• DOI:10.1093/rheumatology/ker235
• Corpus ID: 17752222

Developing anti-TNF and biologic agents.

@article{Taylor2011DevelopingAA,
  title={Developing anti-TNF and biologic agents.},
  author={Peter C. Taylor},
  journal={Rheumatology},
  year={2011},
  volume={50 8},
  pages={
          1351-3
        }
}

• P. Taylor
• Published 1 August 2011
• Medicine, Biology
• Rheumatology

We have witnessed unprecedented advances in the past quarter of the century in our understanding of the pathophysiology of RA. Fortunately, for the majority of people presenting with this condition today, the outlook is much better than it would have been for those a generation ago. Many contemporary trainees in rheumatology might listen with incredulity when their senior colleagues describe the nature of outpatient clinics, inpatient work and pharmacotherapeutic approaches that were employed in the management of RA in previous decades. RA still poses a formidable burden on the lives of many people. Moreover, the impact of this condition on the health-care economy is an enormous challenge, compounded by the costliness of protein-based therapies that specifically target molecules relevant to the pathobiology of RA. Evaluating the economic impact of biologic therapies has not been without controversy. There are difficulties in accurately ascertaining the true cost-effectiveness over the course of a condition that persists over a lifetime from presentation. Yet, it is apparent to rheumatologists familiar with biologic approaches in the clinical management of RA that the gain in quality of life, preservation of functional and employment status, clearly evident in many patients, justifies the use of such costly therapies [1]. Although few people would disagree that we in the UK must be wise custodians of a limited health-care budget, the conclusions extrapolated from the everyday experience of rheumatologists are in contrast with the findings of health economic analysis adopted by National Institute for Health and Clinical Excellence (NICE) that, while rigorous, declines to take into account the broader societal implications of biologic use [2]. The biologic era came about as a consequence of two concurrent advances. First, in the 1980s, as appropriate tools and methodologies became available to catalogue cytokines in tissues derived from the rheumatoid joint, a range of known cytokines could be detected; many with pro-inflammatory activity as might be predicted and more surprisingly, some with anti-inflammatory activity. Secondly, rapid advances in protein engineering allowed production of clinical grade antibodies or engineered derivatives specifically targeting molecules relevant to the pathology of RA. The first cytokine to be identified as a potential therapeutic target in RA was TNF in work undertaken at the Kennedy Institute of Rheumatology in the UK. This development was achieved through a series of preclinical studies of the immunobiology of synovial tissue harvested from patients with active disease and preclinical animal model studies [3]. Full validation of TNF as a target came about in the form of clinical trials on human beings, which unequivocally showed significant benefit in most patients treated [4]. Biologic inhibition of TNF, in combination with concomitant MTX, not only improved symptoms and signs of RA in many patients, but perhaps also most dramatically halted the structural damage previously thought to be an inexorably progressive feature of RA [5]. Preservation of functional capability is a consequence of both reduction in disease activity and prevention of joint damage and as such, not surprisingly, the most impressive benefit of biologic TNF inhibitors has been demonstrated when therapy is initiated in the early stages of RA [6 8]. Biologic anti-TNF therapies have set the height of the bar to which all biologics directed at alternative molecular targets have had to aspire to achieve the magnitude of improvement in symptoms and signs, prevention of joint destruction and preservation or improvement in function. TNF is a pleiotropic cytokine with both proinflammatory and immune regulatory functions. The diverse activities are mediated via ligand interaction with two different receptors, TNFRI and TNFRII, which activate separate transduction pathways resulting in distinct biological effects. In RA, the ampliEed and dysregulated production of this cytokine mediates enhanced synovial proliferation, and enhances angiogenesis, production of prostaglandins and metalloproteinases. In this way, TNF plays a major role in tissue destruction in involved joints and may contribute to peri-articular osteoporosis observed early in the course of RA. TNF also regulates other pro-inflammatory cytokines [9]. Despite these efficacy gains in many, but not all, patients, an ever-present concern from the earliest days of biologic anti-TNF therapies was that of target-related toxicity. Certain adverse events were predictable given the knowledge of TNF biology and the highly specific inhibition of the target associated with biologic intervention. These included the risk of infectious complications, particularly concerning intracellular pathogens. Cases of tuberculosis were reported in approximately 1 in 1000 patients treated in the early days of the anti-TNF era, but this rate has significantly reduced by routinely screening patients for a history or evidence of latent TB before initiation of biologic [10]. But there were also other theoretical concerns around tumour surveillance and possible rare complications where the relative risk might be enhanced despite a very small absolute risk, raising the possibility that detectable signals might not be generated