Treatment Of Immune-mediated Inflammatory Diseases Research Articles

Anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab.

The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs.

Kinetic Profiles and Management of Hepatitis B Virus Reactivation in Patients With Immune‐Mediated Inflammatory Diseases

Immunosuppressive therapy may trigger hepatitis B virus (HBV) reactivation for increased morbidity and mortality. We aimed to describe HBV reactivation in patients receiving treatment for immune-mediated inflammatory diseases (IMIDs) and to evaluate a predefined algorithm for its prevention. Physicians submitted data for patients receiving treatment for IMIDs and exhibiting HBV reactivation, defined as an increase of >1 log10 IU/ml of HBV DNA levels or DNA reappearance. We systematically reviewed cases in the literature. The 35 physician-collected patients had rheumatoid arthritis (n = 14), connective tissue disease (n = 7), vasculitis (n = 5), and other diseases (n = 9). At baseline, 65.7% of patients were positive for hepatitis B surface antigen (HBsAg), 31.4% had a history of HBV infection, and 2.9% had occult HBV infection. Reactivation occurred a median of 35 weeks (range 2-397 weeks) after the start of corticosteroid and/or immunosuppressive therapy. In all, 88.6% of patients were clinically asymptomatic, but 25.7% had severe hepatitis; none had fulminant hepatitis. Management was antiviral therapy for 91.4%, with discontinuation or decrease of immunosuppressive therapy for 45.7%. In pooling these 35 cases and 103 patients from the literature, 73.9% of patients were clinically asymptomatic, 33.3% had severe hepatitis, and 12.3% died and/or had fulminant hepatitis. Reactivation occurred early with rituximab or cyclophosphamide therapy and in HBsAg-positive/HBV DNA-positive patients. Using the predefined algorithm, 78% of patients with reactivation would have received preemptive antiviral therapy. We provide new insights into HBV reactivation in patients receiving treatment for IMIDs. A predefined algorithm may be effective in reducing the risk of HBV reactivation in this population.

Editorial - Signal Transduction Pathways in Chronic Inflammatory Rheumatic Diseases

Editorial - Signal Transduction Pathways in Chronic Inflammatory Rheumatic Diseases

Anti-TNF-α Agents in the Treatment of Immune-Mediated Inflammatory Diseases: Mechanisms of Action and Pitfalls

TNF-α is a potent inducer of the inflammatory response, a key regulator of innate immunity and plays an important role in the regulation of Th1 immune responses against intracellular bacteria and certain viral infections. However, dysregulated TNF can also contribute to numerous pathological situations. These include immune-mediated inflammatory diseases (IMIDs) including rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and severe chronic plaque psoriasis. Animal and human studies concerning the role of TNF-α in IMIDs have led to the development of a therapy based on TNF blockage. This article focuses first on the potential mechanisms by which the three currently licensed agents, adalimumab, etarnecept and infliximab, decrease the inflammatory activity of patients with different IMIDs. Second, it focuses on the risks, precautions and complications of the use of TNF-α inhibitors in these patients.

Optimizing Use of Tumor Necrosis Factor Inhibitors in the Management of Immune-Mediated Inflammatory Diseases

The introduction of anti-tumor necrosis factor (TNF) therapies has dramatically improved the treatment of immune-mediated inflammatory diseases and provides treatment options for patients who do not respond to conventional disease-modifying antirheumatic drugs. However, the use of anti-TNF therapies still needs to be optimized. Dropoff rates, patients' lack of response, and toxicity are issues that need to be addressed to render these therapies more effective for more patients.

Clinical experience with mycophenolate mofetil in systemic autoimmune conditions refractory to common immunosuppressive therapies.

Standard therapies against inflammatory rheumatic diseases consist of immunosuppressive drugs with high toxicities and many side effects. Except in the treatment of systemic lupus erythematosus with renal involvement, controlled studies with mycophenolate mofetil (MMF) are lacking in other autoimmune and inflammatory systemic diseases. Here we describe our clinical experience with MMF in several unusual indications. We collected data including serological findings, adverse events and response to treatment in eleven patients with autoimmune diseases including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), polymyositis (PM), diffuse systemic sclerosis that were treated in our rheumatology unit. Our results show remission in ten patients with minimal side effects and reduced prednisone dosage. The median dose of MMF was 2 g per day. Adverse events were limited, with one case of leucopenia, one tachycardia and one colitis. One patient definitively stopped the treatment because of side effects. MMF seems to be a very powerful and attractive alternative medication in the treatment of immune-mediated inflammatory diseases. The good tolerance and safety profile makes it an excellent therapeutic option permitting a global reduction of corticosteroids doses.

Clinical experience with mycophenolate mofetil in systemic autoimmune conditions refractory to common immunosuppressive therapies.

Standard therapies against inflammatory rheumatic diseases consist of immunosuppressive drugs with high toxicities and many side effects. Except in the treatment of systemic lupus erythematosus with renal involvement, controlled studies with mycophenolate mofetil (MMF) are lacking in other autoimmune and inflammatory systemic diseases. Here we describe our clinical experience with MMF in several unusual indications. We collected data including serological findings, adverse events and response to treatment in eleven patients with autoimmune diseases including systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), polymyositis (PM), diffuse systemic sclerosis that were treated in our rheumatology unit. Our results show remission in ten patients with minimal side effects and reduced prednisone dosage. The median dose of MMF was 2 g per day. Adverse events were limited, with one case of leucopenia, one tachycardia and one colitis. One patient definitively stopped the treatment because of side effects. MMF seems to be a very powerful and attractive alternative medication in the treatment of immune-mediated inflammatory diseases. The good tolerance and safety profile makes it an excellent therapeutic option permitting a global reduction of corticosteroids doses.

The impact of treatment with tumour necrosis factor-α antagonists on the course of chronic viral infections: a review of the literature

Biologics that antagonize the biological activity of tumour necrosis factor (TNF)-alpha, namely infliximab, etanercept and adalimumab, are increasingly used for treatment of immune-mediated inflammatory diseases, including psoriasis, worldwide. TNF-alpha antagonists are known to increase the risk of reactivation and infection, particularly of infections with intracellular bacteria such as Mycobacterium tuberculosis. More frequently these agents are given to patients with viral infections. Viral hepatitis and human immunodeficiency virus infections are often present in these patients, with a considerable geographical variation. Other concomitant viral infections such as herpes, cytomegalovirus and varicella zoster virus may occur much more frequently than tuberculosis or leprosy. General recommendations about the management related to possible problems associated with anti-TNF-alpha treatment and these viral infections are lacking. This short review will give an overview of the most recent data available on the effects of anti-TNF-alpha therapy on viral infections with a particular focus on patient management and screening recommendations.

α-Melanocyte-Stimulating Hormone and Related Tripeptides: Biochemistry, Antiinflammatory and Protective Effects in Vitro and in Vivo, and Future Perspectives for the Treatment of Immune-Mediated Inflammatory Diseases

Alpha-MSH is a tridecapeptide derived from proopiomelanocortin. Many studies over the last few years have provided evidence that alpha-MSH has potent protective and antiinflammatory effects. These effects can be elicited via centrally expressed melanocortin receptors that orchestrate descending neurogenic antiinflammatory pathways. alpha-MSH can also exert antiinflammatory and protective effects on cells of the immune system and on peripheral nonimmune cell types expressing melanocortin receptors. At the molecular level, alpha-MSH affects various pathways implicated in regulation of inflammation and protection, i.e., nuclear factor-kappaB activation, expression of adhesion molecules and chemokine receptors, production of proinflammatory cytokines and mediators, IL-10 synthesis, T cell proliferation and activity, inflammatory cell migration, expression of antioxidative enzymes, and apoptosis. The antiinflammatory effects of alpha-MSH have been validated in animal models of experimentally induced fever; irritant and allergic contact dermatitis, vasculitis, and fibrosis; ocular, gastrointestinal, brain, and allergic airway inflammation; and arthritis, but also in models of organ injury. One obstacle limiting the use of alpha-MSH in inflammatory disorders is its pigmentary effect. Due to its preserved antiinflammatory effect but lack of pigmentary action, the C-terminal tripeptide of alpha-MSH, KPV, has been delineated as an alternative for antiinflammatory therapy. KdPT, a derivative of KPV corresponding to amino acids 193-195 of IL-1beta, is also emerging as a tripeptide with antiinflammatory effects. The physiochemical properties and expected low costs of production render both agents suitable for the future treatment of immune-mediated inflammatory skin and bowel disease, fibrosis, allergic and inflammatory lung disease, ocular inflammation, and arthritis.

Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1−/− mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1α and 1β) was impaired in DUSP1−/− mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1−/− mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo.