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Biomedical subjects

R John Looney

Publications and source records attributed to R John Looney.

At least 19 recordsLinked to original sources
PubMed2007

B cell depletion therapy in autoimmune diseases.

Our understanding of the multiple physiological and pathological functions of B-cells continues to expand at a fascinating rate. A critical part of this expanding knowledge is the realization that B-cells can be responsible, at least in part, for diseases in which they had not been previously suspected and that their pathogenic influence can be mediated by multiple mechanisms. In turn, the availability of effective agents capable of inducing profound and long-lasting B-cell depletion and the safety and efficacy of Rituximab in non-Hodgkin lymphoma has prompted investigators to use this therapeutic approach in a large number of autoimmune diseases. Thus far, the results have been very promising, and in some cases nothing short of spectacular. In this review, we shall discuss the roles of B-cells in health and disease and the available evidence regarding the efficacy of B-cell depletion in human autoimmunity. Finally, we will discuss some of the many challenges and opportunities that the medical and scientific community should address in the foreseeable future.

Autoimmune Diseases↗
PubMed2006

B cell depletion therapy in systemic rheumatic diseases: different strokes for different folks?

Autoantibodies have, until recently, been the overriding focus of investigators of autoantibody-associated diseases. Increasing attention is now being paid to B cells, which not only are the producers of autoantibodies but also contribute to autoimmune disease via autoantibody-independent mechanisms. Therapeutic measures that target B cells for depletion are gaining in popularity. In this review, we will focus on two distinct approaches of depleting B cells; one employing a direct-kill approach by engagement of B cell surface CD20 with an anti-CD20 monoclonal antibody (rituximab), and the other employing an indirect starvation approach by neutralization of B lymphocyte stimulator (BLyS), a potent B cell survival factor. Among the systemic immune-based rheumatic disorders, we will focus on rheumatoid arthritis and systemic lupus erythematosus, two disorders for which therapeutic B cell targeting is being intensely investigated.

Animals↗
PubMed2006

Use of intravenous immunoglobulin G (IVIG).

Intravenous immunoglobulin G (IVIG) has become increasingly important both as replacement therapy in primary and acquired humoral immunodeficiency and as an immunomodulatory therapy in autoimmune disease and transplantation. Multiple potential mechanisms for the effects of IVIG have now been recognized but the contribution of each mechanism in different diseases is uncertain. IVIG is generally well tolerated but serious side effects can occur and need to be addressed. IVIG has Food and Drug Administration (FDA) approval for a half dozen indications but these account for only about half the use of IVIG. This chapter reviews the development of IVIG for primary immunodeficiency, the evidence for efficacy of IVIG in autoimmune and inflammatory conditions, the risks associated with administration of IVIG, and steps that can be taken to minimize adverse events.

Humans↗
PubMed2006

New therapies for systemic lupus erythematosus: cellular targets.

Antilymphocyte antibodies have been widely used in oncology and transplantation and are now being tested in autoimmune diseases. For systemic lupus erythematosus, anti-B-cell antibodies are furthest along in development. This article discusses the B-cell abnormalities found in systemic lupus erythematosus and the clinical and immunologic effects of anti-B-cell therapies.

Antibodies, Monoclonal↗
PubMed2006

Periprosthetic osteolysis: an immunologist's update.

PURPOSE OF REVIEW: Inflammation-induced osteolysis is a problem in both inflammatory arthritis and total joint arthroplasty. New drug therapies have been shown to slow, halt, or even reverse the osteolysis associated with inflammatory arthritis. Unfortunately, similar advances in the medical treatment of periprosthetic osteolysis have not occurred. This review will update the state of periprosthetic osteolysis. RECENT FINDINGS: Preliminary results with phase I and II clinical trials with AMG-162, a human IgG2 that binds receptor activator of nuclear factor kappaB (RANK) ligand, have been reported. Based on these results AMG-162 appears to be safe and to have a potent effect on osteoclast function. Based on animal studies, it is expected that regents such as AMG-162 that block RANK-ligand/RANK interaction will have activity in inflammation-induced osteolysis. Volumetric three-dimensional and magnetic resonance imaging scans for detecting and quantifying periprosthetic osteolysis have been validated in cadaver studies. Lymphocytic infiltrates and positive skin tests to cobalt have been found in patients with periprosthetic osteolysis after second generation metal-on-metal prostheses. These findings again raise the question of whether metal allergy may contribute to implant failure in these patients. A new subset of T helper cells that are neither Th1 nor Th2, but secrete a unique pattern of cytokines including IL-17, has recently been discovered. The importance of these cells in modifying particle-induced osteolysis remains to be determined. SUMMARY: There have been significant advances in our understanding of periprosthetic osteolysis, imaging technology to quantify osteolysis, and drug development. The time now seems ripe to translate these advances in clinical trials.

Antibodies, Monoclonal↗
PubMed2006

Autoimmunity and bone.

Focal erosions of cartilage and bone, which occur in the joints of patients with autoimmune inflammatory arthritis (i.e., rheumatoid arthritis (RA) and psoriatic arthritis [PsA]), represent the most debilitating and irreversible components of the disease. Over the last decade, seminal breakthroughs in our understanding of the cells and signal transduction pathways central to this process have been elucidated. From this information an established paradigm has been developed to explain focal erosions in which osteoclasts responsible for erosions are derived from bone marrow-derived myeloid precursors. Using the tumor necrosis factor (TNF) transgenic mouse model of erosive arthritis and anti-TNF clinical trials with PsA patients, we have demonstrated that systemic TNF induces the migration of CD11b+ osteoclast precursors (OCP) from the bone marrow into peripheral blood. These OCP can then enter the joints in blood vessels, translocate across the receptor activator of NF-kappaB ligand (RANKL) rich inflamed synovium, and differentiate into active osteoclasts. In direct contrast to this, systemic lupus erythematosus (SLE) patients appear to have an innate resistance to bone resorption. Our hypothesis to explain this phenomenon is that systemic interferon-alpha (IFN-alpha) diverts the bone marrow-derived myeloid precursors away from the osteoclast lineage and stimulates their differentiation into dendritic cells (DC). In support of this model, several labs have used microarray analyses to define the IFN-induced transcriptome in peripheral blood mononuclear cells (PBMC) from SLE patients. Here we propose the hypothesis that systemic TNF induces osteoclastic differentiation of PBMC in PsA patients that correlates with their erosive disease, and that the innate immune TNF/IFN axis in patients with autoimmune disease dictates their erosive phenotype. To demonstrate this, we injected wild-type C57B/6 and TNF-Tg mice with poly I:C, which is known to induce systemic IFN responses, and show its dominant effects on increasing the number of circulating CD11b+/CD11c+ precursor dendritic cells (pDC), concomitant with a dramatic reduction in CD11b+/CD11c- OCP. Thus, systemic factors produced by autoimmunity have a dramatic impact on active myelopoiesis and bone homeostasis.

Animals↗
PubMed2006

B cell-targeted therapy for rheumatoid arthritis: an update on the evidence.

Rheumatoid arthritis (RA) is a human systemic autoimmune disease with a prevalence of about 1%. Although an important role for B cells has been demonstrated in animal models of autoimmune, inflammatory arthritis, the importance of B cells in RA has been controversial for decades. The development of therapies targeting B cells may help to resolve this debate. Rituximab, a mouse-human chimeric monoclonal antibody against the B cell-specific antigen CD20, was the first B cell-targeted therapy tested in double-blind, placebo-controlled trials for RA. On the basis of the data from three separate trials, addition of rituximab to methotrexate appears to reduce significantly the signs and symptoms of rheumatoid factor-seropositive RA, as assessed by American College of Rheumatology (ACR) 20, 50 and 70 response criteria, and to be relatively safe. Significant questions about rituximab therapy still need to be addressed, including whether or not treatment with rituximab reduces radiographic progression of joint damage, the safety and efficacy of repeated courses of rituximab, and the long-term effects of rituximab on the immune system. Preliminary data on treatment of RA with belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (a growth and survival factor for B cells) is now available. In a double-blind, placebo-controlled, phase II trial, belimumab was well tolerated and had a significant beneficial effect on the ACR 20 response. Thus, therapies specifically targeting B cells do appear to be effective in the treatment of RA, providing direct evidence that B cells are important in the pathogenesis of RA.

Antibodies, Monoclonal↗
PubMed2005

The therapeutic potential of anti-CD20 "what do B-cells do?".

B-cells play a major role in the immunopathogenesis of autoimmune diseases. Not only do they produce autoantibodies, but they regulate other cell types, secrete cytokines, and present antigens. They are thus potential targets for therapeutic intervention. CD20 is a B-cell specific cell surface molecule of uncertain function. An anti-CD20 chimeric mAb (rituximab) has been FDA approved for treatment of B-cell lymphomas since 1997. Rituximab also depletes normal B-cells by several mechanisms, including ADCC. Over the past seven years, it has shown promise in a number of autoimmune diseases in phase I trials and anecdotal reports. Efficacy in rheumatoid arthritis has already been demonstrated in randomized control trials (RCTs), and RCTs in SLE, inflammatory myositis, and ANCA associated vasculitis are under way. Safety does not appear to be a major problem, but continued vigilance is warranted. The increased use of rituximab, other anti-CD20 agents, and other B-cell targeting therapies holds great promise for substantial clinical benefits, as well as providing special opportunities to understand better disease pathogenesis.

Animals↗
PubMed2005

Treatment of SLE with anti-CD20 monoclonal antibody.

Systemic lupus erythemaotsus (SLE) is an autoimmune disease involving multiple organ systems and characterized by anti-nuclear antibodies. While T cells and dendritic cells may play major roles in SLE, several lines of evidence strongly suggest a central role for B cells. This article will review the role of B cells in human SLE as well as the currently available data on the treatment of SLE by depleting B cells with anti-CD20 (rituximab).

Antibodies, Monoclonal↗
PubMed2005

B cell-targeted therapy in diseases other than rheumatoid arthritis.

There are now numerous case reports and small series using rituximab in autoimmune diseases. While these data must be interpreted with caution, they suggest that rituximab (RTX) may be a promising addition to the therapeutic armamentarium. In patients with refractory chronic idiopathic thrombocytopenic purpura, treatment with RTX was effective in inducing complete responses in a significant proportion of patients, and these responses were usually durable. RTX has also been shown to be effective and well tolerated in children with refractory autoimmune hemolytic anemia. In patients with IgM antibody-associated polyneuropathy, RTX improved muscle strength, and repeated treatments over 2 years were well tolerated. In several case series of patients with systemic lupus erythematosus, depletion of B cells during RTX therapy was associated with improvement in global disease activity. Based on these reports, further controlled studies are warranted to optimize RTX as monotherapy and to develop combination therapies in patients with refractory autoimmune diseases.

Anemia, Hemolytic, Autoimmune↗
PubMed2004

Allergen immunotherapy.

Allergen immunotherapy (also called allergy vaccine therapy) involves the administration of gradually increasing quantities of specific allergens to patients with IgE-mediated conditions until a dose is reached that is effective in reducing disease severity from natural exposure. The major objectives of allergen immunotherapy are to reduce responses to allergic triggers that precipitate symptoms in the short term and to decrease inflammatory response and prevent development of persistent disease in the long term. Allergen immunotherapy is safe and has been shown to be effective in the treatment of stinging-insect hypersensitivity, allergic rhinitis or conjunctivitis, and allergic asthma. Allergen immunotherapy is not effective in the treatment of atopic dermatitis, urticaria, or headaches and is potentially dangerous if used for food or antibiotic allergies. Safe administration of allergen immunotherapy requires the immediate availability of a health care professional capable of recognizing and treating anaphylaxis. An observation period of 20 to 30 minutes after injection is mandatory. Patients should not be taking beta-adrenergic blocking agents when receiving immunotherapy because these drugs may mask early signs and symptoms of anaphylaxis and make the treatment of anaphylaxis more difficult. Unlike antiallergic medication, allergen immunotherapy has the potential of altering the allergic disease course after three to five years of therapy.

Desensitization, Immunologic↗
PubMed2004

Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice.

OBJECTIVE: To investigate the mechanisms whereby tumor necrosis factor alpha (TNFalpha) increases osteoclastogenesis in vivo. METHODS: TNFalpha-transgenic (TNF-Tg) and wild-type mice injected with TNFalpha were studied. In vitro osteoclastogenesis assays, monocyte colony-forming assays, and fluorescence-activated cell sorting were performed using splenocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells to quantify and characterize osteoclast precursors (OCPs). Etanercept, a TNFalpha antagonist, was used to block TNFalpha activity in vivo. The effects of TNFalpha on proliferation, apoptosis, and differentiation of OCPs were assessed using 5-bromo-2'-deoxyuridine labeling, annexin V staining, and reverse transcriptase-polymerase chain reaction. RESULTS: OCP numbers were increased 4-7-fold in PBMCs and spleen, but not in bone marrow of TNF-Tg mice. The OCPs in spleen were in the CD11b(high) population and contained both c-Fms- and c-Fms+ cells. The increased number of OCPs correlated with the initiation of detectable TNFalpha in serum and the onset of inflammatory arthritis in TNF-Tg mice. Etanercept eliminated the increase in peripheral OCPs. TNFalpha did not affect proliferation, survival, or differentiation of CD11b(high) splenocytes in vivo or in vitro, but caused a rapid increase in CD11b+ cells in blood within 4 hours of a single injection and an accumulation of CD11b(high) OCPs in spleen after 3 days of multiple injections. CONCLUSION: Systemic TNFalpha induces a marked increase in circulating OCPs that is reversible by anti-TNF therapy and may result from their mobilization from bone marrow. Our findings provide a new mechanism whereby TNFalpha stimulates osteoclastogenesis in patients with inflammatory arthritis, suggesting that CD11b+ PBMCs could be used to evaluate a patient's potential for erosive disease and the efficacy of anti-TNF therapy.

Animals↗
PubMed2004

B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab.

OBJECTIVE: Safer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE. METHODS: A phase I/II dose-escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (1 week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy. RESULTS: Rituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B cells/microl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by paired t-test). This improvement persisted for 12 months, despite the absence of a significant change in anti-double-stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level > or =100 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion. CONCLUSION: Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.

Adult↗
PubMed2004

Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus.

OBJECTIVE: B lymphocyte depletion has recently emerged as a promising approach to the treatment of systemic lupus erythematosus (SLE). As part of a phase I/II dose-ranging trial of rituximab in the treatment of SLE, we evaluated the fate of discrete B cell subsets in the setting of selective depletion by anti-CD20 monoclonal antibody and during the B cell recovery phase. METHODS: B cell depletion and phenotype were examined by flow cytometry of peripheral blood mononuclear cells for CD19, CD20, CD27, IgD, and CD38 expression. Changes in autoreactive B lymphocytes and plasma cells were assessed by determination of serum autoantibody levels (anti-double-stranded DNA and VH4.34) and by direct monitoring of a unique autoreactive B cell population bearing surface antibodies whose heavy chain is encoded by the VH4.34 gene segment. RESULTS: Compared with normal controls, SLE patients displayed several abnormalities in peripheral B cell homeostasis at baseline, including naive lymphopenia, expansion of a CD27-,IgD- (double negative) population, and expansion of circulating plasmablasts. Remarkably, these abnormalities resolved after effective B cell depletion with rituximab and immune reconstitution. The frequency of autoreactive VH4.34 memory B cells also decreased 1 year posttreatment, despite the presence of low levels of residual memory B cells at the point of maximal B cell depletion and persistently elevated serum autoantibody titers in most patients. CONCLUSION: This study is the first to show evidence that in SLE, specific B cell depletion therapy with rituximab dramatically improves abnormalities in B cell homeostasis and tolerance that are characteristic of this disease. The persistence of elevated autoantibody titers may reflect the presence of low levels of residual autoreactive memory B cells and/or long-lived autoreactive plasma cells.

Adult↗
PubMed2004

A successful challenge in a patient with vancomycin-induced linear IgA dermatosis.

BACKGROUND: Linear IgA bullous dermatosis (LABD), a subepidermal, blistering skin disease, is generally believed to be idiopathic. It has been reported in association with multiple medications, including vancomycin. In each case, complete clearance of the skin lesions occurred with discontinued use of the drug. A subsequent rechallenge reproduced the eruption within hours to days. OBJECTIVE: To present a patient with vancomycin-associated LABD who underwent a successful challenge with the antibiotic 4 years after the initial reaction. METHODS: The patient developed blistering lesions over her trunk and extremities 10 days after the initiation of vancomycin for sepsis. A biopsy specimen of a skin eruption was consistent with linear IgA dermatosis. Following discontinued use of the drug, her skin lesions resolved. Four years later, she required vancomycin for osteomyelitis. RESULTS: The patient underwent a vancomycin-graded challenge of 5 doses over 5 days. On day 1, she received 10 mg, and this was increased in a semilog fashion to 1,000 mg on day 5. She had no recurrence of her skin lesions. CONCLUSIONS: This is the first case, to our knowledge, to show a successful rechallenge in a patient with drug-associated LABD. Since the patient did not have a reaction to the challenge, it is possible that the IgA antibodies responsible for drug-induced LABD are only present transiently and diminish over time.

Autoimmune Diseases↗
PubMed2004

B cells as therapeutic targets for rheumatic diseases.

PURPOSE OF REVIEW: Trials treating human rheumatic diseases with biologic agents and drugs that selectively affect B cells will be reviewed. Rituximab, an anti-CD20 monoclonal mouse/human antibody, will be the primary focus of the review because it has been widely used in several autoimmune and rheumatic conditions, but the limited studies on other reagents such as anti-BlyS, anti-CD154, and B cell tolerogens will also be covered. RECENT FINDINGS: The single most important recent development was the completion of a randomized, double-blind, placebo-controlled trial of rituximab in methotrexate-resistant rheumatoid arthritis. In this trial, B cell depletion with rituximab led to a sustained clinical response with an impressive improvement in America College of Rheumatology 50% response (ACR 50) at both 24 and 48 weeks. Additional open studies of rituximab showing clinical benefit in systemic lupus erythematosus, cryoglobulinemia, antineutrophil cytoplasmic antibodies+ vasculitis, and dermatomyositis are noteworthy but must be interpreted with caution until randomized control trials are available. Two well-designed studies of anti-CD154 antibodies in systemic lupus erythematosus were reported. Unfortunately, one was halted because of unexpected vascular complications, and the other failed to show any beneficial clinical effect. A phase I study using anti-BlyS in SLE demonstrated a selective effect on B cells and no overt toxicity, but in this very short-term study no effect on serology or clinical activity was seen. Two B cell tolerogens have been used in human trials. The first tolerogen, directed at anti-dsDNA responses in SLE, did significantly decrease titers of high-affinity anti-dsDNA antibodies but had no clinically beneficial effect overall. A phase I trial of a tolerogen directed at anti-beta2-glycoprotein I antibodies demonstrated a decrease in antibody titers after a single injection. SUMMARY: Several therapeutic agents targeting B cells have now been tested or are being tested in human trials. The success of rituximab in a well-controlled trial confirms previous preliminary reports indicating that B cell depletion can treat established autoimmune disease.

Antibodies, Monoclonal↗
PubMed2004

Computed tomography to assess pelvic lysis after total hip replacement.

To assess the accuracy of a computer-assisted computed tomography image analysis program in determining the location and volume of periacetabular osteolysis, we designed an osteolysis model by implanting bilateral total hip replacements in human pelvic cadavers and creating osteolytic lesions of varying sizes. The volumes of 48 defects were measured physically, and axial computed tomography scans were obtained. The computed tomography images were processed with streak artifact reduction and segmentation algorithms. The location and volume of lesions were determined from these images. Eighty-one percent (39 lesions) were identified correctly from the computed tomography scans. Detection was location-dependent. More lesions were detected in the ilium (100%) and at the rim (89%) than in the ischium (78%) or the pubis (50%). Computed tomography overestimated lesion volume by a mean of 0.5 +/- 2.3 cm. The volumetric error was unrelated to lesion location but was dependent on lesion size. As lesion size increased above 10 cm, the mean percentage error decreased to 1.8%. Computed tomography image analysis can be used more accurately than plain radiographs to investigate the effectiveness of treatment and the natural history of pelvic osteolysis.

Arthroplasty, Replacement, Hip↗