A short history of biological therapy for psoriatic arthritis.

Psoriatic arthritis (PsA) is an inflammatory disease characterised by the clinical domains of arthritis, enthesitis, dactylitis, spondylitis, and psoriasis, often causing significant functional disability, loss of quality of life, and premature mortality. Prior to the introduction of targeted biologic medications, such as TNF inhibitors, the capacity to control disease activity was limited, with only modest effects noted in most patients with traditional oral medications such as methotrexate and sulfasalazine. The introduction of TNF inhibitors substantially changed the outlook of PsA patients, yielding significant response in all relevant clinical domains and demonstrating the capacity to inhibit progressive structural damage of joints. However, not all patients responded to these agents and many patients displayed initial response which waned over time, partly due to immunogenicity (development of antibodies which blocked full therapeutic effect of the biologic protein), or because of poor tolerability and/or adverse events. Thus, it has been important to develop new medicines which target other key cytokines and immunologic pathways, including ustekinumab which inhibits both IL12 and IL23 and thus is felt to work in both the TH1 and TH7 pathways of inflammation, has been approved for the treatment of PsA as well as psoriasis. IL17 inhibitors, including secukinumab and ixekizumab have demonstrated significant effectiveness in psoriasis and PsA; abatacept, which modulates T cell activity via inhibition the second signal of T cell activation is under study. This article provides an historical overview of this revolution; details of specific biological therapies will be provided in adjacent articles in this supplement.

From inflammation to sickness: historical perspective.

The concept of the four cardinal signs of acute inflammation comes from antiquity as rubor et tumor cum calore et dolore, (redness and swelling with heat and pain) extended later by functio laesa (loss of function). The contemporary understanding of this process we owe to 19th-century milestone discoveries by Rudolph Virchow, Julius Cohnheim and Elie Metchnikoff. In the 20th century, the development of potent technological tools allowed the rapid expansion of knowledge of the cells and mediators of inflammatory processes, as well as the molecular mechanisms of their interactions. It turned out that some mediators of inflammation have both local and distant targets, among them the liver (responding by the production of several acute phase reactants) and neurohormonal centers. In the last decades it has become clear that the immune system shares mediators and their receptors with the neurohormonal system of the body; thus, they form a common homeostatic entity. Such an integrative view, introduced by J. Edwin Blalock, when combined with Hans Selye's concept of stress, led to the contemporary understanding of sickness behavior, defined by Robert Dantzer as a highly organized strategy of the organism to fight infections and to respond to other environmental stressors.