Rheumatoid Arthritis. Module III

Transcription

1 Rheumatoid Arthritis Module III Management: Biological disease modifying anti-rheumatic drugs, glucocorticoids and special situations (pregnancy & lactation) Dr Ved Chaturvedi MD, DM Senior Consultant Rheumatologist, Army Medical Corps President, Indian Rheumatology Association Dr Vinod Ravindran MD, FRCP Assistant Professor of Rheumatology MES Medical College, Perinthalmanna, Kerala Dr Molly Thabah MD Assistant Professor of Medicine JIPMER, Puduchrery 1

2 BIOLOGIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS Since the late 1990s, increasing emphasis has been placed on the use of biologic agents combined with small molecule agents such as MTX. These combinations have proved effective in the treatment of patients with severe or long-standing disease and have proved their ability to slow or prevent radiographic progression of disease. As a class, the most effective of biologic approaches to date has been the combination of TNF antagonists (e.g., adalimumab, etanercept, and infliximab) with MTX. In refractory disease, the addition of adalimumab, etanercept, or infliximab to MTX treatment provides additional benefit to patients with persistent active disease. With all three of the available TNF inhibitors, trials have shown that more than 50% to 70% of the patients had at least a 20% response, and more than 40% of patients had a 50% improvement, as measured by the ACR criteria. Although each of the cohorts studied in these trials was slightly different, no significant side effects were apparent in the combination arms above and beyond what was seen in the MTX-only arms of the studies, suggesting a good safety profile and strong benefit-to-risk ratio when put into perspective with the relative severity of the disease. Beyond the TNF inhibitors, there are increasing data that biologic agents such as abatacept and RTX can work effectively even in patients who have failed TNF inhibitors, continuing to provide disease control in patients with the most refractory disease. INHIBITION BY TUMOR NECROSIS FACTORS The TNF-α has a pivotal role in initiation and perpetuation of the inflammatory and proliferative processes of rheumatoid synovitis. As a class, the TNF inhibitors (adalimumab, etanercept, and infliximab) seem to be one of the most effective means of improving symptoms and signs of disease, increasing function, and reducing structural progression of RA. In the absence of truly useful biomarkers or surrogates to distinguish patients likely to respond to therapy from patients who would not respond, it is reasonable to suggest that most patients should be treated with MTX before advancing to a TNF inhibitor. Should a patient fail to achieve a significant response to MTX over a few months, however, switching the patient to a TNF inhibitor as monotherapy or adding a TNF inhibitor and treating in combination with background DMARDs should be considered. 2

3 Etanercept Etanercept was the first TNF-α inhibitor to be approved by the U.S. Food and Drug Administration (FDA) for use in RA. It is a fusion protein of the soluble portion of the human TNF p75 chain of the receptor and the fragment crystallizable (Fc) portion of human IgG1. The receptor portion binds extracellular TNF-α, effectively neutralizing it, and the Fc moiety prolongs its circulating half-life. This drug is administered as a subcutaneous injection of 25 mg twice weekly or a single 50-mg injection once a week. Infliximab Infliximab is a chimeric monoclonal antibody against TNF. It was the second anti-tnf agent approved for use by the FDA in treatment of RA and had previously been approved for use in Crohn's disease. Most of the antibody is human; however, a small portion of the Fab region is murine in origin. The antibody is given via intravenous infusions of 3 to 10 mg/kg. The recommended dosing regimen is 3 mg/kg with infusions at weeks 0, 2, and 6, and every 8 weeks thereafter. If patients fail to achieve a significant benefit, the dose can be increased, or the dosing interval can be shortened. For pharmacokinetic and pharmacoeconomic reasons, it may be more desirable to shorten the dosing interval rather than to increase the dose. Concomitant administration of MTX gives more sustained benefit, may reduce the clearance of the drug, and possibly may lead to less immunogenicity, reflected by a reduction in human antichimeric antibody formation. Whether concomitant use of other small molecules affords the same advantage is unknown, but plausible. Adalimumab Adalimumab is the third biologic agent directed against TNF for the treatment of RA. Adalimumab is a fully human monoclonal antibody directed against TNF and is delivered as a subcutaneous injection once every other week, or, in patients with insufficient response, it can be given once a week. Use of background MTX with this agent also seems to increase the duration of response, possibly by slowing the clearance of the drug. As was shown with etanercept and infliximab, adalimumab showed significant benefits when combined with MTX. Adverse events with anti-tnf therapy Serious Infections (Excluding Tuberculosis) 3

4 When TNF inhibitors were first introduced in the late 1990s, there was concern that blocking TNF might impair the host defense system. Clinicians have since been reassured that, in general, there have not been significant problems with serious bacterial infections for most patients treated with TNF inhibitors. Occasional patients taking etanercept, infliximab, or adalimumab have developed serious bacterial infections or opportunistic infection, however. Predicting which patients will develop an infection is almost impossible. A degree of vigilance and the recognition that infections can occur should be part of all treatment initiation and monitoring efforts. In addition, it is apparent that in debilitated patients (e.g., patients with infections such as skin ulcers or pneumonia or patients with other illnesses that would increase the risk of infection or diminished immune surveillance) TNF inhibition should be used with caution. Tuberculosis Reactivation of tuberculosis has been reported with all the TNF inhibitors. There seem to be more reports with infliximab than with etanercept or adalimumab. Researchers are unclear as to whether these differences are related to differing mechanism of action, structure, pharmacokinetics, route of administration, or the patient populations studied. Given the potential for reactivation of tuberculosis, appropriate screening should be done before the initiation of treatment with a TNF inhibitor. Malignancies RA conveys an increased risk for the development of lymphoproliferative disease. The development of lymphoma has been reported with each of the TNF inhibitors. It is unclear, however, whether this development is related to the medication itself or the underlying disease. Demyelination Rare cases of multiple sclerosis, optic neuritis, and demyelination have been reported in patients taking TNF inhibitors. These cases have been sporadic and seem mostly to resolve when the TNF inhibitor is withdrawn. Because demyelination is a rare occurrence in the population at large, it is unclear whether these events are occurring more often than expected. It is recommended that TNF inhibition be avoided in patients with a history of demyelinating illness or who have features of unique neurologic problems. Congestive Heart Failure In patients with known congestive heart failure, TNF inhibitors should be used with caution because they may worsen cardiac function. 4

5 IL-1 antagonist IL-1, similar to TNF-α, has been implicated in the pathogenesis of RA. It is produced by rheumatoid synovium and other tissues, predominantly by macrophages. There is, however, a circulating protein found in extracellular tissues, IL-1 receptor antagonist, which is a biologically important protein that functions as a naturally occurring antagonist to IL-1. A recombinant human form, anakinra, has been developed. It is given as a daily subcutaneous injection of 100 mg. Generally, anakinra has been shown to be safe and well tolerated. The most frequent side effect has been injection site reactions, which occur in more than 50% of the patients who take this medication. Although mild and self-limited, this side effect can be very uncomfortable. Anakinra is an infrequently used agent for the treatment of RA and is often reserved for patients who have failed other agents or may be inappropriate candidates for TNF inhibition. This restriction of use is partially related to its cost, the need for daily subcutaneous injections, and the perception of being less effective as a therapeutic biologic compound than are the TNF inhibitors. Abatacept Abatacept is a soluble, recombinant fusion protein that is composed of the extracellular domain of cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and the modified Fc portion of IgG1. It seems to be effective in the treatment of RA by selectively modulating the CD80 or CD86/CD28 costimulatory signal required for full T cell activation. T cells normally require two signals for full activation. The first signal is the antigen expressed in the context of the major histocompatibility complex (MHC) binding to the T cell receptor. The second signal is a costimulatory signal. One important costimulatory pathway is the engagement of CD80/CD86 on the surface of an antigen-presenting cell with CD28 on the T cell, facilitating T cell activation. In the normal sequence of events, the naturally occurring inhibitory molecule CTLA-4 is induced on the surface of the T cell downregulating the CD28-mediated T cell activation. CTLA-4 has a markedly greater affinity for CD80 or CD86 than does CD28, out-competing CD28 for CD80 or CD86 binding. Abatacept, similar to CTLA-4, competes with CD28 for CD80 and CD86 binding and can be used to modulate T cell activation selectively. 5

6 Clinical trials have shown the efficacy of abatacept in the treatment of RA. Abatacept is administered as a 30-minute infusion days 1, 15, and 30, and monthly thereafter. Rituximab RTX is a chimeric monoclonal antibody targeting CD20 + B cells. Clinical trials using RTX have shown efficacy and safety in treating RA and have provided further evidence for the role of B cells in the pathogenesis of the disease. CD20 is a target for B cell depleting therapy because it is uniformly expressed on B cells, but not on stem cells or plasma cells. By binding CD20, RTX depletes peripheral B cells through several postulated mechanisms, including cell-mediated and complement-dependent cytotoxicity and promotion of apoptosis. GLUCOCORTICOIDS Glucocorticoids (GCs); also called corticosteroids or more loosely, steroids are used widely in the management of RA (BOX 1). In some situations there timely usage could be life saving. However their indiscriminate usage could lead to several undesirable side effects. Some of the common side effects of steroid usages are weight gain, facial odema, easy bruising, glaucoma, cataracts, hypertension, diabetes, atherosclerosis, psychosis, infections, delayed wound healing. The adverse effects of steroid therapy therefore should be considered and discussed with the patient before the therapy is started. Initial dose, dose reduction and long-term dosing depend on the underlying rheumatic disease, disease activity, risk factors and individual responsiveness of the patient. When it is decided to start steroid treatment, comorbidities and risk factors for adverse effects should be evaluated and treated where indicated; these include hypertension, diabetes, peptic ulcer, recent fractures, and presence of cataract or glaucoma, presence of (chronic) infections, dyslipidaemia and co-medication with non-steroidal anti-inflammatory drugs. For prolonged treatment, the steroid dosage should be kept to a minimum. During treatment, patients should be monitored for body weight, blood pressure, peripheral oedema, cardiac insufficiency, serum lipids, blood and/or urine glucose and ocular pressure depending on individual patient s risk, GC dose and duration. 6

7 MEDICINES USE FOR RA DURING PREGANANCY AND LACTATION As several rheumatic diseases affect the women of child bearing age group pregnancy and lactation poses special challenges. When treating women of childbearing age with chronic medications, it is imperative that the potential effects of medication use on the developing foetus are considered, whether a future pregnancy is planned or an unanticipated pregnancy is discovered. The goals of treatment are to control maternal disease activity while simultaneously maximizing the potential for a safe and successful outcome for the foetus. Methotreaxate should be discontinued at least 3 months prior to conception. If a woman treated with leflunomide wants to become pregnant, the medication should be stopped and cholestyramine should be administered in order to rapidly decrease the blood levels to the acceptable level. Hydroxycholoquine, azathioprine, steroids and sulphasalazine are some drugs which can be used safely when trying to conceive. Sulfasalazine use can lead to reduced fertility in men owing to oligospermia and reduced sperm motility. Fortunately, this is not an irreversible event; spermatogenesis should return to normal approximately 2 months after cessation of the drug. Men wishing to conceive a child with a partner should be counselled to discontinue the medication 3 months prior to conception. Table 1 lists safety of commonly used drugs for RA in pregnancy and lactation. When counselling women with autoimmune diseases regarding medication use during pregnancy, it is important to balance the potential adverse effects of medication use with the potential adverse effects of untreated, active disease during pregnancy. 7

8 Box 1: Indications for the possible use of glucocorticoids in RA Bridge therapy for patients who have experienced a severe functional decline with limitations interfering with necessary daily living or vocational activities. Patients with NSAID contraindication who have acute inflammation unlikely to respond rapidly enough to second line agents. Rheumatoid vasculitis or other serious life threatening or organ damaging manifestation. Men or women not at reduced risk of bone loss, for whom GCs may be reasonable in combination therapy regimens with a single daily dose of less than 7.5mg/day. Pregnant or lactating women with active RA. 8

9 Table 1: Safety of drugs used in rheumatology in pregnancy and lactation Drugs Safe in pregnancy Safe in lactation Paracetamol Yes Yes NSAIDS Yes (until 32 weeks) Yes COX-II inhibitors No Not known Steroids* Yes Yes Hydroxychlolroquine Yes Yes Sulphasalazine Yes Yes Methotrexate No No Leflunomide No No Azathoprine Yes Yes Calcium and vitamin D Yes Yes Bisphosphonates No No *Prednisolone, methyprednisolone, dexamahasone, betamethasone- all to be used in the lowest possible doses. 9