Biologic therapy in clinical practice: enthusiasm must be tempered by caution

R. Moots1,, A. Taggart2 and D. Walker3

1 University of Liverpool Academic Rheumatology Unit, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL,
2 Department of Rheumatology, Musgrave Park Hospital, Belfast BT9 7JB and
3 Freeman Hospital, Freeman Road, Newcastle upon Tyne NE7 7DN, UK

Rheumatoid arthritis (RA) is a major cause of disability and is associated with significant mortality in its own right [15]. The effects of therapy with traditional disease-modifying drugs on outcomes have previously left much to be desired. This is not surprising, given the poor understanding of pathological mechanisms underlying this disease at the molecular and cellular levels. A few years ago, however, seminal basic science work identified the importance of the proinflammatory cytokines tumour necrosis factor {alpha} (TNF-{alpha}) and interleukin 1ß (IL-1ß) in RA. These observations rapidly led to the development of agents that inhibited these cytokines and suppressed disease in RA. Drugs current1y licensed for use in RA that inhibit these inflammatory molecules—etanercept, infliximab (TNF-{alpha}) and anakinra (IL-1ß)—have been shown clearly to be effective in reducing disease activity. Indeed, their success in clinical trials is the more impressive given that they have tended to be used in patients who had previously failed to respond to a number of conventional disease-modifying drugs.

These biological drugs suppress inflammation in RA by inhibiting the activity of the proinflammatory cytokines TNF-{alpha} and IL-1ß. However, such cytokines have not evolved merely to cause RA; they are essential components of physiological homeostasis and the immune system in particular, with important roles in defence against infection and tumours. One can therefore predict that the chronic inhibition of these cytokines, which appears to be required for effective therapy in RA, might result in an increased incidence of infections or tumours in some patients. Indeed, such potential adverse effects have been investigated carefully in the various clinical trials but not found to be a particular problem [69]. Recently, etanercept and infliximab have been subjected to scrutiny by the National Institute for Clinical Excellence (NICE) in the UK. Its appraisal recommended that these drugs could be used in refractory RA [10], following strict guidelines drawn up by the British Society for Rheumatology (BSR) (Table 1Go) [11].


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TABLE 1. BSR guidelines for anti-TNF-{alpha} therapy

 
Before the NICE ruling, experience with biologic therapies in the UK was mostly limited to clinical trials and a few larger centres that were able to gain funding for the treatment of patients in normal clinical practice. The approval by NICE means that the use of these drugs will increase significantly, and this is most welcome. Nevertheless, the more widespread availability of such drugs will have implications for the workload and working practices of those who use them. In our three centres we have a combined experience of treating nearly 250 patients with etanercept or infliximab in normal clinical practice [1214]. We have been impressed by the efficacy of these drugs, but have also become concerned by the occurrence of a number of severe adverse events, particularly infections. Controlled trials have shown no overall increase in the risk of serious sepsis with these agents [69]. Post-marketing surveillance has identified an increased risk of reactivation of tuberculosis in patients taking infliximab and has led to new guidelines to prevent this [15]. However, our experience suggests that infection in general is an even greater cause for concern when these drugs are used in the general patient population. In Merseyside, four out of the first 20 patients treated with biologics required admission to hospital with severe pneumonia—in some circumstances requiring ventilation [16]. In Northern Ireland, four out of 88 adult patients on biologic therapy developed serious infection requiring hospitalization and two of these patients died [13]. In Newcastle, four of the first 38 patients developed serious infections. Two of these were elderly patients with comorbidities who developed recurrent infections and ultimately died.

Our experience is not unique, but reflects that of a number of other centres throughout the world [1721]. However, one of the striking features we have noted is the rapidity of the onset of the infection, something that has not been observed by others.

Whilst anecdotal reports such as these should not be ignored, we must be careful not to ascribe adverse events to a particular cause without adequate evidence. Association does not necessarily mean causation. The increased risk of infection in RA [22, 23] and its association with premature death are well documented [15]. Many of the candidates for biologic therapy are already taking corticosteroids and other immunosuppressives, both of which add to this risk [24]. Serious infections are also associated with increased disability and comorbidity [25], the very features that one might expect to see in candidates for biologic therapy. Apart from this, the close scrutiny of these patients is likely to draw attention to adverse events that might otherwise go unnoticed.

Long-term safety data about new drug therapies may be gathered from a number of sources, but each has its own inherent biases and weaknesses. Controlled clinical trials provide a comprehensive data set, but trial patients are not always typical of those who receive these drugs in the real world. Case series and anecdotal reports may help to draw attention to important clinical issues but they do not provide an accurate estimate of the relative risk of a particular adverse effect. Case–control studies (such as those being conducted by the BSR) comparing patients on conventional therapies with those on biologic agents should provide useful information over and above the systematic reporting to national bodies such as the BSR Biologics Registry. All of these sources provide complementary information that will ultimately enable us to put our individual clinical experiences into proper perspective. However, it will take several years to yield meaningful results. Whatever the conclusion of this ongoing pharmacovigilance, there seems little doubt that the risk of infection is an important safety issue in patients who are candidates for biologic therapy.

Our clinical experience has taught us that the administration of biologic therapies requires significant resources beyond the costs of the drugs themselves. Training and education of medical, nursing and pharmacy staff requires time and money. Strictly, these drugs do not require regular blood testing, as for conventional disease-modifying anti-inflammatory drugs, but the safety monitoring is much more intensive because patients must be taught about the potential risks before and during treatment and are more likely to require urgent clinical assessment over and above the obligations to provide response data for the Biologics Registry. In our units, prior to NICE guidance, we had already committed research nursing staff to some of these tasks. This may not be possible in smaller units. Despite warnings, some patients have been reluctant to discontinue their treatment temporarily during intercurrent infection, because of a fear that their joint symptoms will return. Patient education is therefore an ongoing process and not just a single intervention at the start of treatment. In addition, continued surveillance for possible infections is crucial. Patients receiving biologics should have ready access to professional advice 24 h a day, and preferably from the centre prescribing and administering their treatment. All of this will require additional resources in many centres.

Many patients will fulfil the BSR guidelines for biologic therapy, but not all will be ideal candidates for such treatment. The onus on us is to maximize patient safety through careful patient selection, education and safety monitoring. We also have an obligation to register all our patients with our national Biologics Registry and to systematically report any significant adverse events to regulatory bodies, such as the Committee on the Safety of Medicines. These standards are a minimum requirement for any unit that intends to administer biologic therapy for severe inflammatory arthritis. If they cannot be attained, then the treatment should be administered in a centre that can cope adequately, so as not to deprive patients of the opportunity for such therapy.

Biologic therapy is an important advance in the treatment of severe inflammatory arthritis. The NICE guidance on the use of etanercept and infliximab for RA [10] has been an important breakthrough and allows some of the worst-affected patients throughout the UK to benefit from these drugs. It is vital that the small but significant number of severe adverse events, particularly infections, should not tarnish their image inappropriately. As their use spreads in normal clinical practice, it is essential to remember that safe and effective administration requires adequate resources, over and above the cost of the drug alone, to allow the selection and monitoring of patients to be as safe as possible.

Notes

Correspondence to: R. J. Moots. E-mail: rjmoots{at}liv.ac.uk Back

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