these agents in order to properly place them into the clinical treatment algorithm. AREAS COVERED IN THIS REVIEW: This review covers the published clinical trial data on the use of certolizumab and golimumab for RA. The literature search included manuscripts published through September 2009 and abstracts from major meetings (ACR and EULAR) in 2007 - 2009. WHAT THE READER WILL GAIN: This paper will review the efficacy and safety of golimumab and certolizumab in the treatment of RA at various stages of disease. Use of these agents will be described in the context of other available alternatives, including other TNF antagonists and other biologic therapies. TAKE HOME MESSAGE: Certolizumab and golimumab have comparable efficacy and safety profiles compared with previously approved TNF antagonists. These two agents have several unique theoretical benefits when compared to existing agents, but the available published data do not suggest a clear clinical advantage at this time.

Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice.

Embryonic stem cell (ESC)-derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC-derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant complication, graft-versus-host disease (GVHD). Herein, we demonstrate that ESC-derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c-kit expression, and injected either i.v. or intra-bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end-stage diabetes. All mice with >5% donor chimerism remained free of diabetes and insulitis, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic-specific autoantigen, but responded normally to third-party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC-derived HSC cells treating disease in an animal model.

Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used.

Patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)-a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.

Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus.

CONTEXT: Manifestations of systemic lupus erythematosus (SLE) may in most patients be ameliorated with medications that suppress the immune system. Nevertheless, there remains a subset of SLE patients for whom current strategies are insufficient to control disease. OBJECTIVE: To assess the safety of intense immunosuppression and autologous hematopoietic stem cell support in patients with severe and treatment-refractory SLE. DESIGN, SETTING, AND PARTICIPANTS: A single-arm trial of 50 patients with SLE refractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement. Patients were enrolled from April 1997 through January 2005 in an autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) study at a single US medical center. INTERVENTIONS: Peripheral blood stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (5 microg/kg per day), enriched ex vivo by CD34+ immunoselection, cryopreserved, and reinfused after treatment with cyclophosphamide (200 mg/kg) and equine antithymocyte globulin (90 mg/kg). MAIN OUTCOME MEASURES: The primary end point was survival, both overall and disease-free. Secondary end points included SLE Disease Activity Index (SLEDAI), serology (antinuclear antibody [ANA] and anti-double-stranded (ds) DNA), complement C3 and C4, and changes in renal and pulmonary organ function assessed before treatment and at 6 months, 12 months, and then yearly for 5 years. RESULTS: Fifty patients were enrolled and underwent stem cell mobilization. Two patients died after mobilization, one from disseminated mucormycosis and another from active lupus after postponing the transplantation for 4 months. Forty-eight patients underwent nonmyeloablative HSCT. Treatment-related mortality was 2% (1/50). By intention to treat, treatment-related mortality was 4% (2/50). With a mean follow-up of 29 months (range, 6 months to 7.5 years) for patients undergoing HSCT, overall 5-year survival was 84%, and probability of disease-free survival at 5 years following HSCT was 50%. Secondary analysis demonstrated stabilization of renal function and significant improvement in SLEDAI score, ANA, anti-ds DNA, complement, and carbon monoxide diffusion lung capacity adjusted for hemoglobin. CONCLUSIONS: In treatment-refractory SLE, autologous nonmyeloablative HSCT results in amelioration of disease activity, improvement in serologic markers, and either stabilization or reversal of organ dysfunction. These data are nonrandomized and thus preliminary, providing the foundation and justification for a definitive randomized trial. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00271934.

Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation.

Systemic lupus erythematosus (SLE) is the most common disease associated with antiphospholipid syndrome (APS). We, therefore, evaluated 46 patients with refractory SLE treated by autologous hematopoietic stem cell transplantation (HSCT) for a history of APS prior to transplantation. The prevalence of SLE-related APS in our patient population was 61% (28 of 46 patients with refractory SLE). Nineteen of 28 patients with APS had lupus anticoagulant (LA) or high titers of anticardiolipin antibodies (ACLAs), either immunoglobulin (Ig)G or IgM, when evaluated at study entry. Six of 8 evaluable LA+ patients became and remained LA-; 5 of 7 initially ACLA IgG+ patients and 9 of 11 ACLA IgM+ patients demonstrated normalization of ACLA titers when followed after HSCT. Eighteen of 22 patients refractory to chronic anticoagulation discontinued anticoagulation therapy a median of 4 months after transplantation; 78% of them remained free of thrombotic events and in complete SLE remission for up to 78 months (median, 15 months) after HSCT. There was no treatment-related mortality. Autologous HSCT may be performed safely in patients with APS and appears to be effective therapy for eliminating ALPAs and preventing thrombotic complications in patients with SLE.

Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease.

BACKGROUND & AIMS: Crohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission. METHODS: We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn's Disease Activity Index (CDAI) of 250-400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34 + enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin. RESULTS: The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8-11) and 9 (range, 9-18), respectively. The initial median CDAI was 291 (range, 250-358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI < or =150. After a median follow-up of 18.5 months (range, 7-37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT. CONCLUSIONS: Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.

Non-myeloablative stem cell transplantation for autoimmune diseases.

Treatment of life-threatening autoimmune diseases in animal models with induced or spontaneous autoimmune diseases can be accomplished by a 2-step procedure involving elimination of self-reactive lymphocytes with an immune ablative conditioning regimen followed by infusion of autologous or allogeneic stem cells, respectively. In animal models it was shown that using such a strategy, autoimmunity could be adequately controlled. It is speculated that de-novo development of the T and B cell repertoire from uncommitted progenitor cells in the presence of the autoantigens may be the best recipe for re-induction of self-tolerance, similarly to the normal ontogeny of the immune system during the induction of self tolerance in fetal stage. For both autologous and allogeneic hematopoietic stem cell transplantation, a non-myeloablative stem cell transplantation (NST) regimen may be used for safer lymphoablation rather than myeloablation. In addition, for allogeneic hematopoietic stem cell transplantation engraftment of disease resistant donor stem cells will alter the genetic predisposition towards autoimmune disease susceptibility.

Induction of remission of severe and refractory rheumatoid arthritis by allogeneic mixed chimerism.

This report describes the first allogeneic hematopoietic stem cell transplantation (HSCT) performed for the indication of rheumatoid arthritis (RA). We used nonmyeloablative allogeneic HSCT to treat a 52-year-old woman who had treatment-refractory RA and a poor prognosis (24 swollen and 38 involved joints). She was treated with fludarabine, cyclophosphamide, CAMPATH-1H, and CD34-selected HSCT (8 million CD34+ donor cells/kg); the donor was the patient's HLA-matched, rheumatoid factor-negative sister. One year post-HSCT, the patient has had no infection except dermatomal varicella-zoster virus infection and no acute or chronic graft-versus-host disease (GVHD). Her RA has remained in remission with no immunosuppressive or immunomodulatory medications. The patient is a mixed chimera, with 55% donor T (CD3+) cells and 70% donor myeloid (CD33+) cells. This is the first published report of allogeneic HSCT performed for the indication of RA. Mixed chimerism has resulted in marked amelioration of RA, without GVHD.

Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial).

BACKGROUND: Age-related macular degeneration (ARMD) is the leading cause of vision loss in aging Westem societies. The objective of the lutein antioxidant supplementation trial (LAST) is to determine whether nutritional supplementation with lutein or lutein together with antioxidants, vitamins, and minerals, improves visual function and symptoms in atrophic ARMD. METHODS: The study was a prospective, 12-month, randomized, double-masked, placebo-controlled trial conducted at an urban midwestern Veterans Administration Hospital from August 1999 to May 2001. Ninety patients with atrophic ARMD were referred by ophthalmologists at two Chicago-area veterans medical facilities. Patients in Group 1 received lutein 10 mg (L); in Group 2, a lutein 10 mg/antioxidants/vitamins and minerals broad spectrum supplementation formula (L/A); and in Group 3, a maltodextrin placebo (P) over 12 months. RESULTS: In Groups 1 L and 2 L/A, mean eye macular pigment optical density increased approximately 0.09 log units from baseline, Snellen equivalent visual acuity improved 5.4 letters for Group 1 L and 3.5 letters for Group 2 L/A, and contrast sensitivity improved. There was a net subjective improvement in Amsler grid in Group 1 L. VFO-14 questionnaires conceming subjective glare recovery were nearly significant at 4 months for Group 2 L/A. Patients who received the placebo (Group 3) had no significant changes in any of the measured findings. CONCLUSION: In this study, visual function is improved with lutein alone or lutein together with other nutrients. Further studies are needed with more patients, of both genders, and for longer periods of time to assess long-term effects of lutein or lutein together with a broad spectrum of antioxidants, vitamins, and minerals in the treatment of atrophic age-related macular degeneration.

Stem cell transplantation for autoimmune diseases.

Hematopoietic stem cell transplantation is an increasingly used therapy for treatment of autoimmune diseases and severe immune-mediated disorders. We address some general concepts and principles in the development of hematopoietic stem cell transplantation in order to understand the principles and design of safe autologous and allogeneic transplant regimens for these unique diseases.

Serum iron, transferrin saturation, ferritin, and dietary data in age-related macular degeneration.

Iron (Fe) is a tightly metabolically controlled mineral and growth factor for all living cells. Iron not bound in erythrocyte hemoglobin is transported by the plasma iron transport protein transferrin (Tf) and bound within cells by ferritin. Apo-Tf and apo-hemopexin are also known to be made locally in the retina. Free Fe is cytotoxic, promotes oxidation/lipid peroxidation, has been implicated as a risk factor in cardiac disease, and is itself associated with age-related macular degeneration (ARMD), the leading cause of blindness in aging western societies. The authors evaluated Fe overload serum markers and dietary intake in patients with atrophic ARMD. After obtaining informed consent, an Fe panel consisting of serum Fe, total Fe binding capacity (TIBC), and ferritin was performed on 75 veterans (70 men, five women) with an average age of 75 years with a diagnosis of atrophic ARMD by combined criteria of International Retinal Classification and psychophysical/symptom abnormalities. Tf saturation was calculated by dividing serum Fe concentration by TIBC. Dietary iron with and without supplementation and vitamin C intake were determined for 86 patients using the Harvard School of Public Health/Department of Nutrition Food Frequency Questionnaire. Statistically significant correlations (P <0.1) were found between serum and dietary Fe (r = -.26), between serum Fe and serum ferritin (r =.34), and between dietary Fe and dietary vitamin C (r =.30). The data on mostly male geriatric veterans with atrophic ARMD indicate that single time-point assessment of systemic Fe status and dietary Fe is not useful. However, serial multiple-year data, correlating Fe markers with disease, may still be important. Also, because Fe transport proteins do not cross the blood-retina barrier, the local cellular toxic effects of Fe must also be considered.