Thalidomide in dermatology: revisited.

The use of thalidomide in relation to dermatology is well- known and enough data is available in the literature about various aspects of thalidomide. Despite being an interesting and useful drug for many dermatoses, it is associated with many health hazards including the birth defects, phocomelia. We hereby present a comprehensive review about thalidomide and its application in dermatology.

What was known?

Thalidomide has been found to have profound beneficial effect singly and as adjuvant therapeutic agent in a variety of dermatoses, but its use is reserved because of many, often serious adverse effects.

History

The synthesis of thalidomide was first started in 1953 by Swiss pharmaceutical firm CIBA, and research/development on it continued by German company Chemie Grunenthal, which synthesized and marketed the drug in 1954 under the name Contergan. It was initially promoted for the treatment of irritability, concentration deficit, stage fright, anxiety, depression, hypothyroidism, and mainly as a hypnotic agent. Later more pharmaceutical companies marketed thalidomide in many countries.[1] Widulind Lenz, a pediatric geneticist reported an association between thalidomide and escalating cases of phocomelia in 1961, leading to subsequent withdrawal of the drug from the market.[2] Thereafter, it remained only as a research product for trial in various dermatological and oncologic conditions. Later, it was found effective for refractory erythema nodosum leprosum (ENL) by Sheskin and granted approval for use by the US Food and Drug Administration (FDA).

Structure of Thalidomide

Thalidomide is a synthetic derivative of glutamic acid with one chiral center and consists of a glutarimide ring and a pthalidimide ring.[3] The pthalidimide ring is thought to be responsible for the teratogenic effects whereas the glutarimide ring, which is structurally similar to other sedatives, mediates sedation. Its international union of pure and applied chemistry (IUPAC) name is (2-[2,6-dioxo-3piperidyl] isoindoline-1, 3 dione) and chemical formula C13H10N2O4, having a molecular mass 258.23g/mol3. The molecular structure is shown in Figure 1.

Figure 1

Molecular structure of thalidomide

It exists as optically active R (+) and S (−) enantiomers, which interconvert rapidly in vivo and also as an optically inactive racemic mixture. S-isomer of thalidomide is associated with the teratogenic effects and R-isomer, devoid of teratogenic properties, is responsible for sedative effects.[4] New analogues with improved activity and less adverse effects have been discovered.[45]

Pharmacokinetics and metabolism

Being insoluble in ethanol and water, no parenteral preparation is available. Thalidomide is absorbed slowly after oral administration; peak levels in the blood are reached in 2-6 h.[6] Administration with a high-fat meal can delay absorption by approximately 2 h.[6] The half-life of thalidomide in humans is approximately 10 h and total body clearance is about 10 L/h. The drug distributes extensively throughout the body fluids and tissues, with higher concentrations in skin and kidneys. It is lipid soluble and crosses the placental barrier easily. The major route of elimination is still undetermined, and it is metabolized mostly by non-enzymatic hydrolytic cleavage.[7] Because thalidomide is not primarily metabolized by cytochrome P450 enzyme system, it is unlikely to interact with drugs metabolized by this enzyme.[8] Some of the drug is excreted in bile, whereas less than 1% is excreted in urine.

Mechanism of Action

The exact mechanism of action of thalidomide has not been clearly delineated; possible effects hypothesised are;

Anti-inflammatory and immune-modulator effects

Most of the biological effects of thalidomide are related to its anti-inflammatory, immune-modulator and anti-angiogenic properties.[910111213] Its anti-inflammatory property involves the dose dependent inhibition of chemotaxis of lymphocytes and neutrophils, and inhibition of phagocytosis by neutrophils and macrophages through modulation of cytokines without cyto-toxicity.[9101112] The drug selectively inhibits tumor necrosis factor (TNF)-α by enhancing the degradation of TNF-α messenger ribonucleic acid (RNA), and also interferon-gamma (IFN-γ). Thalidomide has been shown to decrease the number of T-helper and increase the number of T-suppressor cells, thus decreasing the T-helper (CD4) to T-suppressor (CD8) cell ratio.

Anticancer effects

Invitro research has revealed that thalidomide has a cyto-static activity on cultured HeLa cells[14] and on chick embryo blood cells,[15] suggesting the anti-tumour effect of thalidomide and some of its congeners,[16] along with anti-emetic activity in patients receiving chemotherapy for cancer.[17] Anti-cancer activity of thalidomide also appears to be related to its anti-angiogenic properties via inhibition of vascular endothelial growth factor.[13]

Hypnos-sedative action

The hypnotic/sedative action of thalidomide and its congeners most likely is mediated by the glutarimide ring substituted in the 3-position with a non-specific space-filling group,[18] Such configuration exists in a number of sedative hypnotic drugs, including glutethimide, leading to activation of sleep centre in the forebrain,[18] and therefore does not cause respiratory depression, in-coordination, or hangovers, unlike other sedatives.

Other effects

It down regulates expression of cellular adhesion molecules and class-II major histocompatibility index antigens and also has an inhibitory effect on prostaglandins E2 and F2, histamine, serotonin, and acetylcholine.[11]

Dermatological Uses

Thalidomide has been successfully used on a number of diseases, as described below.

ENL/type II leprosy reaction

Sheskin first reported the dramatic response of ENL to thalidomide in 1965,[19] which is the only US FDA approved indication for thalidomide. Type II leprosy reaction is an immune complex mediated response characterised by systemic features and elevated levels of TNF-α and IFN-γ[6] which is inhibited by thalidomide, making it very effective for the treatment of ENL. Response rates for thalidomide have been greater than 90%, with improvement seen within days and complete resolution within 2 weeks.[20] Because of fewer adverse effects, thalidomide is preferred over corticosteroids for monotherapy. Combination therapy with steroids permits dose reduction of the later.[21] An average daily dose of 100 mg has been found to be effective, although higher initial dose of 400 mg daily and maintenance with 50-100 mg daily have also been tried. Some of the systemic symptoms or signs may take longer to improve.[20]

Aphtous stomatitis

Beneficial effect of thalidomide in mucocutaneous apththae and apthous stomatitis has been demonstrated in various studies,[2223] because of its anti-chemotaxis effect.[824] Thalidomide is also beneficial for human immunodeficiency virus (HIV) associated aphthous ulcers, though less effective in lower intermittent doses for preventing recurrence. Aphthous ulcers often heal of own and thalidomide should be reserved only for the most severe or recalcitrant cases of oro-genital ulceration.[25]

Behçet syndrome

Thalidomide has been used for Behçet disease, resulting in marked and rapid healing of oro-genital lesions, with milder and shorter recurrences, but little effect on ocular lesions and arthritis.[672627] Thalidomide was given at 400 mg daily for the first 5 days, followed by 200 mg daily for the next 15-60 days.

Nodular prurigo

Prurigo nodularis, a distressing pruritic neuro-dermatitis with frequent relapses and protracted course,[28] may be treated effectively with thalidomide in addition to/or as an alternative to other available treatment options,[2930] with 100-300 mg daily dose. This results from its direct action on the proliferation of nervous tissue in nodular prurigo. It has also been found effective in HIV-positive patients with prurigo nodularis.[31]

Actinic prurigo

Varying results have been obtained in different studies while using thalidomide for actinic prurigo, with clinical improvement occurring over 2 weeks to 2 months,[3233] as 50-200 mg daily dosage, with a maintenance dose of 50-100 mg weekly.[33]

Graft versus host disease

Studies in animal models and clinical trials have shown that thalidomide appears to be a safe and effective treatment for acute and chronic form of GVHD,[3435] although results have been inconsistent.[36] It may be especially useful in cases refractory to treatment with prednisone and cyclosporine.[37] It may act at an early stage in the antigen recognition pathway in down-regulating the lymphocyte response in GVHD. Efficacy of thalidomide as a prophylactic agent in the prevention of chronic GVHD following allogenic bone-marrow transplantation is not clear,[38] and many side effects like severe cutaneous ulceration, skin rashes, and neutropenia have been reported when thalidomide has been used to treat chronic GVHD.[39] The treatment group actually developed chronic GVHD more often than the placebo group.[38]

Discoid lupus erythematosus

Varying degrees of response have been noted with thalidomide in DLE in various studies.[4041] A dose of 400 mg/day and maintenance dosage of 25-50 mg/day is recommended to prevent relapse.[40] The proposed mechanism of thalidomide in lupus erythematosus involves stabilization of lysosomal membranes, inhibition of hydroxyl and superoxide free radical production by neutrophils, inhibition of the synthesis of Immunoglobulin M and its subsequent deposition on the basement membrane, or suppression of neutrophil chemotaxis and macrophage phagocytosis.[424344]

Systemic lupus erythematosus

Thalidomide may be used effectively as a reserve and adjuvant drug for SLE, especially for cutaneous manifestations and for cases non-responsive to conventional treatments.[43444546]

It has been shown to stimulate hair re-growth in patients with SLE-induced alopecia and improve the articular manifestation.[9]

Sarcoidosis

Thalidomide may be used as alternative, reserve drug for chronic cases of cutaneous sarcoidosis resistant to conventional therapy, as it inhibits IFN-γ, TNF-α, interleukin (IL)-12 and increases IL-2 which counteracts the effects of IFN-γ and TNF-α. There is a reduction in granuloma size and epidermal thickness after treatment.[474849]

Pyoderma gangrenosum

Multiple case studies suggest that thalidomide can be useful when other treatments have failed or the diseases is refractory, although prolonged treatment is desired to prevent relapses.[5051]

Jessner's lymphocytic infiltrate

Thalidomide has shown good to excellent response for Jessner-Kanof lymphocytic infiltration of the skin, with 100 mg daily dose.[5253] It should be considered in cases with prior inconsistent or negative response to chloroquine. Maintenance dose of 25-50 mg daily for more than 2 years may be needed.[52]

Adult Langerhans cell histiocytosis (histiocytosisX)

Thalidomide has been demonstrated to be effective for the cutaneous lesions of langerhans cell histiocytosis using 300 mg daily with less chances of relapses,[54] but little or no effect on the visceral features of the condition.[55565758] This is because of the effect on proliferative Langerhans cell population, as demonstrated by diminished histiocyte infiltration in histopathological examination.[55]

Toxic epidermal necrolysis

The pathogenesis of toxic epidermal necrolysis involves increased levels of TNF-α, and thalidomide being an inhibitor of TNF-α, may be considered for this condition.[59] The beneficial effect, however, is controversial as the use of thalidomide may stimulate T cells invivo, thereby worsening the condition because T-cell activation occurs in toxic epidermal necrolysis (TEN).[59] So thalidomide should not be routinely used to treat TEN.

Lichen planus

Studies have demonstrated that thalidomide in a dose range of 50-150 mg daily produced a regression of the oral lichen planus lesions and recalcitrant lichen planopilaris.[6061] Higher doses (300 mg daily) or prolonged treatment period of 1-3 years may be required for refractory generalized and oral lichen planus,[62] to prevent recurrence.[6063]

Kaposi's sarcoma

Thalidomide has a potential role in acquired immunodeficiency syndrome (AIDS) relatedKS,[64] in a dose range from 100 mg daily up to 1000 mg in an escalating fashion,[6566] with a decrease in Human herpes virus 8 deoxyribonucleic acidload.[65] Overall response rate ranged from 17% to 40%.[65]

Uremic pruritus

Cases of refractory uraemic pruritus, especially those with less severe symptoms, are likely to respond to thalidomide because of its interference with various inflammatory mediators.[67]

Rheumatoid arthritis

Limited efficacy has been noted with thalidomide for use in rheumatoid arthritis because of its effects on TNF-α, which is deregulated in rheumatoid arthritis,[68] with poor benefit to risk ratio.[69]

Post herpetic neuralgia

Treatment with thalidomide is effective, but associated with recurrences after stopping it.[70]

Erythema multiforme

Thalidomide may be used as an adjuvant/alternative drug for recalcitrant, refractory cases of EM with good results.[71] Maintenance schedule further decreases the chances of relapses.[72]

Waldenströms macroglobulinaemia

Studies have revealed the efficacy of thalidomide in this condition, with the overall response rate of around 25%.[73]

Malignant melanoma

Beneficial effect of thalidomide as a single agent for melanoma is limited. But because of its anti-angiogenic property, it may have a potential cytostatic role in advanced metastatic melanoma.[74]

Pemphigoid disorders

Thalidomide may be used for difficult to treat cases of pemphigoid especially cicatricial variety, when other treatment options cannot be used, or have failed.[75]

HIV infections

Thalidomide has been found to improve appetite, wasting and physical well-being in AIDS and also improve the lesions of KS.[65] It has proven very effective in the treatment of debilitating oro-pharyngeal, oesophageal, rectal, genital, perianal ulcers, especially associated with HIV infection.[7677] It is a useful adjunct therapy, especially when steroids are contraindicated or proven ineffective.

Brachioradial pruritus

Some studies have shown the beneficial effects of thalidomide in this condition.[78]

Scleromyxoedema

Treatment with thalidomide in recalcitrant scleromyxoedema associated with paraproteinemia shows recognizable improvement of the skin lesions, joint mobility and reduction in paraprotein levels.[798081]

Polymorphic light eruption

Use of thalidomide gives satisfactory results in such conditions as polymorphic light eruption and other photo-dermatoses.[828384]

Oral precancerous conditions and cancer

Use of thalidomide for oral cancers, especially those arising secondary to other diseases such as oral lichen planus, DLE, may be promising.[85] More studies and clinical trials are desired in this regard.

Sjögren's syndrome

Because of various immunological effects, thalidomide may benefit Sjögren's syndrome, with decreased expression of cellular receptors HLA-DR, tumor necrosis factor receptorI, CXCRI, and CXCRII.[86]

Other conditions

Beneficial effects of thalidomide for many other conditions has either been proven or presumed in various studies. Notable among these are: Refractory necrobiosis lipoidica, type 1 cryoglobulinemic vasculopathy, mycosis fungoides, palmoplantar pustulosis, small vessel vasculitis like Wegeners granulomatosis, leishmaniasis cutanea recidivans, cold hemagglutinin disease, immune complex vasculitis, cutaneous lymphoid hyperplasia, porphyria cutanea tarda, epidermolysis bullosa pruriginosa, Weber-Christian disease, cutaneous Rosai-Dorfman disease, refractory vulval ulcerations associated with Crohn disease, cancer cachexia, tuberculosis associated wasting, neuropathic pain, perforating folliculitis, Schnitzler syndrome.[108788899091929394]

Palliative therapy

Thalidomide seems to be a potential palliative medication for other diseases and symptom complex because of such effects as sedative, antiemetic, antipyretic, anti-cachetic and potentially analgesic effects.[95] These effects may be based on selective suppression of immune mediators such as IL-6 and TNF-α. These properties have been realised in the treatment of cachexia and painful mucocutaneous ulcers in AIDS, painful subcutaneous nodules in leprosy, Behcet disease, to mention a few.

Dosage

Dosage schedule depends on the type of disease where thalidomide is used.

Adult dosage varies from 50 to 100 mg/day in some conditions to 400-1000 mg/day in others.

Dosage in children ranges from 3 to 9.5 mg/kg/day.

Adverse effects

Teratogenicity with thalidomide, preventable with appropriate precautions, has been the most feared concern. The serious foetal malformations include: Absence of the ears; deafness; absence, or hypoplasia of the arms (phocomelia) preferentially affecting the radius and the thumb; defects of the tibia and femur; cardiac, bowel, uterine, gallbladder malformations; ingrown genitalia. Other adverse effects are shown in Table 1.

Table 1

Side effect profile of thalidomide

Drug interactions

As thalidomide is not primarily metabolized by cytochrome p450 pathway, there are less chances of interaction with other drugs. Thalidomide should be used cautiously with alcohol and other sedatives, viz, barbiturates, chlorpromazine, reserpine, etc., as it potentiates and augments their effect.[11]

Contraindications

The absolute contraindications for thalidomide include sensitivity to the drug, pregnancy and existing severe peripheral neuropathy. Caution is also advised in those with hepatic dysfunction, renal dysfunction, neurological disorders, gastrointestinal dysfunction, hypertension, and hypothyroidism.[1196]

General considerations

Extreme caution should be exercised while prescribing thalidomide in view of the disaster in the past and vigilant monitoring is necessary. The following considerations need a mention.[1197]

Advice before starting therapy

A written, informed consent must be obtained and patient must be explained in detail about the adverse effects and that they must not share the drug with anyone else. Females must follow two methods of contraception, a barrier method along with another highly effective method, starting 1 month before the start of thalidomide and up to 1 month after the end of treatment. As effects of thalidomide on spermatogenesis is not clearly known, male patients too must be advised to use a barrier contraceptive methods at the start of therapy and up to 1 month after the end of therapy.[11] Blood donation during the period of treatment is discouraged.

Evaluation before starting therapy

Before starting treatment, complete clinical examination especially neurological examination should be performed. Besides routine investigations, some specific ones like baseline pregnancy test, complete blood count with an absolute neutrophil count, HIV RNA, electromyography (EMG) or nerve conduction velocity (NCV) study should be conducted.[11]

Follow up and monitoring

While on treatment, pregnancy is ruled out by repeating pregnancy tests initially at weekly intervals for 1 month and then monthly thereafter. Detailed neurological testing is repeated monthly for 3 months and then every 6 months. It is also recommended that EMG and NCV be repeated biannually or with every 10 g increase in the cumulative dose.[97] In HIV positive patients, HIV RNA must be repeated at 1 month, 3 months, and every 3 months thereafter.[11]

Indicators for stopping therapy

It is recommended that the therapy must be withheld or discontinued if[11]:

Failure to comprehend or comply with the instructions

Positive pregnancy test

Development of par-aesthesia

Decrease in sensory nerve action potential by more than 40%

Absolute neutrophil count falls below 750/cubic mm.

Conclusion

Thalidomide is a versatile promising drug with many biological effects and potential for effective use in many dermatological diseases, either singly or as adjuvant therapy. The adverse effects particularly teratogenicity effect should be given due consideration and caution exercised, before, during and after starting the therapy.

What is new?

Thalidomide is a double-edged weapon. Because of its deleterious adverse effects, the therapeutic use of this drug must be kept under strict control and its adverse effects must serve as a reminder to exercise extreme caution and vigil when using this drug. At the same time, if used judiciously, it can work miracles in many recalcitrant conditions.