Six biologic therapies are currently approved for the treatment of RA and other chronic inflammatory conditions. Three of them, Humira, Enbrel and Remicade, work in different ways to inhibit an inflammatory cytokine called tumor necrosis factor (TNF). Remicade is used in combination with methotrexate. The fourth, Kineret, blocks the action of another inflammatory cytokine called interleukin-1. The fifth is Orencia, and it is approved for use in patients who have failed prior treatment with disease-modifying anti-rheumatic drugs (DMARDs) or TNF antagonists. Orencia is a T-cell inhibitor, and T-cells are part of the inflammatory process in RA. These drugs can treat symptoms of RA and also slow or prevent damage to joints. The sixth and most recent is Rituxan. This drug is approved for use in combination with methotrexate to reduce signs and symptoms in patients who have failed prior treatment with one of the anti-TNF agents. Rituxan targets certain B cells that are also part of the inflammatory process in RA. There have been serious side effects noted with these therapies, and risks and benefits should be discussed and its use monitored carefully by a physician. The currently available biologic therapies must either be injected under the skin (Enbrel, Humira, and Kineret) or infused through an intravenous infusion (IV) (Remicade, Orencia and Rituxan).
Tumor Necrosis Factor (TNF) Alpha Inhibitors
Remicade, generic name infliximab, is an IV injectable antibody that blocks the effects of tumor necrosis factor alpha (TNF alpha). By blocking the action of TNF-alpha, Remicade reduces the signs and symptoms of inflammation. This anti-TNF drug is classified as one of the BRMs (biologic response modifiers). TNF alpha has been found in the joints of RA patients and in stools of patients with Crohn's disease and correlates with elevated disease activity. Infliximab (Remicade) is supplied as a sterile lyophilized powder for intravenous infusion. Elevated levels of TNF have also been implicated in many inflammatory diseases. Remicade is given under medical supervision and is often prescribed in combination with the DMARD methotrexate.
Enbrel is a genetically engineered protein and represents a class of drugs for the treatment and management of RA. Enbrel binds to TNF, a naturally occurring protein in the body, and inhibits its action. TNF, which promotes inflammation in the body, is found at elevated levels in the fluid surrounding the affected joints of RA patients.
Although many patients with RA respond well to currently available treatments, many are also disabled and suffer severe pain from the disease. It is estimated that RA, an autoimmune disease, affects more than two million Americans, with as many as one third to one half of these people estimated to have moderate to severe RA.
First approved for RA, Enbrel is now approved for five typically chronic inflammatory diseases. Besides RA the inflammatory diseases are polyarticular-course juvenile RA, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.
Humira is a human-derived antibody that binds to human TNF alpha. TNF is naturally produced by the body and is involved with normal inflammatory and immune responses. By working against the inflammatory process, Humira, like other TNF blockers has been shown to be effective in controlling symptoms of the disease.
Cimzia (certolizumab pegol)
Cimzia is the first and only PEGylated Tumor Necrosis Factor alpha antibody (anti-TNFa) indicated for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderate to severe active disease who have an inadequate response to conventional therapy. In May 2009, the FDA approved Cimzia to treat moderately to severely active RA.
Cimzia is administered by subcutaneous injection. The initial dose of CIMZIA is 400 mg given as two subcutaneous injections of 200 mg. For Crohn’s Disease, Cimzia may be administered at 400 mg initially and at weeks two and four. If response occurs, follow with 400 mg every four weeks. For RA, Cimzia may be administered 400 mg initially and at weeks two and four, followed by 200 mg every other week. For maintenance dosing, 400 mg every four weeks may be considered.
Simponi is a human monoclonal antibody that targets and neutralizes excess TNF-alpha. The first once-monthly subcutaneous anti-TNF-alpha therapy, Simponi was FDA approved in May 2009 for the treatment of moderately to severely active RA, active psoriatic arthritis and active ankylosing spondylitis, and is available either through the Simponi SmartJect autoinjector or through a prefilled syringe. Simponi is also being studied as an intravenous infusion therapy for the treatment of RA
T-Cell Costimulation Modulator
Orencia, a selective costimulation modulator, inhibits T-cell activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a co-stimulatory signal necessary for full activation of T lymphocytes, implicated in the pathogenesis of RA. Activated T lymphocytes are found in the synovium of patients with RA.
Rituxan is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. B-cells are believed to play a role in the pathogenesis of RA and associated chronic synovitis. In this setting, B-cells may be acting at multiple sites in the autoimmune/inflammatory process including rheumatoid factor and other autoantibody production, antigen presentation, T cell activation, and/or proinflammatory cytokine production. Rituxan is administered in two 1000 mg IV infusions separated by two weeks. It is given in combination with methotrexate.
The FDA expanded the approved indications for Rituxan in April 2011 to include the treatment of two forms of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, (1) Wegener’s granulomatosis (WG) and (2) microscopic polyangiitis (MPA). Vasculitis is a family of 15+ rare autoimmune diseases that can affect people of all ages, according to the Vasculitis Foundation (VF). WG mostly affects the respiratory tract (sinuses, nose, trachea, and lungs) and kidneys, while MPA commonly affects the kidneys, lungs, nerves, skin, and joints. Both are considered orphan diseases because they each affect less than 200,000 people in the United States.
Stelara is a fully human IgG1κ monoclonal antibody to interleukin (IL)-12/23 produced in a murine myeloma cell line using recombinant DNA technology. Stelara™ is administered by subcutaneous injection for patients:
- Weighing <100 kg (220 lbs) - recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
- Weighing >100 kg (220 lbs) - recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. In subjects weighing >100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects
Stelara reduces the immune systems ability to fight infections. Infections can be caused by viruses, fungi, or bacteria that have spread throughout the body. There may also be an increased risk of developing cancer. In addition, patients being treated with Stelara should not receive live vaccines. BCG vaccines should not be given during treatment with Stelara or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving Stelara because of the potential risk for shedding from the household contact and transmission to patient.
Actemra is a humanized anti-human IL-6 receptor monoclonal antibody that works by competitively blocking the binding of IL-6 to its receptor. Thus, it inhibits the proliferative effects of IL-6, which lead to synovial thickening and pannus formation in RA.
The FDA approved Actemra on January 8th 2010 for adult patients with RA who have failed other approved therapies because of serious safety concerns that were noted in clinical studies. These safety concerns include elevated liver enzymes, elevated Low-density lipoprotein (LDL) or bad cholesterol, hypertension, and gastrointestinal perforations. In April 2011 the FDA approved Actemra for patients two years of age and older with active systemic juvenile idiopathic arthritis (SJIA).
The recommended dose of Actemra for adult patients is once every 4 weeks as a 60-minute single intravenous drip infusion. When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response. Reduction of dose from 8 mg/kg to 4 mg/kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia. Doses exceeding 800 mg per infusion are not recommended.
Actemra for SJIA patients is given once every two weeks as a 60-minute single intravenous drip infusion. The dose is dependent on kilogram of body weight.
Benlysta is a fully human monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), also known as B cell activation factor of the TNF family (BAFF). Benlysta was FDA approved on March 9, 2011 for treatment of systemic lupus erythematosus (SLE). The recommended dosage regimen is 10 mg/kg at 2-week intervals for the first three doses, and at four-week intervals thereafter.
Interleukin 1 Blocker
Kineret is a recombinant, non glycosylated form of the human interleukin-1 receptor antagonist (IR-1Ra). Kineret acts by blocking the biological effects of the chemical messenger IL-1. IL-1 (a protein) is produced by many cells in the body and is found, in increased amounts within joints that are inflamed by RA. IL-1 promotes the inflammation and destruction of cartilage and bone in RA.
Ilaris is an interleukin-B blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPs), in adults and children four years of age and older. CAPS are a group of rare inherited auto-inflammatory conditions. Signs and symptoms include recurrent rash, fever/chills, joint pain, fatigue, and eye pain/redness. In more severe forms, additional symptoms occur, such as deafness, systemic amyloidosis (protein accumulation in tissues and organs, such as the kidneys), significant central nervous system disabilities, including mental retardation/intellectual disability and vision loss, and substantial joint and bone deformities.
The recommended dose of Ilaris is 150 mg for CAPS patients with body weight greater than 40 kg. For CAPS patients with body weight between 15 kg and 40 kg the recommended dose is 2 mg/kg. For children 15 to 40 kg with an inadequated response, the dose can be increased to 3mg/kg. Ilaris is administered every eight weeks as a single dose via subcutaneous injection.
Krystexxa is a PEGylated uric acid specific enzyme indicated for the treatment of chronic gout. Krystexxa achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Krystexxa was FDA approved September 14, 2010, and is indicated for the treatment of chronic gout in adult patient’s who are refractory to conventional therapy.
The recommended dose and regimen of Krystexxa for adult patients is 8 mg (uricase protein) given as an intravenous infusion every two weeks. The optimal treatment duration has not been established.
Amevive is a dimeric fusion protein that consists of the extracellular CD2 binding portion of the human leukocyte function antigen -3 (LFA-3) linked to the Fc portion of IgG1. Amevive interferes with lymphocyte activation by specifically binding to CD2 on lymphocytes thereby inhibiting LFA-3/CD2 interaction. Amevive was FDA approved January 2003 for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.
The recommended dose of Amevive is 7.5 mg given once weekly as an IV bolus, or 15 mg given once weekly as an IM injection. The recommended schedule consists of 12-weekly injections. Retreatment with an additional 12-week schedule may be initiated provided that CD4+ T lymphocyte counts are within the normal range, and a minimum of a 12-week interval has passed since the previous course of treatment. Data on retreatment beyond two cycles are limited.
Special Note Regarding Severity of Psoriasis
The National Psoriasis Foundation Medical Board has described criteria to assist medical professionals in distinguishing between mild, moderate, and severe disease based on body surface area (BSA) and impact on quality of life. Affected BSA has been frequently used to assess disease severity. One percent of BSA is approximately equal to the patients open hand with fingers tucked together and thumb tucked to the side. In clinical trials, severe disease often is commonly defined as more than 10% affected BSA and the FDA has used 20% BSA to indicate severe disease. In 2002, the American Academy of Dermatology published a consensus statement on psoriasis therapies that also used the mild, moderate, and severe criteria to guide treatment plans. In this system, patients with mild disease have limited BSA involvement and may be treated with topical therapies. Although moderate and severe disease categories my overlap, patients with moderate to severe disease generally have greater than 5% affected BSA, and appropriate therapies include phototherapy or systemic therapy.