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ABSTRACT
Biologic therapies for autoimmune diseases, which are
targeted at molecules involved in the mechanisms of the immune system, provide an alternative to the existing treatment methods of disease-modifying anti-rheumatic drugs and other immunosuppressive medications. However, the current drawbacks of biologic therapies, including the inconvenience of intravenous administration, the high costs of these drugs, and the adverse events associated with them, prevent their wide use as first-line medications. This review provides an update of the recent literature on the new biologic therapies available. The review concentrates on nine drugs: tocilizumab, rituximab, of atumumab, belimumab, epratuzumab, abatacept, golimumab, certolizumab, and sifalimumab, which are used as therapies for rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, or vasculitis.INTRODUCTION
The use of biologic therapies as an adjunct to disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of autoimmune and rheumatologic diseases is rapidly expanding, owing to the good efficacy and safety profiles of these drugs, and the better understanding of the initial targets of altered immune regulation and activity in various diseases. Targeted therapies such as these are often well tolerated by patients. However, the inconvenience of intravenous (IV) administration, as well as the high costs and adverse events (AEs) associated with these drugs prevent their wide use as first-line medications. The major targets of most biologic therapies are cytokines, B cells, and co-stimulation molecules. Anti-cytokines include anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-1, and anti-IL-6 molecules. B-cell depletion includes use of anti-CD20 antibodies and B cell receptor (BCR) modulation by the B-lymphocyte stimulator (BLyS). Although some of the biologic therapies have been found to be useful in more than one disease, others are specific for a single disease. Research is ongoing to identify other molecular targets.
In this review, we provide an update on some of the new agents that have become available in the past 5 years for clinical treatment of rheumatoid arthritis (RA), spondyloarthropathy, systemic sclerosis (SyS), systemic lupus erythematosus (SLE), and vasculitis.
METHODS
We performed a thorough literature review of all papers in English published in PubMed during the period 1 January 2007 to 30 April 2012. We matched the terms: ‘rheumatoid arthritis’, ‘spondyloarthropathy’, ‘systemic sclerosis’, ‘systemic lupus erythematosus’, and ‘vasculitis’ with the terms ‘biologics’, ‘tocilizumab’, ‘rituximab’, ‘ofatumumab’, ‘belimumab’, ‘epratuzumab’, ‘abatacept’, ‘golimumab’, ‘certolizumab’, and ‘sifalimumab’. Reports of randomized controlled trials (RCTs) and case series were included. Case reports and any reports of biologic therapies that are not yet available for clinical use were excluded. We excluded articles that were in a language other than English.
SCREENING FOR BIOLOGIC TREATMENT
Over a decade has passed since the introduction of biologic therapies for autoimmune diseases. Currently, screening is routine practice prior to administration of these drugs, and is often performed during the initial visits to the outpatient clinic to prevent unnecessary waits for the patient when a biologic is indicated. Screening consists of evaluation for previous or current tuberculosis (TB) infection (based on history, purified protein derivative (PPD) test, chest radiography), serological evidence of hepatitis B and C, history of malignancies or neurological disease. Based on the screening results, the physician will assess which biologic treatment is recommended or if prior treatment is warranted before the initiation of the biologic therapy. The choice of biologic agent for rheumatologic diseases is then tailored to the patient's needs and lifestyle.
TOCILIZUMAB
Mechanism
Tocilizumab (TCZ; trade names Actemra, Roactemra) is a recombinant monoclonal IgG1 anti-human IL-6 receptor (IL-6R) antibody IL-6 binds to either membrane-bound or soluble IL-6R, and this complex in turn binds to the 130 gp signal transducer. This process enhances the inflammatory cascade, inducing angiogenesis and amplifying the activity of adhesion molecules and the activation of osteoclasts. IL-6 is also responsible for activating both T and B helper cells, and is involved in B-cell differentiation, thus by blocking IL-6, the inflammatory response is decreased.
INDICATIONS AND DOSAGE
TCZ is indicated for the treatment of RA following an inadequate response or treatment failure with DMARDs or TNF alpha antagonists (anti-TNF alpha drugs). It is also indicated as first-line therapy for patients with severe systemic juvenile idiopathic arthritis (SJIA) and for Castleman's disease.
The recommended dose of TCZ is 8 mg/kg every 4 weeks. The drug was approved for RA in January 2010 in the USA, but the US recommendations are for a starting dose of 4 mg/kg once every 4 weeks, followed by an increase to 8 mg/kg depending on clinical response. The route of administration is IV, with the dose of 4 to 8 mg/kg IV administered as a single infusion every 4 weeks for RA and 12mg/kg or 8mg/kg IV (depending on body weight) for SJIA. Within an RA population, in Disease Activity Score(DAS) remission rate was 55.3% for patients treated for 5 years on monotherapy .
EFFICACY
A meta-analysis examined published articles on double-blind, randomized, placebo-controlled trials that indirectly compared TCZ with one or more of the following biologics: abatacept, rituximab, or anti-TNF-alpha blockers (etanercept, infliximab, and adalimumab), in patients with inadequate response to DMARDs and/or anti-TNF-alpha blockers. TCZ was non-inferior compared with the other biologic therapies according to the American College of Rheumatology (ACR) criteria for a 20% (ACR20) or 50% (ACR50) improvement, and was superior for a 70% improvement (ACR70). Furthermore, the response to TCZ occurred early, soon after the first infusion.
Monotherapy with TCZ for 52 weeks resulted in significantly reduced radiographic change (total Sharp score) compared with DMARDs. In a 24-week study comparing TCZ and methotrexate (MTX), TCZ was found to be non-inferior to MTX in the first week and superior to MTX in the second week in the intention-to-treat group, as measured by ACR20. Several other studies comparing monotherapy of MTX with that of TCZ have also shown superiority of TCZ. In a study of 1,196 patients with RA who responded partially to MTX, treatment with TCZ led to suppression in radiographic progression and improvement in physical function. Other studies reported response to TCZ in patients with RA who failed to respond to anti-TNF-alpha blockers .
ADVERSE EFFECTS AND SAFETY
Favorable safety results for TCZ were reported for both short-term and long-term treatment of moderate to severe RA. In one meta-analysis, TCZ was well tolerated for more than 2.4 years of treatment, and the AEs were less severe compared with other biologic therapies. In a 24-week study of 286 patients with RA, 66.1% experienced AEs related to the drug, which were mild to moderate and transient. A small number of patients experienced serious AEs, which were predominantly infections.
In a study integrating the three phases of TCZ safety, the AEs were similar to the other treatment groups (DMARDs or anti-TNF-alpha). The most common AEs were infections, mostly of the upper respiratory tract (URTI) and gastrointestinal (GI) tract. More severe AEs included cardiac events, serious infections, solid-organ malignancies, non-melanoma skin tumors, and hematological disturbances. Higher rates of serious infections were related to previous anti-TNF-alpha treatment. The most common infections were pneumonia, gastroenteritis, and urinary-tract infections. Some patients were diagnosed with TB despite being screened before treatment in accordance with the guidelines. Higher doses of TCZ (8mg/kg) were associated with higher risks for infection, but rates were still similar to those encountered with DMARDs or anti-TNF-alpha blockers. GI perforation occurred in 16 patients (predominantly women) exposed to TCZ in the phase III trials, with 11 of them developing diverticuli. Some patients developed a significant increase in liver-function tests, indicating liver dysfunction; a dose reduction was sufficient for the continuation of the study. Only 2.3% of TCZ-exposed patients had to discontinue treatment because of liver abnormalities.There was a reduction in neutrophil count in patients receiving TCZ, which stabilized after 2weeks of therapy. Some patients developed grade 4 neutropenia, but the neutrophil count normalized after discontinuation of therapy.
In other studies of monotherapy with TCZ, the AEs reported were nasopharyngitis, GI symptoms, and infections. There was no difference in the incidence of AEs with TCZ compared with anti- TNF-alpha blockers. TCZ was associated with increases in cholesterol levels and in the ratios of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol, and of total to HDL cholesterol.
In conclusion, TCZ is beneficial and safe for treatment of RA in cases of non-response to anti-TNF-alpha therapy or when anti-TNF-alpha therapy is contraindicated.
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