Defective Expression and Function of the Leukocyte Associated Ig-like Receptor 1 in B Lymphocytes from Systemic Lupus Erythematosus Patients

Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies and dysregulation of B cell function. The leukocyte associated Immunoglobulin (Ig)-like receptor (LAIR)1 is a transmembrane molecule belonging to Ig superfamily which binds to different types of collagen. Herein, we have determined the expression and function of LAIR1 on B lymphocyte from SLE patients. LAIR1 expression in peripheral blood B lymphocytes from 54 SLE, 24 mixed connective tissue disease (MCTD), 20 systemic sclerosis (SSc) patients, 14 rheumatoid arthritis (RA) and 40 sex and age matched healthy donors (HD) have been analyzed by immunofluorescence. The effect of LAIR1 ligation by specific monoclonal antibodies, collagen or collagen producing mesenchymal stromal cells from reactive lymph nodes or bone marrow on Ig production by pokeweed mitogen and B cell receptor (BCR)-mediated NF-kB activation was assessed by ELISA and TransAM assay. The percentage of CD20+ B lymphocytes lacking or showing reduced expression of LAIR1 was markedly increased in SLE and MCTD but not in SSc or RA patients compared to HD. The downregulation of LAIR1 expression was not dependent on corticosteroid therapy. Interestingly, LAIR1 engagement by collagen or collagen-producing mesenchymal stromal cells in SLE patients with low LAIR1 expression on B cells delivered a lower inhibiting signal on Ig production. In addition, NF-kB p65 subunit activation upon BCR and LAIR1 co-engagement was less inhibited in SLE patients than in HD. Our findings indicate defective LAIR1 expression and function in SLE B lymphocytes, possible contributing to an altered control of B lymphocytes behavior

Successful treatment with belimumab of severe systemic lupus erythematosus not responding to standard therapy: a case report

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by complex pathophysiology and heterogeneous clinical picture. Belimumab is the first biological therapy licensed for SLE. We report the case of a 24 years old woman affected by a severe form of systemic lupus erythematosus with arthritis, muscle weakness, cervical lymphadenopathy, cutaneous involvement, fever, leukopenia, low complement levels and positivity for anti-dsDNA antibodies. Treatment with high dose steroids, hydroxychloroquine, and mycophenolate mofetil did not induce remission and several disease flares were observed. Therapy with anti-BLys monoclonal antibody belimumab leads to a fast clinical and laboratory response and to stable remission lasting for 30 months allowing steroid tapering to very low maintenance dose

Pharmacogenetics of etanercept: role of TNF-\u3b1 gene polymorphisms in improving its efficacy

During the last decade, many new biological immune modulators have entered the market as new therapeutic principles. Biologics, including TNF-\u3b1 inhibitors, are the new frontier in the treatment of immune-mediated or inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ankylosing spondylitis, systemic sclerosis, disseminated granuloma annulare, psoriasis and/or psoriatic arthritis. TNF-\u3b1 inhibitors have demonstrated efficacy and are well tolerated in large, randomized, controlled clinical trials. However, a substantial proportion of patients do not respond to these agents and potential adverse drug reactions may be associated with its use

Impact of pharmacogenomics upon the therapeutic response to etanercept in psoriasis and psoriatic arthritis

Introduction: TNF-\uce\ub1 inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases. Etanercept is a decoy receptor\ue2\u80\u9d for TNF-\uce\ub1 and it is composed of two p75 TNF-\uce\ub1 receptors fused to human IgG1. Areas covered: We discuss the potential role of pharmacogenetics in predicting the response to etanercept in patients with Ps and PsA. Expert opinion: Pharmacogenetics represents the new frontier for the discovery of potential genetic markers of biological response to TNF-\uce\ub1 inhibitors. Clinical studies showed that TNF-\uce\ub1 \ue2\u88\u92308\uc2 G/G, +489 GG and the +489\uc2 GA, TNF-\uce\ub1 \ue2\u88\u92857C (rs1799724), TNFRSF1B 676T (rs1061622), TNFAIP3\uc2 G SNP (rs610604), Fc\uce\ub3RIIIA-V158F, HLA-C*06, IL-17 A (rs2275913 and rs10484879), IL-17F (rs763780) and IL17RA (rs4819554) SNPs favor the response to etanercept. However, most of these studies are often small and not sufficiently powered to detect an effect and markers tend to be more prognostic than predictive of therapeutic response. Furthermore, studies often examines only the effects of a single SNP, while it would be more useful to analyze more haplotypes in contemporary in the same patients. Appropriately designed clinical trials are needed before a pharmacogenetic approach may be applicable in daily clinical therapeutic practice

Immunogenicity of infliximab and adalimumab: What is its role in hypersensitivity and modulation of therapeutic efficacy and safety?

reserved7noIntroduction: TNF-α Inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying antirheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohns disease, ankylosing spondylitis, psoriasis and/or psoriatic arthritis, and may be administered off-label to treat disseminated granuloma annulare systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept.Areas covered: infliximab and adalimumab can induce the development of anti-infliximab (anti-IFX) and anti-adalimumab (anti-ADA) monoclonal antibodies (mAbs). In this review, we discuss the impact of anti-IFX and anti-ADA mAbs upon efficacy and safety of these biological agents.Expert opinion: IgG/IgE neutralizing antibodies against infliximab and adalimumab decrease the possibility of achieving a minimal disease activity state or clinical remission, decrease drug survival, increase the need for doctors to prescribe a higher drug dosage and, finally, favor the occurrence of adverse events. Concomitant administration of DMARDs such as methotrexate or leflunomide prevents the development of neutralizing Abs against infliximab and adalimumab.mixedMurdaca, Giuseppe; Spanò, Francesca; Contatore, Miriam; Guastalla, Andrea; Penza, Elena; Magnani, Ottavia; Puppo, FrancescoMurdaca, Giuseppe; Spano', Francesca; Contatore, Miriam; Guastalla, Andrea; Penza, Elena; Magnani, Ottavia; Puppo, Francesc

Infection risk associated with anti-TNF-α agents: A review

reserved7noIntroduction: TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of chronic immune-mediated diseases. TNF-α inhibitors can be administered either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs (DMARDs) to treat chronic immune-mediated diseases.Areas covered: Patients receiving TNF-α inhibitors are at high risk of infections. Based on our experience, in this paper, we discuss the risk of infections associated with the administration of TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events.Expert opinion: Infliximab more so than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis (LTB) infection and the overall risk of opportunistic infections should be considered before beginning TNF-α inhibitor therapy. A careful medical history, Mantoux test and chest-x-ray should always be performed before prescribing TNF-α inhibitors. Particular attention should be paid to risk factors for Pneumocystis jirovecii infection. Hepatitis B and C virological follow-up should be considered during TNF-α inhibitor treatment. Finally, patients who are at high risk of herpes zoster (HZ) reactivation would benefit from a second vaccination in adulthood when receiving TNF-α inhibitors.mixedMurdaca, Giuseppe; Spanò, Francesca; Contatore, Miriam; Guastalla, Andrea; Penza, Elena; Magnani, Ottavia; Puppo, FrancescoMurdaca, Giuseppe; Spano', Francesca; Contatore, Miriam; Guastalla, Andrea; Penza, Elena; Magnani, Ottavia; Puppo, Francesc