Tocilizumab: A novel humanized anti-interleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic,inflammatory rheumatic diseases

Abstract

Tocilizumab is a highly effective therapeutic agent for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. Furthermore, a large amount of case study data reveals that tocilizumab can be an effective therapy for not only rheumatoid arthritis but also for other mostly rare inflammatory rheumatic diseases. By blocking the interleukin-6 pathway tocilizumab can be a useful therapeutic alternative when conventional treatment fails. It is successful in treating diseases such as the adult-onset Still's disease, amyloidosis, giant cell arteritis, multiple myeloma, polymyalgia rheumatica, relapsing polychondritis, remitting seronegative symmetrical synovitis with pitting edema-syndrome, systemic lupus erythematosus, systemic sclerosis, and Takayasu arteritis. Studies underway are now recruiting patients to acquire further data on treating patients with non-rheumatic arthritis, inflammatory diseases. This review focuses on tocilizumab as a promising agent for treating rare and orphan diseases in rheumatology for which no satisfactory treatment is yet available.     

Autologous haemopoietic stem cell transplantation for autoimmune diseases

Introduction: Autoimmune diseases are signified by complex errors of immune-regulation, and the development of autoreactive T and B cells targeting self-antigens, which eventually can lead to permanent organ damage. Despite novel therapeutic protocols, the disease course is chronic, debilitating and in some instances the outcome is lethal. Previously, stem cell transplantation has been reported to be beneficial in autoimmune animal models, as well as in autoimmune diseases related to hematological abnormalities, which opened potential new avenues in the treatment of human autoimmune diseases.

Areas covered: In this review, the authors describe the compound cellular regulatory effects of autologous hemopoietic stem cell transplantation (ASCT) and also clinical observations, related to the therapy in a variety of organ-specific and systemic autoimmune diseases.

Expert opinion: ASCT has a broad effect on the re-populated immune system, complex regulatory potentials and long term beneficial effect via down-regulating immune-reactivity, yet its widespread use in autoimmune diseases is limited, mostly due to the serious side-effects of the conditioning treatments. However, in certain autoimmune diseases with severe debilitating, or even life-threatening course, including systemic lupus erythematosus, systemic sclerosis or multiple sclerosis, ASCT can be a reasonable choice when conventional therapy has failed.     

Nutrition and the Rheumatic Diseases

Long-term, dietotherapy is particularly important in the management of the rheumatoid diseases since so little is known of their etiology. The chronic character of these conditions, their capricious onset and exacerbations, and their unpredictable remissions can lead the patient to accept dangerous food fads.

Nutritional norms are given for treating nonarticular rheumatism, osteoarthritis, gout, arthritis due to infections, rheumatoid arthritis, rheumatic fever, systemic lupus erythematosus, progressive systemic sclerosis (scleroderma), and polyarteritis nodosa.     

The use of ustekinumab in autoimmune disease

Importance of the field: The advent of biologic therapies has revolutionized the treatment of autoimmune diseases including psoriasis, autoimmune arthritides and inflammatory bowel disease. With recent advances in our understanding of the immunogenetic pathways involved in the pathogenesis of these conditions, newer, more targeted biologic therapies have been developed. Ustekinumab is an antibody to the common p40 subunit of IL-12 and IL-23, which has been studied in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Areas covered in this review: This review details the efficacy and safety of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites.

What the reader will gain: Readers will gain a comprehensive understanding of the mechanism of action of ustekinuamb, its pharmacodynamic and pharmacokinetic profile, and its clinical efficacy and safety in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Take home message: Ustekinumab has shown significant efficacy in the treatment of chronic plaque psoriasis in Phase III studies, and promising results in Phase II studies in psoriatic arthritis. Efficacy has been shown in Crohn's disease only in non-responders to infliximab. Ustekinumab did not show benefit in the treatment of multiple sclerosis.     

Targeting B cells with biologics in systemic lupus erythematosus

Importance of the field: The use of biologics as immune modulators in several autoimmune diseases has provided new tools to the physician's therapeutic armamentiarium and has led to improved patients' outcomes and quality of life. By producing autoantibodies, B cells in systemic lupus erythematosus (SLE) are key players in the pathogenesis of the disease and in its clinical manifestations. Therefore, biologics that target B cells in SLE aim at reducing the activity of these cells for the induction of remissions and/or amelioration of disease activity, reduction of organ involvement, and limitation of the complications and side effects caused by immunosuppressive therapies.

Areas covered in this review: This review describes the past and current clinical trials with B-cell-targeted biologics in SLE, to provide a historical perspective and the state-of-the-art on the topic.

What the reader will gain: We review how the disappointment in the field from promising agents has been instrumental in providing valuable lessons leading to an improved design of new trials that are now giving encouraging results.

Take home message: In systemic lupus erythematosus (SLE), the use of B-cell-based biologics in clinical trials has shown both disappointment and promise.     

The role of Toll-like receptors in immune disorders

Toll-like receptors (TLRs) play an important role in innate immunity. Individual TLRs recognise microbial components that are conserved among pathogens. Such recognition initiates necessary inflammatory immune responses and induces subsequent activation of adaptive immunity. Studies in people with polymorphisms in genes encoding TLR signalling can elucidate the relationship between TLRs and human diseases, such as infectious diseases, atherosclerosis and immunodeficiency. Indeed, accumulating data in respect to TLR signalling suggest that TLRs are closely related with the pathogenesis of autoimmune diseases. This review looks at the role of TLRs in various immune disorders, and discusses the pathogenesis of diseases.     

The role of Toll-like receptors in immune disorders

Toll-like receptors (TLRs) play an important role in innate immunity. Individual TLRs recognise microbial components that are conserved among pathogens. Such recognition initiates necessary inflammatory immune responses and induces subsequent activation of adaptive immunity. Studies in people with polymorphisms in genes encoding TLR signalling can elucidate the relationship between TLRs and human diseases, such as infectious diseases, atherosclerosis and immunodeficiency. Indeed, accumulating data in respect to TLR signalling suggest that TLRs are closely related with the pathogenesis of autoimmune diseases. This review looks at the role of TLRs in various immune disorders, and discusses the pathogenesis of diseases.     

Is there still a role for abatacept in the treatment of lupus?

Introduction: The quest for safer and more effective treatments for systemic lupus erythematosus (SLE) has led to the development of many new biologic therapies. Abatacept is the first drug targeting co-stimulation between T cells and antigen presenting cells, with abundant pre-clinical evidence to support its use in SLE.

Areas covered: This review will present the relevant aspects of lupus pathophysiology pertaining to the mechanism of action of abatacept, a summary of murine studies and the latest human clinical trials.

Expert opinion: Abatacept has demonstrated efficacy in both rheumatoid arthritis and psoriatic arthritis, and earlier studies have suggested tantalising evidence of efficacy in SLE. However, the latest randomised double-blinded study showed disappointingly negative results, much like the case of rituximab in SLE. Currently, abatacept remains a possible therapeutic option as an off-label therapy, and it is a part of our therapeutic armamentarium in difficult cases. The need to find appropriate definitions of response and optimal study design continues to be paramount in the field of lupus therapies.     

Brodalumab-an IL-17RA monoclonal antibody for psoriasis and psoriatic arthritis

Introduction: IL-17 is a growing target for autoimmune and inflammatory diseases. Brodalumab is a fully human anti-IL-17RA monoclonal antibody that has been investigated in a range of disease including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease and asthma.

Areas covered: This review aims to summarize up-to-date pharmacological properties of brodalumab and the clinical efficacy and safety data presented in clinical trials. The focus of this review will be on psoriasis, psoriatic arthritis and rheumatoid arthritis although we will briefly touch on the other indications in which the drug has been studied as we feel it adds to our understanding of the IL-17 pathway and highlights areas where research is still needed.

Expert opinion: Brodalumab has shown good efficacy in psoriasis in small but extended studies with a moderate effect on psoriatic arthritis. Brodalumab studies are clearly negative in rheumatoid arthritis and inflammatory bowel disease. The data are equivocal in asthma; however, further studies in this disease are justifiable. The safety profile of this drug thus far is not worrisome although longer studies in more patients are needed.     

Allogenic bone-marrow-derived mesenchymal stem cells transplantation as a novel therapy for systemic lupus erythematosus

Importance of the field: Bone-marrow-derived mesenchymal stem cells (BMMSC) are multipotent non-hematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases including systemic lupus erythematosus (SLE).

Area covered in this review: Our aim is to discuss recent progress in understanding the role of malfunctioning BMMSC in etiopathogenesis of SLE and to explore allogenic BMMSC transplantation as a potential therapy for SLE.

What the reader will gain: Recent evidence suggests that the functions of BMMSC are disrupted in SLE pathology. This malfunction may result as a corollary of the disease, or may play a more fundamental role in its etiopathogenesis. We provide a brief characterization of BMMSC immunomodulatory effects, and describe our current understanding of the mechanisms by which it plays a part in treating SLE. We also present our clinical trial using allogenic BMMSC in this context.

Take home message: Allogenic BMMSC appear to be a safe therapeutic option for treatment-resistant SLE as illustrated in our clinical trial.     

A comparison of performance on the Keitel Functional Test by persons with systemic sclerosis and rheumatoid arthritis

Purpose: The purpose of this study is to compare lower extremity impairments in persons with systemic sclerosis, rheumatoid arthritis, and healthy controls.

Methods: The participants were a convenience sample of 64 persons with systemic sclerosis, 58 persons with rheumatoid arthritis, and 30 healthy controls. The Keitel Functional Test was used to assess lower extremity joint motion and strength. Demographic information on age, disease duration, employment, and perceived overall health was also collected.

Results: Significant differences were found between the healthy control group and both the systemic sclerosis and rheumatoid arthritis groups in rising from a chair, squatting, walking 30?m, walking up and downstairs, and the total score. For hip external rotation, there were significant differences between all three groups for the right hip; for the left hip, the systemic sclerosis group had significantly less motion than the other two groups. For standing on toes, there was only a significant difference between the systemic sclerosis and the healthy control groups.

Conclusions: Persons with systemic sclerosis and rheumatoid arthritis have similar levels of lower extremity impairments but greater impairments compared to the healthy controls. These impairments may lead to decreased mobility paired with difficulties with activities of daily living such as lower extremity dressing, bathing, and feet care.

• Implications for Rehabilitation

• Persons with systemic sclerosis and rheumatoid arthritis have similar levels of lower extremity impairments but greater impairments compared to the healthy controls.

• Findings from this study indicate a need for rehabilitation for persons with systemic sclerosis and rheumatoid arthritis as the lower extremity impairments may lead to decreased mobility paired with difficulties with daily living activities such as lower extremity dressing, bathing, and feet care.

• The Keitel Functional Test could be used as a quick screening test for lower extremity impairments.

     

Detection of soluble immune complexes by the technique of ADCC inhibition in human diseases

Soluble immune complexes were detected using inhibition of antibody-dependent cell-mediated cytotoxicity (ADCC) in sera of patients with various diseases. Results were positive in 32/41 patients with rheumatoid arthritis (78%), in 27/38 systemic lupus erythematosus patients (71%), in 7/10 cutaneous lupus erythematosus patients (70%), in 6/8 mixed connective tissue disease patients (75%), in 11/26 membranous glomerulonephritis patients (42%), in 6/20 membranoproliferative glomerulonephritis patients (30%) and in 3/12 multiple sclerosis patients (25%). ADCC inhibition was compared with PEG precipitation technique and was found to be more sensitive for detecting soluble immune complexes. Various pitfalls are discussed.     

Pleural fluid complement, complement conversion, and immune complexes in immunologic and nonimmunologic diseases

Forty-four pleural fluids and 41 blood specimens from patients with various diseases were examined for concentration of whole complement, C4, C3, conversion products of C3 and C3PA, and immune complexes. C3 conversion was found in all eight pleural fluids from patients with rheumatoid arthritis, five of seven with lupus erythematosus, two of six with congestive heart failure, and nine of 23 with malignant diseases. Conversion of C3PA correlated closely with C3 conversion and both were significantly inversely related to whole complement, C4, and C3. Concentration of immune complexes was highest in patients with rheumatoid arthritis. Pleural fluid immune complex concentrations correlated positively with conversion of C3 and C3PA. These findings suggest that the reduced levels of pleural fluid complement in rheumatoid arthritis and lupus erythematosus may be secondary to complement conversion by immune complexes.     

siRNA therapy for cancer and non-lethal diseases such as arthritis and osteoporosis

Importance of the field: Gene silencing mediated by siRNA has been widely investigated as a potential therapeutic approach. The success of these therapies depends on effective systems capable of selectively and efficiently conveying siRNA to targeted cells/organs with minimal toxicity.

Areas covered in this review: This review discusses current experimental approaches to siRNA delivery strategies available for arthritis treatment and the management of other musculoskeletal disorders. The review covers literature on the subject from 2000 to 2010.

What the reader will gain: In the last decade, extensive improvements have been made to optimize siRNA-based gene therapy and have been tested on several arthritis and orthopedic conditions. However, except for Phase I – II DNA-based gene therapy trials on arthritis, no clinical studies have reported siRNA application in these domains.

Take home message: Most musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis, fracture, aseptic loosening, cartilage and intervertebral disc degeneration are non-fatal and age-related chronic inflammatory conditions, but represent significant morbidity and a socio-economic burden. siRNA-based gene therapy offers treatment opportunities that are less invasive, more effective and less expensive than existing modalities. Future directions for siRNA therapy include the development of safe and more efficient delivery systems and the selection of optimal gene targets for disease control.     

Golimumab — a new tool in the armoury against inflammatory arthritis

Abstract

The development of biological drugs blocking tumour necrosis factor-alpha (TNF-α) has had a dramatic impact on the treatment of inflammatory arthritis in recent years. Golimumab is a fully human monoclonal antibody which inhibits TNF-α. It is licensed for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this review we evaluate the results of phase III studies using golimumab and explore the place of golimumab in the treatment of these diseases.     

Positioning ustekinumab in moderate-to-severe ulcerative colitis: new kid on the block

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract. Dysregulated innate and adaptive immune pathways contribute to intestinal inflammation in IBD, and cytokines, including IL-12 and IL-23, play a key role. The blockade of both IL-12 and IL-23 may have an impact on different pathways of inflammation and could be effective for the treatment of inflammatory bowel diseases.

Ustekinumab is a fully human IgG1κ monoclonal antibody which binds to the shared p40 protein subunit of IL-12 and ?23. It is currently approved for several immune-mediated diseases such as moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn’s disease, and has shown promising results in UC.

Areas covered: A review of the literature was performed to understand several aspects including the role of IL-12 and ?23 in UC, the potential therapeutic role of ustekinumab in inflammatory bowel disease, and the positioning of ustekinumab in the therapeutic algorithm of UC, based on extrapolated data from available randomized clinical trials.

Expert opinion: Ustekinumab is effective and safe in UC, and shows potential advantages compared to other drugs in moderate-to-severe UC.     

The role of tocilizumab in the management of rheumatoid arthritis

Introduction: The introduction of biological treatments has improved the outlook for patients diagnosed with rheumatoid arthritis. There are now a range of different agents, targeting various pathways involved in the inflammatory process. Tocilizumab, a fully humanised anti-interleukin-6 receptor monoclonal antibody is licensed for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis.

Areas covered: This article reviews and appraises the available evidence regarding the efficacy and safety of tocilizumab in rheumatoid arthritis, as identified in PubMed and Embase searches.

Expert opinion: Clinical trial data suggest that tocilizumab has similar efficacy both clinically and in reducing structural progression to that seen with the TNF inhibitors. Patients who might be particularly suitable for tocilizumab are those who have failed multiple TNF inhibitors, those with a high inflammatory response as part of their disease and those unable to tolerate methotrexate, given the good responses seen with monotherapy.     

Platelets and autoimmunity

Vascular injury is the initial manifestation of inflammation resulting in the recruitment and activation of various cell types. The integrity of the vascular wall is monitored by platelets that become activated in the presence of exposed subendothelium. Besides their well‐established role in haemostasis, ample data are now emerging on the many immunoregulatory functions of platelets. Platelets store and release a large plethora of cytokines, chemokines and growth factors. They also represent the largest circulating pool of many inflammatory mediators like P‐selectin, CD40L and non‐neuronal serotonin. Furthermore, complement activation occurs on the platelet surface and deposition of complement results in platelet activation. Overall, platelets have multiple functions in both innate and adaptive immunity. Further insight into the multifaceted role of platelets could therefore provide important clues into how we could implement current platelet therapy to reduce both platelet‐induced thrombosis and inflammation. In this review, we discuss the current perceptions of platelet involvement in various autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and multiple sclerosis.     

The therapy of autoimmune diseases by anti-interleukin-6 receptor antibody

Interleukin (IL)-6 plays essential roles not only in the immune response, but also in haematopoiesis and the central nervous system. Deregulated production of IL-6 has been found in chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (soJIA), Crohn's disease (CD) and systemic lupus erythematosus (SLE). Furthermore, IL-6 activities can explain many symptoms of these diseases. More importantly, serum levels of IL-6 are correlated with disease activity. Based on these facts, the authors planned to develop a humanized anti-IL-6 receptor antibody, tocilizumab (previously known as MRA), as a therapeutic agent for these inflammatory autoimmune diseases. Tocilizumab is a neutralising antibody to suppress IL-6 signalling mediated by both membranous and soluble IL-6R. Clinical efficacy of tocilizumab in RA, soJIA, adult-onset Still's disease or CD patients has been discussed in this review. In all of these diseases, tocilizumab has improved the disease activity, suggesting that IL-6 plays an essential role in the pathogenesis of these diseases.