Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation.

Objective: Leflunomide, a potent disease-modifying antirheumatic drug of the isoxazole class, exhibits antiinflammatory, antiproliferative, and immunosuppressive effects by largely unknown mechanisms, although alterations of pyrimidine synthesis have been proposed. Successful immune responsiveness requires T cell activation by interaction with antigen-presenting cells (APCs), and integrin activation and formation of an immunologic synapse (IS). In this study, we evaluated the impact of the active leflunomide metabolite teriflunomide on T cell integrin activation, evolution of the IS, and antigen-specific formation of stable T cell/APC conjugates.

Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states.

Objective: Several composite scores are available to assess the activity of rheumatoid arthritis (RA). Criteria for remission and active RA based on these continuous scores are important for use in clinical practice and clinical trials. We aimed to reevaluate or to define such criteria for the Disease Activity Score in 28 joints (DAS28) and the Simplified Disease Activity Index (SDAI).

Pro-inflammatory cytokines in rheumatoid arthritis: pathogenetic and therapeutic aspects.

Therapy of rheumatoid arthritis (RA) aims at interfering with the disease process, namely inflammation and destruction of the joints, and thus at preventing long-term disability. Proinflammatory cytokines play a decisive role in the generation of the inflammatory and destructive response. Aside from traditional disease-modifying anti-rheumatic drugs and tumor necrosis factor-blocking agents, a number of targeted therapies are currently in evaluation, such as abatacept (interfering with co-stimulation), rituximab (an anti-B-cell agent) and tocilizumab (an anti-interleukin-6 receptor antibody).

Pathogenesis of rheumatoid arthritis: targeting cytokines.

Although considerable progress has been made by adequate treatment with traditional disease-modifying antirheumatic drugs (DMARDs), therapy of rheumatoid arthritis (RA) still remains difficult. The discovery of the importance of cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-15 (IL-15), which are also stimulated by consequences of autoimmune responses, has led to the development of anticytokine therapies ("biologicals"). Blocking TNF or also, to some extent, IL-1 has proved beneficial in DMARD-resistant RA patients in multiple clinical trials.

Does mixed connective tissue disease exist? Yes.

For patients who have combined features of rheumatoid arthritis, the limited cutaneous form of systemic sclerosis, and inflammatory myopathies, the concept of mixed connective tissue disease (MCTD) often helps to predict and diagnose organ problems and to educate the patient accordingly. With high titer IgG antibodies to U1 ribonucleoprotein (U1-snRNP), this concept is supported by a specific serologic marker, and autoantibodies to U1-snRNP and to heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 display MCTD specificity with regard to the recognized epitopes. In addition, the association of MCTD with HLA-DR4 distinguishes it from systemic erythematosus lupus and systemic sclerosis, and speaks to its being a disease entity, rather than a mixture of yet undifferentiated collagen vascular diseases.

Interaction between synovial inflammatory tissue and bone marrow in rheumatoid arthritis.

Rheumatoid arthritis (RA) leads to destruction of cartilage and bone. Whether rheumatoid arthritis also affects the adjacent bone marrow is less clear. In this study, we investigated subcortical bone marrow changes in joints from patients with RA.

Use of combination of leflunomide with biological agents in treatment of rheumatoid arthritis.

An Expert Panel Meeting was held in May 2004 to assess experience with combination therapy with leflunomide and biological agents in the treatment of rheumatoid arthritis (RA), to identify both optimal use of such combinations and precautions for use. Eleven published prospective or retrospective studies were reviewed, principally evaluating combination of leflunomide with infliximab, as well as patient registry data. Available data suggest that combination therapies are more efficacious than monotherapies, reflecting the complementarity of mechanisms of action.

Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score.

Introduction: Frequent assessments of rheumatoid arthritis (RA) disease activity allow timely adaptation of therapy, which is essential in preventing disease progression. However, values of acute phase reactants (APRs) are needed to calculate current composite activity indices, such as the Disease Activity Score (DAS)28, the DAS28-CRP (i.e.

Validating the International Classification of Functioning, Disability and Health Comprehensive Core Set for Rheumatoid Arthritis from the patient perspective: a qualitative study.

Objective: To validate the International Classification of Functioning, Disability and Health (ICF) Comprehensive Core Set for Rheumatoid Arthritis (RA) from the patient perspective.

Methods: Patients with RA were interviewed about their problems in daily functioning. Interviews were tape recorded and transcribed verbatim.

The active metabolite of leflunomide, A77 1726, interferes with dendritic cell function.

Leflunomide, a potent disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA), exhibits anti-inflammatory, antiproliferative and immunosuppressive effects. Although most of the beneficial effects of leflunomide have been attributed to its antimetabolite activity, mainly in T cells, other targets accounting for its potency might still exist. Because of mounting evidence for a prominent role of dendritic cells (DCs) in the initiation and maintenance of the immune response in RA, we analyzed the effect of the active metabolite of leflunomide (A77 1726; LEF-M) on phenotype and function of human myleloid DCs at several stages in their life cycle.

Listeria-associated arthritis in a patient undergoing etanercept therapy: case report and review of the literature.

Listeriosis can be a cause of infectious arthritis. Here, we present a case of articular listeriosis in a patient with rheumatoid arthritis receiving treatment with etanercept, a tumor necrosis factor antagonist. We review the literature of articular listeriosis and discuss the role of tumor necrosis factor blockade in precipitating listeriosis.

Physical function and health related quality of life: analysis of 2-year data from randomized, controlled studies of leflunomide, sulfasalazine, or methotrexate in patients with active rheumatoid arthritis.

Objective: To determine whether improvements in physical function and health related quality of life (HRQOL) are sustained over 2 years of blinded treatment with leflunomide (LEF), methotrexate (MTX), or sulfasalazine (SSZ) in patients with active rheumatoid arthritis (RA).

Methods: Three phase III randomized, controlled trials compared LEF, MTX, and SSZ in patients with active RA. Improvements in physical function were assessed by Health Assessment Questionnaire Disability Index (HAQ-DI) and Modified Health Assessment Questionnaire (MHAQ); monthly MHAQ and mean HAQ scores were used to calculate American College of Rheumatology responses; HAQ-DI was assessed at baseline and 6-month intervals.

CD44 is a determinant of inflammatory bone loss.

Chronic inflammation is a major trigger of local and systemic bone loss. Disintegration of cell-matrix interaction is a prerequisite for the invasion of inflammatory tissue into bone. CD44 is a type I transmembrane glycoprotein that connects a variety of extracellular matrix proteins to the cell surface.

Depletion of endothelial progenitor cells in the peripheral blood of patients with rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is characterized by increased cardiovascular morbidity and mortality that cannot be explained solely by traditional cardiovascular risk factors. Cardiovascular morbidity is related to disease activity and can be normalized by effective therapy. Because the quantity of endothelial progenitor cells (EPCs) in the peripheral blood is correlated inversely with cardiovascular risk, we studied whether such abnormalities could also be observed in patients with RA.

JNK1 is not essential for TNF-mediated joint disease.

Tumour necrosis factor (TNF) signalling molecules are considered as promising therapeutic targets of antirheumatic therapy. Among them, mitogen-activated protein kinases are thought to be of central importance. Herein, we investigate the role in vivo of TNF-alpha signalling through c-Jun N-terminal kinase (JNK)1 in destructive arthritis.

Immunoadsorption (IAS) as a rescue therapy in SLE: considerations on safety and efficacy.

Objective: In SLE, extracorporeal procedures aiming at reduction of immunoglobulin (Ig) and immune complexes (IC) are used as a rescue therapy. Plasma exchange (PE) has not been proven overall effective in SLE, and long-term treatment in particular has been associated with severe bacterial and viral infections. Immunoadsorption (IAS), in contrast, selectively removes Ig and IC and may thus be safer.

Content comparison of occupation-based instruments in adult rheumatology and musculoskeletal rehabilitation based on the International Classification of Functioning, Disability and Health.

Objective: To compare the content of clinical, occupation-based instruments that are used in adult rheumatology and musculoskeletal rehabilitation in occupational therapy based on the International Classification of Functioning, Disability and Health (ICF).

Methods: Clinical instruments of occupational performance and occupation in adult rehabilitation and rheumatology were identified in a literature search. All items of these instruments were linked to the ICF categories according to 10 linking rules.

Therapeutic strategies in early rheumatoid arthritis.

Rheumatoid arthritis (RA) therapy rests primarily on the use of disease-modifying antirheumatic drugs (DMARDs). It has been unequivocally shown that DMARD therapy early in the course of RA retards progression of damage and disability to a larger degree compared with delayed institution; the most effective DMARD is methotrexate (MTX). Moreover, combination therapy including intermediate to high doses of glucocorticoids and combinations of MTX with tumour necrosis factor blockers are more effective than monotherapies.

Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial.

Objective: To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti-tumor necrosis factor alpha [anti-TNFalpha] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of < or =3 years' duration.

Methods: RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX-placebo, MTX-3 mg/kg infliximab, and MTX-6 mg/kg infliximab.

Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: an open-label study.

Objective: To investigate the safety of therapeutic tumor necrosis factor alpha (TNFalpha) blockade in patients with systemic lupus erythematosus (SLE), in whom this proinflammatory cytokine is significantly increased and may be involved in the disease pathogenesis.

Methods: In an open-label study, 6 patients with moderately active SLE (4 with nephritis and 3 with arthritis refractory to other therapies) were given 4 300-mg doses of infliximab, a chimeric anti-TNFalpha antibody, in addition to immunosuppression with azathioprine or methotrexate.

Results: The only significant adverse events observed were urinary tract infection in 3 patients, 1 of which was accompanied by Escherichia coli bacteremia, and a prolonged febrile episode of putatively viral origin in 1 of them.

Phenotypic and functional deficiencies of monocyte-derived dendritic cells in systemic lupus erythematosus (SLE) patients.

Systemic lupus erythematosus (SLE) represents an autoimmune disease for which alterations of T cells, B cells as well as various antigen-presenting cell (APC) populations have been described. In order to better define APC-associated deficiencies, we analyzed morphologic, phenotypic and functional characteristics of in vitro-generated monocyte-derived dendritic cells (MoDC) from SLE patients as compared with healthy controls. Analysis of MoDC at different stages of maturation revealed substantial phenotypic and functional defects of MoDC from SLE patients as compared with healthy controls.

Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis.

Objective: Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast-targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function.

Endothelial precursor cells in the synovial tissue of patients with rheumatoid arthritis and osteoarthritis.

Objective: To find evidence for the presence of endothelial precursor cells, which can induce new vessel formation, in the synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA).

Methods: Precursor cells in the synovial tissue of 18 RA patients and 15 OA patients were identified by immunohistochemistry, morphometric analysis, and confocal laser scanning microscopy using the following phenotype markers: CD31, CD34, STRO-1, CD133, vascular endothelial growth factor receptor 2 (VEGFR-2), and CXCR4. The presence of CD31, CD34, CD133, VEGFR-2, and CXCR4 messenger RNA in the synovial tissue was determined by reverse transcriptase-polymerase chain reaction, and the message for CXCR4 was quantified by an RNase protection assay.

Lefunomide in combination therapy.

In most studies of disease modifying antirheumatic drug therapy, in combination with either leflunomide or biological agents, patients are given an additional agent after they have failed treatment with methotrexate (MTX). This review of clinical studies shows that leflunomide is clinically efficacious and well tolerated when added to either sulfasalazine or MTX, as both an initial and ongoing treatment for rheumatoid arthritis (RA). Experience in combining leflunomide with biological agents is limited to a small number of open-label studies with infliximab.

Leflunomide: a manageable safety profile.

The safety profile of leflunomide in the treatment of rheumatoid arthritis has been well documented in clinical trials, postmarketing surveillance, and epidemiological studies. Both postmarketing surveillance and epidemiological study results are consistent with the safety profile of leflunomide reported in clinical trials, and no increased risk was observed with leflunomide, compared with other disease modifying antirheumatic drugs; these studies have allowed a more precise representation of the incidence of adverse events occurring with leflunomide under normal conditions of care. The most common leflunomide-associated adverse events include diarrhea, elevated liver enzymes, alopecia, and rash.