Working things out on the basis of mechanism and logic

Many physicians base clinical decisions on an understanding of the aetiology and patho-physiology of disease and logic.10,11 This paradigm is problematic because the accepted hypothesis for the aetiology and pathogenesis of disease changes over time, and so the logically deduced treatments change too. For example, in the past 20 years, hypotheses about the aetiology of psoriasis have shifted from a disorder of keratinocyte proliferation and homeostasis, to abnormal signalling of cyclic AMP, to aberrant arachidonic acid metabolism, to aberrant vitamin D metabolism, to the current favourite: a T-cell-mediated autoimmune disease. Each of these hypotheses led to logically deduced treatments. The efficacy of many of these treatments has been substantiated by rigorous RCTs, whereas other treatments are used even in the absence of systematically collected observations. We thus have many options for treating patients with severe psoriasis (for example UVB, Goeckerman treatment, psoralen-UVA, methotrexate, ciclosporin and anti-interleukin-2 receptor antibodies) and mild-to-moderate psoriasis (for example dithranol, topical corticosteroids, calcipotriol and tazarotene). However, we do not know which is best, in what order they should be used, or in what combinations. We do not know how well methotrexate works (no well-designed clinical trials of methotrexate have been performed) or the optimal dose or dosing schedule for it.6,10

Treatments based on logical deduction from pathophysiology can have unexpected consequences. For example, the observation that antiarrhythmic drugs could prevent abnormal ventricular depolarisation after myocardial infarction logically led to their use to prevent sudden death after myocardial infarction. However, RCTs showed increased mortality in patients treated with antiarrhythmic drugs compared with placebo.12,13 This highlights the dangers of using surrogate outcome measures, such as electrocardiograms, for more meaningful outcomes such as disability or death, simply because the surrogate measurements are easily made. The challenge with surrogate outcome measures is to ensure that they measure important things rather than trying to make measurable things important.

Some "designer" drugs such as topical tazarotene were promoted on the basis of their molecular mechanisms of action and may have appeared attractive at launch, but have been less exciting when tested in practice.5 It might also be argued that the frequent narration of the superantigen story as a mechanism for antistaphylococcal treatments for atopic eczema is a smoke screen that obscures the real lack or uncertainty of evidence of clear benefit for such agents.5

Given these lessons, many dermatologists have become less interested in how treatments work and are now daring to ask questions such as: "Does it work?" and "How well does it work compared with existing, more established treatments?".

Natural Treatments For Psoriasis

Natural Treatments For Psoriasis

Do You Suffer From the Itching and Scaling of Psoriasis? Or the Chronic Agony of Psoriatic Arthritis? If so you are not ALONE! A whopping three percent of the world’s populations suffer from either condition! An incredible 56 million working hours are lost every year by psoriasis sufferers according to the National Psoriasis Foundation.

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