Anakinra

Anakinra (Kineret) is the first biologic drug that has been developed specifically as an interleukin (IL)-1 receptor antagonist (Ra) and is derived from an endogenous IL-1Ra. The drug blocks the activity of IL-1 in synovial joints, reducing the inflammatory and joint destructive processes associated with rheumatoid arthritis (RA). In randomized, placebo-controlled trials of up to 52 weeks' duration, anakinra has shown efficacy both as monotherapy and in combination with other disease-modifying antirheumatic drugs (DMARDs) in adults with RA. It is subcutaneously administered and is generally well tolerated. Anakinra offers a useful addition to the range of drugs available for the treatment of RA.     

A scientific update on biosimilar infliximab (CT-P13) in rheumatic diseases

The development of biologic drugs has undoubtedly enhanced the spectrum of treatments available for immune-mediated inflammatory rheumatic diseases such as rheumatoid arthritis. However, despite their clear clinical benifits, use of biologics is often hindered by their high costs. The manufacture and subsequent approval of more cost-effective ‘biosimilar’ versions of these drugs may address this issue and improve patient access. CT-P13 (Remsima^®, Inflectra^®), a biosimilar of infliximab (Remicade^®), has shown comparable efficacy, safety and pharmacokinetics to its originator drug in clinical studies. The articles in this supplement present a scientific update on the development and use of biosimilars in rheumatic disorders, with specific focus on CT-P13. The information discussed highlights the predicted positive clinical and economic impact of biosimilars on the management of rheumatic diseases.     

Leflunomide in the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic and highly morbid disease affecting approximately 1% of the world’s population. With the advent of disease-modifying antirheumatic drugs, patients are increasingly able to maintain control of their arthritis and prevent joint destruction. However, not all patients respond adequately to any single disease-modifying antirheumatic drug, and many newer parenteral therapies are cost prohibitive. Leflunomide, an inhibitor of pyrimidine biosynthesis, is the first oral disease-modifying antirheumatic drug to have been approved for rheumatoid arthritis in the USA in the last 15 years, and is now widely used in over 70 countries around the world. Leflunomide is efficacious when used as monotherapy or in combination with methotrexate to treat patients with rheumatoid arthritis, and is generally well tolerated. As clinical use increases, new ways to use leflunomide in order to minimize toxicity and maximize efficacy are being explored.     

Certolizumab pegol: a new biologic targeting rheumatoid arthritis

The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis. This is mostly due to targeted biologic agents that have changed the outcome of this disease. Certolizumab pegol (Cimzia^®, UCB Inc., GA, USA), which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn’s disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy. This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease-modifying antirheumatic drugs and other biologic agents. Treatment recommendations are beyond the scope of this review; however, with many options available, there will be annotations on current trends in the care of this chronic disease.     

Certolizumab pegol: a new biologic targeting rheumatoid arthritis

The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis. This is mostly due to targeted biologic agents that have changed the outcome of this disease. Certolizumab pegol (Cimzia(?), UCB Inc., GA, USA), which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn's disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy. This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease-modifying antirheumatic drugs and other biologic agents. Treatment recommendations are beyond the scope of this review; however, with many options available, there will be annotations on current trends in the care of this chronic disease.     

Risks and Benefits of Low-Dosage Cyclosporin in Rheumatoid Arthritis

The effects of cyclosporin on the activity of rheumatoid arthritis have mainly been investigated in patients with active, refractory, long-standing disease. The data obtained in these trials suggest that cyclosporin is not only a symptomatic treatment for rheumatoid arthritis but can also be considered a disease-modifying antirheumatic drug (DMARD), since it seems to be capable of slowing the progression of cartilage and bone damage due to rheumatoid arthritis. The trials conducted so far have led to a better understanding of cyclosporin toxicity and, therefore, to better monitoring of patients in order to avoid it. The reasons for studying the role of cyclosporin in patients with early, active and potentially severe rheumatoid arthritis are the poor prognosis of the disease despite the use of the presently available DMARDs, and the hypothesis that the drug is more efficacious and better tolerated in early rheumatoid arthritis. A new classification of antirheumatic drugs proposes that disease-controlling antirheumatic therapies decrease inflammatory synovitis and prevent structural joint damage or significantly reduce its rate of progression. However, few existing drugs meet these criteria. The 12-month results of a disease-controlling antirheumatic therapy clinical trial with a blinded radiological end-point, named GRISAR (Gruppo Reumatologi Italiani Studio Artrite Reumatoide) comparing cyclosporin with conventional DMARDs in patients with early rheumatoid arthritis provide strong evidence that cyclosporin offers better control of ongoing joint damage than do conventional DMARDs.     

Severe pancytopenia after leflunomide in rheumatoid arthritis

Leflunomide is a novel drug recently introduced for treatment of rheumatoid arthritis as a DMARD (disease-modifying antirheumatic drug). So far, leflunomide has not been associated with severe bone marrow toxicity and pancytopenia. We report of a 62-year-old woman with a 14-year history of rheumatoid arthritis with bone marrow toxicity and reversible pancytopenia developing after treatment with leflunomide.     

Biosimilars for the management of rheumatoid arthritis: economic considerations

Biologic drugs have proved highly effective for the treatment of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA). These drugs are often considered cost-effective for well-defined RA patient populations not responding adequately to conventional treatment, but are used first-line relatively rarely, partly due to high costs. Furthermore, not all clinically eligible patients can access biologics even as second-line therapy. Recently, there has been a rise in interest in ‘biosimilar’ drugs that are highly comparable to the ‘reference medicinal product’ (RMP) in terms of efficacy and safety but may generally be lower in price. This review summarizes the cost burden of RA and considers the potential role of biosimilars in reducing drug costs and increasing patient access to biologics.     

A new CHO (Chinese hamster ovary)-derived cell line expressing anti-TNFα monoclonal antibody with biosimilar potential

Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that mediates the homeostasis of immune responses; its exacerbated production is associated with the pathogenesis of autoimmune and chronic inflammatory diseases. Anti-TNFα drugs have revolutionized the treatment of inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. Currently, a worldwide race is on stage for the production of biosimilars moved by patent expiration of monoclonal antibodies (mAbs), such as anti-TNFα adalimumab. Our goal was to develop the first stage of an adalimumab biosimilar candidate with potential for national production, through the generation of a productive and stable cell line and assess its functionality. The robotic system ClonePix was used for screening and isolation of colonies from transfected CHO-S stable pools plated in semisolid medium. Selected clones were expanded based on growth and productivity. Purified mAbs from different clones were tested for binding and functional activity. The binding affinity of the denominated adabut clones to TNFα and FcRγ did not differ statistically when compared to reference adalimumab. One functional activity assay demonstrated the antibody neutralization capacity of the cytotoxicity induced by TNFα in L929 murine fibroblasts. A second assay confirmed adabut as an antagonist of the TNFα activity by the inhibition of the cell adhesion molecule expression in HUVEC cultures. The binding and functional activity analyses performed with selected adabut clones in comparison to reference adalimumab represent an important status of “non-inferiority,” part of the process required for a biosimilar development. We generated and selected high-quality adabut clones which mAbs may be further developed as the first in-house made Brazilian biosimilar, demonstrating a success case for our incipient biotechnology industry, or also modified as biobetters, thus representing an innovative strategy for the patients’ welfare.     

Tocilizumab for the treatment of rheumatoid arthritis

Tocilizumab is a humanized anti-human IL-6 receptor antibody that specifically inhibits the biological activity of IL-6 by competitively inhibiting the binding of IL-6 to the IL-6 receptor. Clinical trials have shown that tocilizumab 8 mg/kg administered by monthly infusion not only improves clinical signs and symptoms of refractory rheumatoid arthritis but also suppresses radiographic progression. In regard to safety, the most common adverse event was nonsevere infection, such as nasopharyngitis, although the incident rate of adverse events was slightly higher than that of disease-modifying antirheumatic drug treatment. Studies have shown that there is no specific infection or prolongation of infection related to tocilizumab treatment. Tocilizumab is a promising therapeutic agent with statisfactory efficacy and safety for rheumatoid arthritis.     

Scientific rationale behind the development and approval of biosimilar infliximab (CT-P13) in Europe

Biosimilars are drugs developed to be highly similar to their originator biologic (or ‘reference medicinal product’) with no clinically meaningful differences in purity, efficacy or safety. Production of biologics and biosimilars is highly complex and sensitive, with any change in manufacturing process having a potential impact on efficacy and safety. This review provides an overview of the manufacturing process for these drugs and considers the implications of any process changes. The scientific rationale underlying the regulatory comparability exercise for process-changed reference medicinal products and biosimilars is also discussed, as is the issue of ‘switchability’ from a reference medicinal product to its biosimilar. CT-P13 (Remsima^®, Inflectra^®), a biosimilar of infliximab, is used as a case study to discuss these issues.     

Discussion: DMARDs and biologic therapies in the management of inflammatory joint diseases

Therapy for inflammatory joint diseases, such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis, includes various conventional disease-modifying antirheumatic drugs (DMARDs). These therapeutic agents are termed DMARDs because they have the potential to reduce or prevent joint damage and preserve joint integrity and function. Conventional DMARDs are used as monotherapy or in combination and include methotrexate, leflunomide, azathioprine, ciclosporin, hydroxychloroquine, sulfasalazine, gold and minocycline. Biologic response modifiers, which are based on proteins made by living cells, are newer agents available for the treatment of various inflammatory joint diseases. Biologic therapies now approved for use in inflammatory joint diseases are TNF inhibitors, T-cell modulators and B-cell depleters. They have all been shown to have clinical efficacy and are able to retard structural damage. However, all current immune-modulating therapies also have potential side effects, and the decision to use a particular agent for treatment should be based on a thorough discussion of the benefits and risks with the patient. Newer biologic response modifiers and other immunologic therapies are currently being developed for the treatment of inflammatory joint diseases and are discussed in this review.     

Immunologic laboratory testing in clinical practice for rheumatoid arthritis

The recent clinical practices for rheumatoid arthritis have changed greatly. First, biologic agents such as tumor necrosis factor blocker have been developed as well as disease-modifying antirheumatic drugs, with great efficacy in intractable RA. On the other hand, the importance of early effective therapeutic intervention has been recognized since early treatment prevents the progression of joint damage. However, early diagnosis of RA is not so easy because of the lack of appropriate diagnostic criteria. New laboratory tests have appeared for the diagnosis and prognostic prediction of RA. Among them, anticyclic citrullinated peptide antibodies (anti-CCP), which bind epitopes containing citrulline, seem to be attracting the most attention. Although rheumatoid factor (RF) is the only serologic marker among the seven classification criteria of the American College of Rheumatology (ACR) for RA, variability of the RF assay within laboratories and/or between laboratories, and quality assurance has not been established. We must address the standardization of RF assay as soon as possible.     

Iguratimod for the treatment of rheumatoid arthritis in Japan

Iguratimod (IGU), a small-molecule compound, was developed as a disease-modifying antirheumatic drug in Japan. The pharmacological studies showed that inhibition of the production of cytokines and immunoglobulins mainly contributes to its improvement effect on animal arthritis models. The first clinical study of IGU in Japanese patients with rheumatoid arthritis was started in 1992 and Phase III studies were started in 1998. From the results of Phase II studies, a dose-escalating regimen was recommended to relieve the side effects. In a double-blind study comparing the efficacy and safety of the drug with those of placebo and salazosulfapyridine, it was confirmed that IGU was superior to placebo and was not inferior to salazosulfapyridine. Furthermore, a double-blind controlled trial of IGU in combination with methotrexate revealed an efficacious and manageable safety profile. IGU would be widely used as a new option for rheumatoid arthritis treatment and combination drug with methotrexate.     

Similar Names for Similar Biologics

Approval of the first biosimilar in the USA may occur by the end of 2014, yet a naming approach for biosimilars has not been determined. Biosimilars are highly similar to their biologic reference product but are not identical to it, because of their structural complexity and variations in manufacturing processes among companies. There is a need for a naming approach that can distinguish a biosimilar from its reference product and other biosimilars and ensure accurate tracing of adverse events (AEs) to the administered product. In contrast, generic small-molecule drugs are identical to their reference product and, therefore, share the same nonproprietary name. Clinical trials required to demonstrate biosimilarity for approval may not detect rare AEs or those occurring after prolonged use, and the incidence of such events may differ between a biosimilar and its reference product. The need for precise biologic identification is further underscored by the possibility of biosimilar interchangeability, a US designation that will allow substitution without prescriber intervention. For several biologics, the US Food and Drug Administration (FDA) has used a naming approach that adds a prefix to a common root nonproprietary name, enabling healthcare providers to distinguish between products, avoid medication errors, and facilitate pharmacovigilance. We recommend that the FDA implement a biosimilars naming policy that likewise would add a distinguishable prefix or suffix to the root nonproprietary name of the reference product. This approach would ensure that a biosimilar could be distinguished from its reference product and other biosimilars in patient records and pharmacovigilance databases/reports, facilitating accurate attribution of AEs.     

Treatment with etanercept for patients with juvenile rheumatoid arthritis in Taiwan--a preliminary report.

Tumor necrosis factor (TNF) is a major inflammatory cytokine involved in the pathogenesis of juvenile rheumatoid arthritis (JRA). Etanercept, approved in the United States and in Europe for use in patients with rheumatoid arthritis (RA) and JRA, is an effective inhibitor of TNF that has been shown to provide rapid and sustained improvement in both diseases. Here we report the preliminary results of etanercept use in 3 cases of JRA with poor response to traditional therapy including non-steroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs. Two of the patients had polyarticular JRA and 1 had systemic JRA. Etanercept was administered at a dosage of 0.4 mg/kg (maximum 25 mg) subcutaneously twice a week. Clinical as well as inflammatory parameter improvement was noted after use of etanercept in all cases. The preliminary results of etanercept use in these 3 cases showed significant clinical benefit without obvious adverse effects.     

Felty’s Syndrome

Felty's syndrome is a complication of rheumatoid arthritis whereby patients develop neutropenia of varying severity. Although the main clinical concern is the development of serious infections, often patients remain asymptomatic or continue with clinical problems related to the rheumatoid arthritis and not to the neutropenia. There is now considerable clinical experience with the use of the recombinant human haemopoietic growth factors granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) in the treatment of patients with Felty's syndrome. The only indication for the use of either growth factor for Felty's syndrome is the onset of infectious complications, which may be recurrent and serious. In general, when this occurs, the neutropenia is severe (<10(8) cells/L). The mechanism(s) underlying development of the neutropenia in Felty's syndrome is similar to that in other forms of immune-mediated neutropenia, and in general is associated with a terminal defect in neutrophil maturation. It is likely that the maturational defect is a consequence of ;immune based' inhibition, although we lack detailed understanding of this inhibitory process. Growth factor therapy does not relieve the defect in terminal maturation, but in general may induce a significant improvement in the peripheral white cell count. Instances where growth factor therapy does not work appear to be due to an inability to overcome the maturational defect. Thus, the level of granulopoietic inhibition mediated by the rheumatoid process varies in severity among patients. To date, treatment options for Felty's syndrome have included disease-modifying antirheumatic drugs, corticosteroids and splenectomy. The addition of growth factor therapy is a welcome addition to these less than optimal treatment options. However, all of the above therapies fail on occasion. Moreover, the dosage and frequency of growth factors must be titrated to keep the white blood cell count <5 x 10(9) cells/L, since overshoot may result in complications, the most common being exacerbation of the rheumatoid arthritis. Another mechanism by which these drugs may exacerbate rheumatoid arthritis is through activation of neutrophils. The addition of disease-modifying drugs may relieve the maturational defect, improve the peripheral white cell count and minimise disease exacerbation by limiting neutrophil exposure to the administered haemopoietic growth factor. However, long term monotherapy with G-CSF has been successfully employed without requiring disease-modifying therapy.     

Adalimumab

Adalimumab (Humira) is a recombinant, fully human IgG1 monoclonal antibody that binds specifically to tumor necrosis factor (TNF)-alpha, thereby neutralizing the activity of the cytokine. Subcutaneous adalimumab has been investigated in well designed trials in patients with active rheumatoid arthritis despite treatment with disease-modifying antirheumatic drugs (DMARDs). Patients receiving adalimumab 40mg every other week in combination with methotrexate (Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab [ARMADA] and DE019 trials) or standard antirheumatic therapy (Safety Trial of Adalimumab in Rheumatoid Arthritis [STAR] trial) for 24-52 weeks had significantly higher American College of Rheumatology (ACR) 20, ACR50, and ACR70 response rates than patients receiving placebo plus methotrexate or standard antirheumatic therapy. In ARMADA, an ACR20 response was achieved in 25%, 52%, and 67% of adalimumab plus methotrexate recipients at weeks 1, 4, and 24, respectively. In ARMADA and DE019, improvements in the individual components of the ACR response were significantly greater with adalimumab 40mg every other week plus methotrexate than with placebo plus methotrexate. Monotherapy with adalimumab 40mg every other week was associated with significantly higher ACR20, ACR50, and ACR70 response rates than placebo, as well as significantly greater improvements in the individual components of the ACR response.ACR responses were sustained with adalimumab according to the results of extension studies in which patients received adalimumab in combination with methotrexate (up to 30 months) or as monotherapy (up to 5 years). In both concomitant therapy and monotherapy trials, adalimumab was associated with significantly greater improvements from baseline in health-related quality of life (HR-QOL) measures than placebo; adalimumab also retarded the radiographic progression of structural joint damage to a significant extent compared with placebo. Adalimumab was generally well tolerated as both concomitant therapy and monotherapy. In ARMADA, there were no significant differences between adalimumab and placebo (in combination with methotrexate) in the incidence of adverse events; however, in STAR, the incidence of injection site reactions, rash, and back pain was significantly higher with adalimumab than with placebo (in combination with standard antirheumatic therapy). No cases of tuberculosis were reported in either trial.In conclusion, subcutaneous adalimumab in combination with methotrexate or standard antirheumatic therapy, or as monotherapy, is effective in the treatment of adults with active rheumatoid arthritis who have had an inadequate response to DMARDs. Adalimumab has a rapid onset of action and sustained efficacy. The drug also retards the progression of structural joint damage, improves HR-QOL, and is generally well tolerated. Thus, adalimumab is a valuable new option for the treatment of DMARD-refractory adult rheumatoid arthritis.     

Rheumatoid arthritis is the major risk factor for septic arthritis in rheumatological settings

Septic arthritis (SA) is a clinical emergency with considerable morbidity and mortality that can lead to rapid joint destruction and irreversible functional loss. The reported incidence varies from 2-5 cases/100,000 person-years in the general population to 70 cases/100,000 person-years among patients with rheumatoid arthritis. In fact, individuals with rheumatoid arthritis are at particular risk for developing SA. This may be due to several reasons: joint disease predisposes to bacterial joint colonization and RA itself and its treatment with corticosteroids, disease-modifying antirheumatic drugs (DMARDs) and biological therapies may decrease the immune function required for protection from pathogens. Steroids and DMARDs seem to affect the leukocyte synovial count; indeed, RA patients with SA have a leukocyte count in synovial fluid (SF) lower than patients with SA without underlying rheumatic diseases. The diagnosis of SA in RA patients can be difficult because the development of a hot painful joint is often confused with a relapse of the underlying joint disease leading to delay in diagnosis. For this reason the microscopic analysis and culture of synovial fluid are crucial to exclude septic arthritis.