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Editorials

New roles for thalidomide

BMJ 1996; 313 doi: https://doi.org/10.1136/bmj.313.7054.377 (Published 17 August 1996) Cite this as: BMJ 1996;313:377
  1. R J Powell, Consultant clinical immunologist
  1. Clinical Immunology Unit, Directorate of Medicine, University Hospital, Nottingham NG7 2UHs

    <it>A unique anti-inflammatory, but use it only when no alternatives exist</it>

    Thalidomide was synthesised in 1954 at Chemie Grunenthal, Germany. Four years later it was marketed as a sedative. It was considered a particularly safe drug, as even massive doses (up to 10 000 mg/kg) failed to kill laboratory rodents. Recognition in 1960 of its neuropathic potential, and in 1961 of its devastating teratogenic effects, led to the product licence being revoked in many countries, including Britain. However, use has continued in many countries around the world, and in Britain on the “named patient” basis. A clinical guideline for its safe use has been published.1

    No single mechanism has been identified which could account for all the clinical effects of thalidomide. It is an anti-inflammatory, immunomodulant drug, not an immunosuppressant. It acts on phagocytic cells and endothelial cells but has no direct effect on T lymphocytes. Specifically it modulates blood monocyte cytokine synthesis, particularly tumour necrosis factor (alpha) (TNF(alpha)), in vitro and in vivo. Intravital microscopy has recently shown that the induction of adhesiveness in post capillary venules by lipopolysaccharide is also modulated by thalidomide. Data from in vivo studies in humans have also shown altered leucocyte phenotypic expression, but in vitro evidence is lacking, suggesting that in vivo redistribution of leucocyte antigens may account for such observations. Therefore thalidomide acts by interfering with patterns of leucocyte migration and modulating tumour necrosis factor (alpha). These are likely to be separate functions.

    The astute clinical observations of Sheskin in 1964 eventually led to thalidomide being proved effective in over 90% of type II leprosy reactions (erythema nodosum leprosum).2 This accounts for most of its current use worldwide. Thalidomide has no direct activity against mycobacteria, but a trial organised by the World Health Organisation in four countries established its superiority over aspirin in erythema nodosum leprosum.3

    The beneficial effects on erythema nodosum leprosum led to the use of thalidomide in morphologically similar immunopathological conditions—those based on inflammation of post-capillary venules, such as severe mucocutaneous ulceration. Major aphthae involving mouth, oesophagus, genitals, and anus can occur in isolation, as part of Behcet's disease, or in HIV infection. Thalidomide produces considerable clinical benefit in these ulcers, for which there are few therapeutic alternatives. In an uncontrolled series of 59 patients with intractable severe orogenital ulceration (unrelated to HIV infection), 81% had complete resolution of ulcers within one month at a dose of 200 mg at night.4 Similar benefit in HIV related mucocutaneous ulcers (culture negative for herpes virus and fungi) has also been established.5 Thalidomide does not inhibit HIV viral replication, but may have a role in reversing HIV associated cachexia.

    Thalidomide has no apparent effect on allograft rejection but has beneficial effects particularly in chronic graft versus host disease.6 In a large series of patients with chronic graft versus host disease who were unresponsive to corticosteroids and cyclosporin A, sustained improvement occurred in 20%, but side effects led to stopping treatment in 36% who were treated with thalidomide.7

    Various dermatological conditions including discoid lupus erythematosus, prurigo nodularis, actinic prurigo, erythema multiforme, pyoderma gangrenosum, ulcerative colitis, rheumatoid arthritis, and post-herpetic neuralgia are all reported to respond to thalidomide. Use in these conditions has been reviewed8 but must be balanced against the availability of effective alternatives and major side effects notable with thalidomide. The risk of thalidomide induced axonal neuropathy in prurigo nodularis approaches 100%.

    Uncontrolled formation of new blood vessels (angiogenesis) is a feature of malignancy and diabetic retinopathy. Thalidomide has been reported to inhibit angiogenesis, possibly through modulation of tumour necrosis factor alpha. However, two uncontrolled clinical trials failed to show any benefit from treating patients who had advanced solid tumours with thalidomide,9 10 and recently an experimental rat model suggested that thalidomide treatment could result in an increase in metastasis.11 Studies of thalidomide in people with proliferative retinopathy are awaited, but animal studies have shown no benefit.

    A clinical guideline for the use of thalidomide emphasises the need for adequate contraception. It also emphasises the need for regular monitoring, before and during treatment, of the amplitudes of sensory nerve action potentials, in an attempt to predict the onset of the painful peripheral neuropathy.1 Preventing neuropathic symptoms is essential as they can be irreversible.

    Thalidomide is a unique anti-inflammatory and immunomodulant whose clinical role is expanding. But it has major side effects—more than 10 000 children were affected by its teratogenic potential between 1959 and 1961—and consequently its uncontrolled use worldwide is rightly condemned. It is paramount that the medical profession and the pharmaceutical industry ensure that thalidomide is used responsibly—that is, only in those conditions for which satisfactory therapeutic alternatives are not available.

    Reference

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