Thalidomide: dermatological indications, mechanisms of ...

REVIEW ARTICLE DOI 10.1111/j .1365-2133.2005.06747.x

Thalidomide: dermatological indications, mechanismsof action and side-effectsJ.J. Wu,* D.B. Huang,�§– K.R. Pang,�� S. Hsu� and S.K. Tyring**��

*Department of Dermatology, University of California, Irvine, Irvine, CA, U.S.A.

�Division of Infectious Diseases, Department of Medicine, and �Department of Dermatology, Baylor College of Medicine, Houston, TX, U.S.A.§Division of Infectious Diseases, Department of Medicine, –University of Texas at Houston School of Public Health, and

**Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, U.S.A.

��Department of Dermatology, Wayne State University School of Medicine, Detroit, MI, U.S.A.

��Center for Clinical Studies, Houston, TX, U.S.A.

CorrespondenceStephen K. Tyring,

2060 Space Park Drive, Suite 200, Houston, TX

77058, U.S.A. E-mail: [email protected]

Accepted for publication13 February 2005

Key words:dermatological uses, thalidomide

Conflicts of interest:None declared.

There were no funding sources for this paper. This

topic was presented as a poster at the American

Academy of Dermatology 62nd Annual Meeting,

Washington, DC, 6–11 February 2004.

Summary

Thalidomide was first introduced in the 1950s as a sedative but was quicklyremoved from the market after it was linked to cases of severe birth defects.However, it has since made a remarkable comeback for the U.S. Food and DrugAdministration-approved use in the treatment of erythema nodosum leprosum.Further, it has shown its effectiveness in unresponsive dermatological conditionssuch as actinic prurigo, adult Langerhans cell histiocytosis, aphthous stomatitis,Behcet’s syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythemamultiforme, Jessner–Kanof lymphocytic infiltration of the skin, Kaposi sarcoma,lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyodermagangrenosum and uraemic pruritus. This article reviews the history, pharmacol-ogy, mechanism of action, clinical uses and adverse effects of thalidomide.

Thalidomide was first synthesized in West Germany in 1954

and was introduced to the German market as Contergan in

1956 as an over-the-counter medication.1 Two years later it

was marketed to other industrialized nations. In the U.K. it

was known as Distaval. It was thought to be one of the safest

sedatives ever produced as it was effective in small doses, was

not addictive, and did not have acute side-effects such as

motor impairment.2,3 Accidental overdosing or deliberate sui-

cide attempts at doses as high as 14 g did not result in adverse

effects. Its use started to become widespread in the home and

hospital, and it became popular among pregnant women to

reduce morning sickness.2

However, by 1960 it became clear that long-term thalido-

mide use was associated with polyneuritis.4 Further, rare con-

genital abnormalities such as phocomelia (Fig. 1) [courtesy of

the Thalidomide Victims Association of Canada (TVAC):

http://www.thalidomide.c./en/index.html] began to appear

in infants born to women who used thalidomide during preg-

nancy. In mid-1961, thalidomide was withdrawn from the

world market due to the increasing numbers of infants born

with deformities. It was estimated to have caused more than

12 000 congenital birth defects, mostly in West Germany, and

to have incurred more than $27 million in legal expenses.5

In 1965, it was given to patients with leprosy in Israel

for use as a sedative to relieve ‘lepra suffering’.6 Researchers

noticed an unexpected clinical improvement in the signs

and symptoms of erythema nodosum leprosum (ENL). After

multiple reports from other countries confirmed the results,

thalidomide emerged as an effective treatment for ENL. In

Europe, thalidomide has not been approved by any health

authority, but it has received orphan drug status. Pharmion,

the pharmaceutical company producing thalidomide in Eur-

ope, filed for a Marketing Authorization Application (MAA)

for multiple myeloma and ENL to the European Agency for

the Evaluation of Medicinal Products. However, in May

2004 it withdrew the MAA for ENL to focus on the mul-

tiple myeloma indication. In 1998, thalidomide was

approved by the U.S. Food and Drug Administration (FDA)

for ENL and is classified as an orphan drug.7 The orphan

drug status has led to its use in many currently unapproved

dermatological conditions that are refractory to other medi-

cations.

254 � 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp254–273

In preparing this manuscript, the following literature searches

were performed over the course of July 2002 to September

2004. Using the National Library of Medicine website at

http://www.pubmed.org, the word combinations of ‘thalido-

mide and dermatology’, ‘thalidomide and cutaneous’ and ‘tha-

lidomide and skin’ generated 20, 125 and 294 separate entries,

respectively. Each of these articles was examined to determine

relevance and suitability. Finally, to ensure that all relevant arti-

cles had been cited, the word ‘thalidomide’ was used to gener-

ate over 3700 entries, and all articles published after 1990

(appropriately 2000 articles) were briefly scanned. This com-

prehensive article reviews the pharmacology, adverse effects

and use of thalidomide in multiple dermatological conditions.

Mechanism of action

It appears that thalidomide may have several modes of action

through its sedative, immunomodulatory and other properties

(Table 1).

Therapeutic use

Although thalidomide is FDA-approved only for ENL, many

dermatological conditions appear to be treated effectively with

thalidomide (Table 2). In most of these situations, patients

received thalidomide only after conventional treatment failed.

The following diseases have been grouped into very effective,

moderately effective, possibly effective and contraindicated

when treated with thalidomide.

Very effective

Erythema nodosum leprosum

ENL is a lepra reaction that occurs in lepromatous patients on

multiple drugs or from interferon (IFN)-c intradermal injec-

tions. It usually presents within the first year of multidrug

therapy with both cutaneous and visceral manifestations.8 Skin

reactions are erythematous nodules (Figs 2 and 3) associated

with arthralgia, fever, iritis, malaise and neuritis. Visceral

manifestations can include hepatosplenomegaly, nephritis,

orchitis and pleuritis.

ENL is the only approved indication for thalidomide. The

first case report of six patients with ENL treated successfully

with thalidomide 300 mg daily led to further clinical trials.6

In a crossover study, 44 patients received thalidomide for act-

ive lepromatous leprosy and chronic ENL.9 Based on preven-

tion of new ENL lesions and a temperature of less than

37Æ6 �C, 68% of patients treated with thalidomide responded

to therapy, whereas none of the patients treated with placebo

responded.

A double-blind trial of thalidomide vs. acetylsalicylic acid

was conducted by the World Health Organization.10 After the

first course of treatment until the end of the 9-month study,

48% of patients in the thalidomide group did not have any

infectious reactions compared with 21% of patients in the ace-

tylsalicylic acid group. Within 48 h of treatment, 75% of

patients in the thalidomide group were afebrile compared

with 36% of patients in the acetylsalicylic acid group. Thalido-

mide caused regression of skin lesions twice as often as did

acetylsalicylic acid.

Sheskin11 reviewed 4522 patients treated with thalidomide

for ENL, and found that 4479 (99%) improved while only 43

(1%) had no change or worsened. The best initial dose

seemed to be 400 mg daily, with a maintenance dose of

50–100 mg daily. The duration of therapy ranged from spor-

adic use to continuous use for greater than 6 years. As in the

clinical studies, most skin lesions regressed after 24–48 h of

therapy, and other signs and symptoms such as arthralgia,

emesis, headache, myalgia, hepatosplenomegaly and orchitis

resolved quickly as well. Laboratory findings such as white

blood cell count and erythrocyte sedimentation rate decreased.

Patients with ENL also had rapid improvement in their various

neurological conditions, and neuropathy was found not to be

a common side-effect.12

Fig 1. A baby girl born in the late 1950s with phocomelia whose

mother was given thalidomide during pregnancy. Courtesy of the

Thalidomide Victims Association of Canada:

http://www.thalidomide.c./en/index.html

� 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp254–273

Thalidomide in dermatology, J.J. Wu et al. 255

Although thalidomide is considered first-line for ENL, no

trials have compared it with corticosteroids or clofazimine. It

has been noted that ENL is not a serious disease and that tha-

lidomide should not be used because of its well-documented

risks,13 but most would agree that thalidomide greatly lessens

the morbidity of ENL.

Aphthous stomatitis

The first report of thalidomide for recurrent aphthous stomati-

tis was in 1979.14 Six patients had scrotal and mouth ulcers

and were treated with thalidomide 100 mg daily. The lesions

were painless after 2–3 days and completely resolved after

7–10 days. Multiple small clinical studies (Table 3) and case

reports have reported similar results. Thalidomide is also bene-

ficial for human immunodeficiency virus (HIV)-associated

aphthous ulcers (Table 3). However, it appears that thalido-

mide in lower intermittent doses is not effective for prevent-

ing recurrence of aphthous ulcers in patients with HIV. As

aphthous ulcers often heal on their own, thalidomide should

be reserved for only the most severe or recalcitrant cases of

orogenital ulceration.15

Behcet’s syndrome

After reports of the efficacy of thalidomide in treating aphthous

ulcers, thalidomide was used for the first time in Behcet’s syn-

drome in an open trial of 22 patients.16 Thalidomide was given

at 400 mg daily for the first 5 days, followed by 200 mg daily

for the next 15–60 days. Oral and genital lesions healed very

rapidly, with milder and shorter recurrences. However, there

was no effect on ocular lesions or arthritis. These results were

similar to that of another open trial.15 Other trials showed sim-

ilar efficacy (Table 4). A pilot study was conducted from 1993

to 1996 to determine the dosage of thalidomide leading to the

best efficacy ⁄ toxicity ratio, and it was concluded that an initial

dose of 50 mg daily is efficacious and that 50 mg every 2 or

3 days is efficacious to maintain remission in more than 60%

of patients.17

Thalidomide may work in Behcet’s syndrome by reducing

the production of hydroxyl and superoxide radicals that cause

tissue damage at sites of inflammation.18 The pathogenesis of

Behcet’s syndrome is associated with an increase in chemotac-

tic activity of neutrophils, neutrophil migration, and circula-

ting immune complex-mediated vascular damage.18 Although

thalidomide decreases chemotaxis of neutrophils and cell-

mediated immunity, no change in these factors was found

when patients with Behcet’s syndrome were successfully trea-

ted with thalidomide.19 As the lesions of Behcet’s syndrome

tend to resolve on their own, thalidomide should be used

only in severe or unresponsive cases.15

Lupus erythematosus

In 1977, thalidomide was first used successfully for discoid

lupus erythematosus in 20 patients.20 Several studies have

Table 1 Mechanism of action for thalidomide

Sedative

Activation of the sleep centre in the forebrainImmunomodulatory

Inhibition of phagocytosis by neutrophilsInhibition of chemotaxis of monocytes and leucocytes

Prevention of lymphocyte proliferation in response to mitogenic and antigenic stimuli by changing the lymphocytic response fromT-helper 1 to 2

Decrease in the CD4 ⁄CD8 ratio by reducing the number of CD4+ cells and increasing the CD8+ cellsDecrease the HIV binding to CD4+ cells by blocking the expression of CD26 on the T lymphocytes

Suppression of the production of IgM antibodies

Inhibition of tumour necrosis factor-aInhibition of IL-8, IL-12

Enhancement of IL-2, IL-4, IL-5Enhancement of interferon-cDownregulation of expression of class II MHC antigens and cellular adhesion moleculesInhibition of cytokine-induced NF-jB gene expression

Increase in the expression of CD40LDecrease of B lymphocytes in the spleen

OtherAntagonism of acetylcholine, histamine, prostaglandins E2 and F2, and serotonin

Stabilization of lysosomal membranesInhibition of basic fibroblast growth factor-induced angiogenesis

Reduction of cellular proliferation, myelin phagocytosis and subperineural oedema. Decrease in the production of hydroxyl andsuperoxide radicals at sites of inflammation

Decrease in the capacity to release elastase and lactoferrin by lipopolysaccharide or lipoteichoic acid-stimulated granulocytes

HIV, human immunodeficiency virus; IL, interleukin; MHC, major histocompatibility complex.


256 Thalidomide in dermatology, J.J. Wu et al.

shown strong efficacy (Table 5). The response rates are lower

than the published literature might suggest, as most of these

trials consisted of patients who were refractory to other

conventional therapies. Not only is it effective, thalidomide

administration also allowed a reduction in prednisone and

azathioprine. In our own clinical experience, thalidomide is

very effective for systemic lupus erythematosus (Figs 4 and 5),

discoid lupus erythematosus, subacute cutaneous lupus erythe-

matosus and tumid lupus erythematosus. However, it seems

that the skin manifestations recur within days to 1 week after

stopping the medicine.

The mechanism of thalidomide in lupus erythematosus is

not known. It may stabilize lysosomal membranes,21 inhibit

hydroxyl and superoxide free radical production by neutroph-

ils,22 inhibit the synthesis of IgM and its subsequent depos-

ition on the basement membrane,23 or suppress neutrophil

chemotaxis and macrophage phagocytosis. One study found

that thalidomide 100 mg daily for 4 weeks inhibited acute

ultraviolet (UV) B erythema at 24 h after exposure, with the

equivalent of a sun protection factor of 1Æ56 to > 4Æ0, which

may explain the therapeutic effects of thalidomide in photo-

sensitive disorders.24

Prurigo nodularis

In 1965, Sheskin was also the first to treat prurigo nodularis

with thalidomide.6 Twelve patients had a decrease in pruritus

after 2–3 weeks of treatment and had a disappearance of

lesions after several months.3 After receiving thalidomide

100–300 mg daily, four patients had a response after 1 month

and resolution within 4–6 months.25 Two to 3 years later,

two patients were still in remission.

Twenty-two patients with prurigo nodularis were treated

with thalidomide 50–300 mg daily for an average of

12 months (range 2 weeks)5 years).26 Twenty patients had

an immediate relief from pruritus and a significant decrease in

size and number of skin lesions after 1–2 months. However,

the therapy had to be discontinued in 13 patients (59%) due

to side-effects, of which neuropathy occurred in five patients.

In an uncontrolled, prospective case series, 10 HIV-positive

patients with prurigo nodularis were treated with thalido-

mide.27 Two of the patients were lost to follow-up, but the

Fig 2. A patient with erythema nodosum leprosum, with

erythematous nodules of the skin and subcutaneous tissue leading to

scarring and hypopigmentation.

Table 2 Clinical uses

Strong supporting literature (randomized controlled trials or

multiple series)Erythema nodosum leprosum

Actinic prurigoAdult Langerhans cell histiocytosis (histiocytosis X)

Aphthous stomatitisAphthous ulceration associated with human

immunodeficiency virusBehcet’s syndrome

Cutaneous sarcoidosis

Erythema multiformeGraft-versus-host disease

Jessner–Kanof lymphocytic infiltration of the skinKaposi sarcoma

Lichen planusLupus erythematosus

MelanomaPrurigo nodularis

Uraemic pruritusLess supporting literature (single series or case reports)

Chronic erythematous oedemaCutaneous benign lymphoid hyperplasia

Cutaneous Rosai–Dorfman diseaseCutaneous vasculitis

Generalized eruptive histiocytosisImmune complex vasculitis

Palmoplantar pustulosisPemphigoid

Perforating folliculitisPolymorphic light eruption

Porphyria cutanea tardaPostherpetic neuralgia

Pyoderma gangrenosumRefractory vulval ulcerations associated with Crohn disease

Schnitzler syndromeScleromyxoedema

Weber–Christian disease



remaining eight all had a greater than 50% decrease of itch

over a mean of 3Æ4 months. Seven patients had a greater than

50% decrease of skin involvement over a mean of 5 months.

However, three patients developed thalidomide-induced per-

ipheral neuropathy.

Phototherapy also has efficacy in prurigo nodularis, and a

prospective open trial sought to determine if both thalidomide

and phototherapy could effectively treat the disease.28 Thalido-

mide administration was followed by narrowband UVB

(TL-01) irradiation until complete or almost complete remis-

sion of the disease occurred. A high rate of response was

achieved after an average of 12 weeks of thalidomide therapy

and 32 UVB courses.

In patients with prurigo nodularis treated with thalidomide,

70% of patients have been reported to have peripheral neur-

opathy.29 In our clinical experience, thalidomide works very

well in prurigo nodularis in terms of alleviating the pruritus.

Neuropathy has not been a major problem in our experience

in treating these patients.

Several theories have been proposed about the mechanism

of thalidomide in prurigo nodularis. Thalidomide may have

a local effect on proliferated neural tissue in prurigo nodular-

is.30 A central effect of thalidomide may be the secondary

peripheral neuropathy (to lose the sensation to scratch) and

the sedation. The sedative properties of thalidomide may dis-

rupt the itch–scratch cycle, but this seems unlikely as other

sedatives do not control pruritus well.30 With treatment, zinc

and iron content in the lesions of prurigo nodularis decreased

towards the normal range.31

Moderately effective

Actinic prurigo

The first study of thalidomide in treating actinic prurigo was

in the early 1970s.32 Thirty-four patients were given thalido-

mide 300 mg daily tapered to maintenance doses of 15 mg

daily. All but two patients showed clinical improvement

within an average of 50 days. However, upon discontinuing

treatment, the condition recurred. Another study of 51

patients with actinic prurigo reported similar results.33 An

additional 14 patients were treated with thalidomide

50–200 mg daily, with 11 showing prolonged improvement

within 1–3 weeks.34 Eight of these patients required a main-

tenance dose of 50–100 mg weekly, while the other three

patients did not need to continue treatment.

One group of investigators performed immunohistochemi-

cal studies on biopsy specimens from 20 Mexican patients

with actinic prurigo.35 It was found that keratinocytes con-

tained high amounts of tumour necrosis factor (TNF)-a and

calprotectin. They believed that in these genetically predis-

posed patients, UV radiation may trigger excessive TNF-a pro-

duction by keratinocytes, which could be prevented by

treatment with the TNF-a antagonist thalidomide. Another

study demonstrated that complete resolution of actinic prurigo

cheilitis was more frequently seen with the combination of

topical steroids, thalidomide and sun-protection measures

(42Æ2%) than with topical steroids and sun-protection meas-

ures (16Æ3%).36

Adult Langerhans cell histiocytosis (histiocytosis X)

The first successful treatment of Langerhans cell histiocytosis

with thalidomide was documented in 1987.37 Another

patient with cutaneous histiocytosis treated with thalidomide

300 mg daily had complete remission after 1 month and no

recurrence after cessation of therapy.38 Eight other patients

with adult Langerhans cell histiocytosis remitted after

1–3 months of therapy, but they had frequent relapses after

cessation of therapy. There was little or no effect on the

visceral features of the condition.39–45 Histopathological

examination after treatment in one patient showed no histi-

ocytic infiltrate, implying an effect on the proliferative

Langerhans cell population.41 A patient with both cutaneous

Langerhans cell granulomatosis and systemic lupus erythe-

matosus was first successfully treated with the purine ana-

logue, 2-chlorodeoxyadenosine (cladribine), and then with

thalidomide.46 One patient did not respond to 100 mg

daily, which led to neuropathy.41

Fig 3. A patient with erythema nodosum leprosum, with violaceous

plaques and nodules on the legs.



Table

3Clin

ical

tria

lsof

thalid

omid

efo

rap

htho

usul

cera

tion

s

Publ

icat

ion

No.

ofpa

tien

tsDes

crip

tion

ofstud

yClin

ical

resp

onse

Oth

erco

mm

ents

Tor

rasetal.1

28

910

0m

gda

ilyfo

r10

days

for

apht

hous

stom

atitis

Hea

led

ulce

rs,re

duce

dpa

in,an

d

leng

then

edin

terv

als

betw

een

relaps

esin

8of

9pa

tien

ts

Jenk

insetal.1

29

1540

0m

gda

ilyfo

r5

days

and

then

200

mg

daily

for

28da

ysfo

rap

htho

usstom

atitis

Withi

n5–

21da

ys,14

patien

tsha

dto

talhe

alin

g,an

d1

had

major

impr

ovem

ent

Altho

ugh

rem

ission

was

mai

ntai

ned

during

ther

apy,

mos

tre

laps

edw

ithi

n

1m

onth

oftrea

tmen

tce

ssat

ion.

130

Grins

pan1

31

40If

seve

reap

htho

usstom

atitis,30

0m

g

daily

for

7–30

days

was

give

n,an

dif

less

seve

re,10

0m

gda

ily

Reg

ardl

ess

oftrea

tmen

tgr

oup,

75%

ofpa

tien

tsre

spon

ded

wel

l

Patien

tsw

ith

relaps

esw

ere

succ

essful

ly

trea

ted

with

100

mg

daily

for

12da

ys

Ran

selaar

etal.1

32

67A

larg

era

ndom

ized

,do

uble

-blin

d,pl

aceb

o-co

ntro

lled,

cros

sove

rfo

r

apht

hous

stom

atitis:

100

mg

daily

orpl

aceb

ofo

r2

mon

ths

each

and

then

switch

edtrea

tmen

tw

itho

uta

was

hout

period

Inth

egr

oup

trea

ted

with

thalid

omid

e,48

%ha

da

com

plet

ere

mission

com

pare

dw

ith

only

9%in

the

grou

ptrea

ted

with

plac

ebo

Tho

setrea

ted

with

thalid

omid

ealso

had

few

erul

cers

and

less

impa

irm

ent

Rev

uzetal.1

33

73A

rand

omiz

ed,pl

aceb

o-co

ntro

lled,

cros

sove

rtria

lfo

rap

htho

usstom

atitis:

thalid

omid

e10

0m

g

daily

vs.pl

aceb

oea

chfo

r2

mon

ths

Inth

egr

oup

trea

ted

with

thalid

omid

e,

32of

73pa

tien

ts(4

4%)

had

aco

mpl

ete

rem

ission

com

pare

dw

ith

only

6(8

%)

inth

egr

oup

trea

ted

with

plac

ebo

Tha

lidom

ide-

indu

ced

rem

ission

lasted

anav

erag

eof

20da

ysbe

fore

recu

rren

ce

Pate

rson

etal.1

34

20H

IV-

positive

patien

tsA

retros

pect

ive

revi

ewfrom

1989

to19

93fo

rap

htho

usul

cera

tion

ofth

eor

opha

rynx

,

oeso

phag

usan

dre

ctum

,20

0m

gda

ilyfo

r2

wee

ks

14pa

tien

tsha

dco

mpl

ete

healin

gan

d

6ha

dclin

ical

impr

ovem

ent

The

rew

asno

chan

gein

CD4+

cell

coun

tsdu

ring

oraf

ter

trea

tmen

t

Wei

dle1

35

14H

IV-

positive

men

7-da

yco

urse

ofth

alid

omid

e30

0or

600

mg

daily

was

com

pare

d

with

plac

ebo

Thr

ee-q

uarter

sof

the

thalid

omid

egr

oup

resp

onde

dto

ther

apy

vs.

none

ofth

epl

aceb

ogr

oup

Jaco

bson

etal.1

36

57H

IV-

positive

patien

tsA

doub

le-b

lind,

rand

omiz

ed,

plac

ebo-

cont

rolle

dstud

yfo

ror

alap

htho

usul

cers

,4-

wee

kco

urse

ofei

ther

thalid

omid

e20

0m

gda

ilyor

plac

ebo

Inth

eth

alid

omid

egr

oup,

16of

29

patien

ts(5

5%)

had

com

plet

ehe

alin

gof

the

ulce

rsaf

ter

4w

eeks

com

pare

dw

ith

only

2of

28pa

tien

tsin

the

plac

ebo

grou

p(7

%)

(P<

0Æ00

1)

Tha

lidom

ide

also

impr

oved

the

abili

tyto

eatan

dde

crea

sed

pain

.7

patien

tsco

mpl

aine

dof

both

som

nole

nce

and

rash

each

,

and

6of

the

29pa

tien

tsce

ased

trea

tmen

tbe

caus

eof

toxi

city



Cutaneous sarcoidosis

The first case report of cutaneous sarcoidosis in four patients

treated successfully with thalidomide was in 1983.47 Ten

patients with chronic cutaneous sarcoidosis resistant to conven-

tional therapy were treated with thalidomide.48 With a daily

dose of 1Æ84 mg kg)1 for 2Æ8 months there was a complete

response in three patients and a partial response in four patients,

and no response in three patients. Thalidomide was gradually

reduced in five of seven patients who had clinical improvement.

Three of these five patients relapsed and thalidomide was again

given, which reduced or resolved the symptoms.

In another open study, eight patients with chronic skin sar-

coidosis were treated with thalidomide for 16 weeks.49 All

skin biopsies showed reductions in granuloma size and in epi-

dermal thickness after treatment. In another open-label study,

15 patients with cutaneous sarcoidosis were treated with tha-

lidomide.50 Of the 14 patients who completed 4 months of

therapy, all showed patient-evaluated improvement, and 10 of

12 showed improvement based on photography. In a retro-

spective study of 12 patients with cutaneous sarcoidosis trea-

ted with thalidomide, four patients achieved complete

responses, six had partial responses, and two had no change

in their disease status.51 However, despite these trials, thalido-

mide has not been effective for cutaneous sarcoidosis in our

clinical experience.

Interleukin (IL)-2, IFN-c and TNF-a are the major cytokines

that drive the granulomatous inflammation of sarcoidosis.52,53

Thalidomide inhibits both IFN-c and TNF-a as well as IL-12,

which stimulates IFN-c production. Thalidomide increases

IL-2, which counteracts the effects of IFN-c and TNF-a. After

thalidomide treatment, there is an increase in T-cell recruit-

ment into granulomas, the appearance of multinucleated giant

cells, and increased numbers of dermal Langerhans cells and

mature dendritic cells.49 High levels of serum angiotensin-

converting enzyme are normalized, suggesting that thalido-

mide may inhibit macrophages from producing and releasing

angiotensin-converting enzyme.54

Erythema multiforme

The first case report of recurrent erythema multiforme treated

with thalidomide was in 1982.55 After receiving thalidomide

200 mg daily for a few days, the lesions on the hands, feet,

lips and glans penis had healed. The patient did not have any

relapses while on 100 mg daily for 6 months. After thalido-

mide administration, two patients with recurrent erythema

multiforme had fewer and milder episodes.56 A 23-year-old

woman with disseminated skin erythema multiforme erup-

tions that had started at menarche and spread during two

pregnancies responded well to thalidomide treatment.57 Two

other patients responded to thalidomide 100 mg daily, but

later relapsed after tapering the drug and eventually discontin-

ued therapy due to neuropathy.58 A 73-year-old woman with

recurrent erythema exudativum multiforme associated with

herpes simplex was treated successfully with thalidomide.59

Table

3(C

ontinu

ed)

Ram

irez

-Am

ador

etal.1

37

16H

IV-

positive

patien

tsA

doub

le-b

lind,

rand

omiz

ed,

plac

ebo-

cont

rolle

dclin

ical

tria

l

whe

re10

partic

ipan

tsw

ere

give

nth

alid

omid

ean

d6

wer

egi

ven

plac

ebo.

The

8-w

eek

cour

sestar

ted

with

anin

itia

lor

aldo

sage

of40

0m

gda

ily

for

1w

eek,

follo

wed

by20

0m

gda

ilyfo

r7

wee

ks

After

8w

eeks

,9

patien

ts(9

0%)

inth

eth

alid

omid

egr

oup

had

com

plet

e

healin

gof

thei

ror

alul

cers

,co

mpa

red

with

2of

6pa

tien

ts(3

3%)

inth

e

plac

ebo

grou

p(P

¼0Æ

03)

Altho

ugh

ther

ew

asa

sign

ifica

ntde

crea

sein

larg

estul

cer

diam

eter

inth

eth

alid

omid

e

grou

p,80

%of

thes

epa

tien

tsalso

exhi

bite

da

thalid

omid

e-in

duce

dra

sh

Jaco

bson

etal.1

38

49H

IV-

positive

patien

tsA

mul

tice

ntre

,do

uble

-blin

d,ra

ndom

ized

,pl

aceb

o-co

ntro

lled

stud

yfo

ror

alan

doe

soph

agea

l

apht

hous

ulce

rs,10

0m

gor

plac

ebo

3tim

espe

rw

eek

for

6m

onth

s

Inth

eth

alid

omid

egr

oup,

14of

23pa

tien

ts(6

1%)

had

recu

rren

ce

com

pare

dw

ith

11of

26pa

tien

ts

(42%

)in

the

plac

ebo

grou

p(P

¼0Æ

221)

The

rew

asno

differ

ence

inpl

asm

ale

vels

ofH

IVRN

A,TN

F-a,

and

solu

ble

TN

F

rece

ptor

IIat

the

tim

eof

ulce

rre

curr

ence

HIV

,hu

man

imm

unod

efici

ency

viru

s;TN

F,tu

mou

rne

cros

isfa

ctor

.



Table

4Clin

ical

tria

lsof

thalid

omid

efo

rBe

hcet

’ssy

ndro

me

Publ

icat

ion

No.

ofpa

tien

tsDes

crip

tion

ofstud

yClin

ical

resp

onse

Oth

erco

mm

ents

Ham

za18

30m

enO

pen

stud

y,10

0–30

0m

gda

ilyfo

r1–

2m

onth

s20

had

aco

mpl

ete

resp

onse

,an

d6

had

apa

rtia

lre

spon

seH

owev

er,w

ithd

raw

ing

thalid

omid

eca

used

recu

rren

ce

in12

of13

patien

ts,w

hich

was

cont

rolle

din

all12

afte

r

restar

ting

thalid

omid

e

Gar

dner

-

Med

win

etal.1

39

59pa

tien

tsw

ith

seve

re

oral

orge

nita

lul

cera

tion

s(2

3of

who

mha

dBe

hcet

’s

synd

rom

e)

Ret

rosp

ective

stud

yThe

rew

asco

mpl

ete

reso

lution

in

81%

ofpa

tien

tsw

ithi

n1

mon

thof

thalid

omid

eth

erap

y

atdo

ses

of20

0m

gda

ily.

No

furthe

rth

alid

omid

ew

as

requ

ired

by20

%of

patien

tsre

spon

ding

,an

din

the

rem

aini

ng80

%,im

prov

emen

tw

asm

aint

aine

dw

ith

smalle

r

dose

sof

7–20

0m

gda

ily

The

inci

denc

eof

sym

ptom

atic

neur

opat

hyse

cond

ary

toth

alid

omid

eus

ew

as

dete

rmin

edto

be13

Æ5%

Ham

uryu

dan

etal.1

40

96In

ara

ndom

ized

,do

uble

-blin

d,

plac

ebo-

cont

rolle

dtria

l,th

alid

omid

e10

0or

300

mg

or

plac

ebo

was

give

nda

ilyfo

r24

wee

ks

Inth

eth

alid

omid

e10

0m

gda

ily

grou

p,2

of32

patien

ts(6

%)

had

aco

mpl

ete

resp

onse

.In

the

thalid

omid

e

300

mg

daily

grou

p,5

of31

patien

ts(1

6%)

had

aco

mpl

ete

resp

onse

.

Inth

epl

aceb

ogr

oup,

none

had

are

spon

se(P

¼0Æ

031)

Withi

n4

wee

ksaf

ter

ther

apy

ende

d,m

ostpa

tien

tsha

da

recu

rren

ce

deW

azie

res

etal.1

717

patien

tsw

ith

oral

and

geni

tal

ulce

rs,4

ofw

hom

had

Behc

et’s

synd

rom

e

Api

lotstud

yw

asco

nduc

ted

from

1993

to19

96to

dete

rmin

e

the

dosa

gele

adin

gto

the

best

effic

acy⁄to

xici

tyra

tio,

50m

g

daily

for

1m

onth

.If

the

patien

tim

prov

ed,th

edo

sage

was

redu

ced

to50

mg

ever

yot

her

day

for

1m

onth

and

50m

g

ever

y3

days

ther

eafter

10pa

tien

tsun

derw

entre

mission

withi

nth

efirs

tm

onth

,an

d7

othe

r

patien

tsim

prov

ed.6

patien

tsha

da

com

plet

ere

mission

afte

r2

mon

ths

of

trea

tmen

t,an

d1

patien

taf

ter

4m

onth

s.A

dosa

geof

200

mg

over

8da

ys

indu

ced

prol

onge

dre

mission

in12

patien

ts.A

dosa

geof

100

mg

over

8da

ysin

duce

dpr

olon

ged

rem

ission

in5

of6

patien

ts

Ner

veco

nduc

tion

stud

ies

show

eda

decr

ease

inse

nsor

yne

rve

action

pote

ntia

lsin

6pa

tien

tsaf

ter

8.5

mon

ths

Kar

ietal.1

41

10ch

ildre

nRet

rosp

ective

stud

y,

1mg

kg)1

wee

kly

to1

mg

kg)1

daily

3ch

ildre

nha

dco

mpl

ete

rem

ission

,

and

2ha

dle

ssfreq

uent

and

mild

eror

alul

cers

How

ever

,ne

urop

athy

deve

lope

d

in2

child

ren

and

was

irre

vers

ible

inon

eof

them



Table

5Clin

ical

tria

lsof

thalid

omid

efo

rlu

pus

eryt

hem

atos

us(L

E)

Publ

icat

ion

No.

ofpa

tien

tsDes

crip

tion

ofstud

yClin

ical

resp

onse

Oth

erco

mm

ents

Hou

sman

etal.2

323

patien

tsun

resp

onsive

toco

nven

tion

alag

ents,

includ

ing

antim

alar

ialag

ents

Ret

rosp

ective

revi

ew,10

0m

g

daily

74%

dem

onstra

ted

com

plet

e

reso

lution

ofth

ecu

tane

ous

man

ifes

tation

sof

LE,13

%

dem

onstra

ted

75%

orgr

eate

rim

prov

emen

t,an

d13

%ha

dle

ss

than

75%

impr

ovem

ent

Ofth

epa

tien

tsex

perien

cing

aco

mpl

ete

orpa

rtia

lre

spon

se,91

%sa

wim

prov

emen

tw

ithi

n8

wee

ksof

thalid

omid

etrea

tmen

t

initia

tion

Kyr

iaki

setal.1

42

22pa

tien

tsw

ith

chro

nic

disc

oid

LEAn

open

unco

ntro

lled

tria

l,50

–200

mg

daily

The

rew

asa

55%

com

plet

ere

spon

sera

te,23

%pa

rtia

lre

spon

sera

te,an

d

14%

wer

ew

ithd

raw

nfrom

the

tria

ldu

eto

drug

into

lera

nce

Rel

apse

s,w

hich

wer

em

ild,oc

curr

edw

ithi

n39

Æ4±

21Æ4

days

afte

rdr

ugdi

scon

tinu

atio

n

Kno

petal.1

43

60pa

tien

tsw

ith

disc

oid

LE20

0m

gtw

ice

daily

,ta

pere

dto

50–1

00m

gda

ilyaf

ter

a

clin

ical

resp

onse

54pa

tien

ts(9

0%)

had

atle

asta

partia

lre

spon

se,an

d39

patien

ts(6

5%)

had

com

plet

ere

gres

sion

ofle

sion

s

Ofth

epa

tien

tstrea

ted

for

mor

eth

an3

mon

ths,

11of

41pa

tien

tsre

mai

ned

asym

ptom

atic

for

2–8

mon

ths

afte

rth

erap

y.After

cess

atio

nof

ther

apy,

30pa

tien

ts

relaps

edbu

tre

spon

ded

tore

star

ting

thalid

omid

e

Atra

and

Sato

22

23pa

tien

tsw

ith

system

icLE

300

mg

daily

or4

mg

kg)1

daily

inch

ildre

n18

of20

patien

ts(9

0%)

had

aco

mpl

ete

resp

onse

,an

d2

had

apa

rtia

lre

spon

se

7of

20re

laps

edon

withd

raw

alof

ther

apy

Sato

etal.1

44

18pa

tien

tsw

ith

system

ic

LEno

tre

spon

sive

toch

loro

quin

e

Mai

ntai

ned

atlo

wdo

se(2

5–10

0

mg

daily

)fo

ra

min

imum

of6

mon

ths

72%

com

plet

ere

spon

sera

tean

d

28%

partia

lre

spon

sera

te

Ord

i-Ros

etal.1

45

22pa

tien

tsw

ith

cuta

neou

slu

pus

(9w

ith

disc

oid

LE,7

with

suba

cute

cuta

neou

sLE

,4

with

lupu

spr

ofun

da,2

with

nons

peci

fic

rash

)

Apr

ospe

ctiv

estud

y,10

0m

gda

ilyCom

plet

ere

mission

occu

rred

in12

of16

patien

ts(7

5%),

partia

lre

spon

se

was

achi

eved

in4

of16

patien

ts(2

5%),

and

nore

spon

seoc

curr

edin

3of

19pa

tien

ts(1

6%)

Has

per1

46

11pa

tien

tsw

ith

chro

nic

cuta

neou

sLE

(7w

ith

disc

oid

LEan

d4

with

suba

cute

cuta

neou

sLE

)

100–

300

mg

daily

7pa

tien

tsha

da

com

plet

ere

mission

,

2im

prov

edsign

ifica

ntly

,an

d1

had

nore

spon

seaf

ter

3m

onth

s

oftrea

tmen

t

Ofth

ere

spon

ding

patien

ts,6

relaps

edaf

ter

disc

ontinu

ing

ther

apy,

and

resp

onde

dto

am

aint

enan

cedo

seof

12Æ5

–50

mg

daily

Stev

ensetal.1

47

11pa

tien

tsw

ith

disc

oid

LE,3

with

suba

cute

cuta

neou

sLE

,1

with

suba

cute

cuta

neou

s

LEpl

usm

alar

rash

,an

d1

with

nons

peci

fic

chro

nic

patc

hy

eryt

hem

a

50–1

00m

gda

ily7

of16

patien

ts(4

4%)

had

aco

mpl

ete

resp

onse

,6

of16

(37%

)ha

da

partia

lre

spon

se,an

d3

did

notre

spon

d

11pa

tien

tsw

ere

mai

ntai

ned

on25

–50

mg

daily

.All

relaps

esaf

ter

withd

raw

alof

thalid

omid

eim

prov

edw

ith

restar

ting

the

drug



In a retrospective study, 26 patients with chronic erythema

multiforme unresponsive to conventional therapies were trea-

ted with thalidomide 100 mg daily.60 On average, the dur-

ation of each episode was reduced by 11 days. Six of the

patients had subacute erythema multiforme, and lesions

resolved within 5–8 days. A maintenance dose kept the

patients in remission.

Graft-versus-host disease

The first use of thalidomide in humans for graft-versus-host

disease (GVHD) was in 1988 when a patient with acute cuta-

neous GVHD unresponsive to corticosteroids after allogeneic

bone marrow transplant improved within 3 days of starting

thalidomide.61 Several trials have shown moderate efficacy

(Table 6) in patients refractory to other therapies. The

response rates are lower than the published literature might

imply as most of these studies consisted of patients who were

refractory to other conventional therapies. Similar to lupus

patients, patients with GVHD may be able to decrease or cease

other immunosuppressive drugs.

One prospective randomized trial showed that thalidomide

may not offer any clinical benefit when incorporated as an ini-

tial therapy for chronic GVHD.62 Patients were randomized to

receive either ciclosporin and alternate-day prednisone (n ¼27) or ciclosporin, prednisone and thalidomide (200–800 mg

daily; n ¼ 27). In the thalidomide group and no-thalidomide

group, response rates were 83% vs. 89% at 2 months (P ¼0Æ7), 88% vs. 84% at 6 months (P > 0Æ8) and 85% vs. 73% at

1 year (P ¼ 0Æ5). In the thalidomide group and no-thalido-

mide group, survival rates were 66% vs. 74% at 1 year, and

66% vs. 54% at 2 years (P ¼ 0Æ85). The authors concluded

that despite a high response rate and survival rate, thalidomide

offers no clinical benefit as initial therapy for chronic GVHD.

Thalidomide is not useful as prophylaxis of chronic GVHD; it

is associated with a higher rate of GVHD and higher mortality

rate.63

It is believed that the metabolites of thalidomide act at an

early stage in the antigen recognition-activation pathway of

graft T lymphocytes, which downregulates normal lymphocyte

function.64 This may be achieved by allowing the develop-

ment of antigen-specific suppressor cells and inhibiting the

development of cytotoxic cells.65

Fig 5. Malar rash of systemic lupus erythematosus 1 month after

thalidomide 50 mg nightly.Fig 4. Malar rash of systemic lupus erythematosus before thalidomide

treatment in a 22-year-old Asian woman. She had failed prednisone

40 mg daily and hydroxychloroquine 200 mg twice daily for several

months.



Table

6Clin

ical

tria

lsof

thalid

omid

efo

rgr

aft-ve

rsus

-hos

tdi

seas

e(G

VH

D)

Publ

icat

ion

No.

ofpa

tien

tsDes

crip

tion

ofstud

yClin

ical

resp

onse

Oth

erco

mm

ents

Vog

elsa

ngetal.1

48

44pa

tien

tsre

frac

tory

with

orhi

gh-r

isk

chro

nic

GVH

D

800

mg

daily

was

give

nfo

r3–

6m

onth

s14

patien

tsha

da

com

plet

ere

spon

se,

12ha

da

partia

lre

spon

se(d

efine

das

impr

ovem

entin

mor

eth

an50

%bu

t

less

than

100%

ofallaf

fect

edor

gan

system

s),an

d18

had

nore

spon

se

Inth

ere

frac

tory

GVH

Dgr

oup

surv

ival

was

76%

,an

din

the

high

-risk

GVH

Dgr

oup

surv

ival

was

48%

Park

eretal.1

49

80pa

tien

tsw

ith

chro

nic

GVH

Dun

resp

onsive

topr

edni

sone

with

orw

itho

utci

clos

porin

100

mg

four

tim

esda

ily,w

hich

was

incr

ease

dto

200–

400

mg

four

tim

esda

ilyde

pend

ing

onth

ere

spon

se

16pa

tien

ts(2

0%)

had

are

spon

se,

with

56%

expe

rien

cing

aco

mpl

ete

resp

onse

and

44%

apa

rtia

lre

spon

se

Ofth

ose

with

the

stan

dard

-risk

chro

nic

GVH

D,24

%re

spon

ded,

com

pare

dw

ith

16%

ofth

ehi

gh-r

isk

chro

nic

GVH

Dgr

oup

Rov

ellietal.1

50

14ch

ildre

nw

ith

refrac

tory

orhi

gh-r

isk

chro

nic

GVH

D3–

9Æ5

mg

kg)1

daily

give

ntw

ice

orfo

urtim

esda

ilyAfter

2m

onth

sof

trea

tmen

t,6

patien

tsha

da

com

plet

ere

spon

se,

4pa

tien

tsha

da

partia

lre

spon

se,

and

4di

dno

tre

spon

d

3w

ith

aco

mpl

ete

resp

onse

and

1w

ith

apa

rtia

lre

spon

sew

ere

able

tostop

thalid

omid

ew

itho

utan

yre

laps

es

Brow

neetal.1

51

37allo

gene

icbo

nem

arro

wtran

splant

atio

npa

tien

tsw

ith

chro

nic

GVH

Dre

frac

tory

tostan

dard

imm

unos

uppr

essive

ther

apy

Sing

le-ins

titu

tion

stud

y14

of37

patien

ts(3

8%)

had

are

spon

seaf

ter

thalid

omid

ew

as

star

ted

(1co

mpl

ete,

13pa

rtia

l).4

of16

adul

ts(2

5%)

and

10of

21

child

ren

(46%

)re

spon

ded

Ove

rall,

the

2-ye

arKap

lan–

Mei

ersu

rviv

alw

as41

%(9

5%co

nfide

nce

inte

rval

24–5

9%)

afte

rth

alid

omid

ew

asstar

ted

van

dePo

el

etal.1

52

12pa

tien

tsw

ith

GVH

Dre

frac

tory

toch

roni

cpr

edni

sone

and

ciclos

porin

Clin

icpa

tien

tsbe

twee

n

1991

and

2001

4pa

tien

tsha

da

com

plet

ere

spon

se,

and

5sh

owed

apa

rtia

lre

spon

se

How

ever

,of

thes

e5

patien

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Jessner–Kanof lymphocytic infiltration of the skin

The first clinical trial of thalidomide for Jessner–Kanof lymph-

ocytic infiltration of the skin was in 1983.66 Three of the five

patients had a prior inconsistent or negative response to chlo-

roquine. All five cases had an excellent response with thalido-

mide 100 mg daily. However, skin lesions in four patients

reappeared when treatment was stopped. With a maintenance

dose of 25–50 mg daily for more than 2 years, three of five

patients had normal skin.

In a randomized controlled trial, 28 patients were randomly

assigned to receive thalidomide 100 mg daily or placebo over

a period of 2 months and were then switched to the other

treatment.67 After the first period, 11 of 13 patients treated

with thalidomide were in complete remission, and the other

two patients did not respond. For those who received placebo,

there was no complete remission in the patients (P < 0Æ0001).

After the switch, nine of 14 patients who had received thali-

domide in the second period were in complete remission, and

10 of the 13 patients who had received thalidomide during

the first period were in complete remission. Complete remis-

sion occurred in 19 (76%) after thalidomide therapy and in

four (16%) after placebo (P < 0Æ001). Of the 27 patients who

received thalidomide, 16 (59%) were in complete remission

after 1 month and 20 (74%) were in complete remission after

2 months.

Uraemic pruritus

One patient with severe pruritus of unknown cause did not

improve with thalidomide.56 In a randomized, double-blind,

crossover trial, 29 patients with refractory uraemic pruritus

were treated with thalidomide 100 mg daily or placebo

daily for 1 week.68 Two-thirds of patients had an 80%

reduction in pruritus (P < 0Æ05). Those with less severe

symptoms seemed more likely to respond. The mechanism

is not known, but it may be related to interference of

inflammatory mediators.

Possibly effective

Kaposi sarcoma

A 14-year-old girl with HIV and Kaposi sarcoma was treated

with thalidomide for oral ulcers.69 There was a reduction in

the size of existing Kaposi sarcoma lesions, and no new

lesions appeared. Further, there was a decrease in the human

herpesvirus type 8 DNA level in the peripheral blood. How-

ever, it was also argued that the response was due to the

withdrawal of corticosteroids rather than treatment with tha-

lidomide.70 A 46-year-old woman with chronic myelogenous

leukaemia who had received an allogeneic haematopoietic

stem cell transplantation presented with human herpesvirus

8-associated Kaposi sarcoma involving her left leg.71 Since her

transplant, she had been on continuous immunosuppres-

sive therapy because of chronic GVHD. Irradiation was

administered to debulk disease on her legs. Thalidomide was

started with alitretinoin 0Æ1% gel applied twice daily to the

nonirradiated lesions. Over 7 months, there was a partial

response in both irradiated and nonirradiated lesions.

A phase II study of thalidomide was performed to evaluate

its efficacy and toxicity for cutaneous AIDS-related Kaposi sar-

coma and to determine if the clinical response correlated with

a decrease in titre of human herpesvirus 8 DNA in peripheral

blood.72 Seventeen men with AIDS-related Kaposi sarcoma

were given thalidomide 100 mg daily for 8 weeks. Six of 17

patients (35%) had a partial response, and eight patients with-

drew (six due to toxicity, one to noncompliance, and one to

early progression of disease). Human herpesvirus 8 DNA load

decreased to undetectable levels in three of the five partial

responders.

In a phase II dose-escalation study, 20 patients with AIDS-

related Kaposi sarcoma were treated with an initial dose of

thalidomide 200 mg daily, which was increased to a maxi-

mum of 1 g daily for up to 1 year.73 The overall response rate

was 40%. The median duration of drug treatment was

6Æ3 months; the median time to progression was 7Æ3 months.

The median thalidomide dose at the time of response was

500 mg daily (range 400–1000). The antiangiogenic proper-

ties of thalidomide may have possible clinical efficacy in a

malignancy very dependent on angiogenesis such as Kaposi

sarcoma.

Lichen planus ⁄ lichen planopilaris

A patient with generalized lichen planus refractory to multiple

drugs was given thalidomide 300 mg daily for 2 weeks and

then 200 mg daily for another 10 weeks, which resulted in

resolution of all his lesions.74 Four patients with refractory

oral lichen planus were successfully treated with thalidomide

25–150 mg daily for 15–36 months without recurrence or

adverse effects.56,75,76 A patient with erosive flexural lichen

planus was successfully treated with a combination of thalido-

mide and tacrolimus 0Æ1% ointment.77

In a retrospective study of six patients with severe erosive

lichen planus treated with thalidomide, four patients had com-

plete healing for 4 months, one had partial healing, and one

had no change in the disease. In the five patients with a clin-

ical improvement, oral erosions rapidly relapsed after thalido-

mide therapy ended.78

A 53-year-old woman with recalcitrant lichen planopilaris

was successfully treated with thalidomide 50 mg twice

daily for 6 months.79 We reported a woman with lichen plan-

opilaris who was started on 150 mg daily for 1 month, which

resulted in regrowth of hair.80 One month later, the thalido-

mide was tapered to 50 mg daily, which prevented a recur-

rence of hair loss. Despite the positive results in our case

report, the use of thalidomide has not consistently yielded

good results in other patients.81 Since the publication of our

case report, we have treated several more patients with lichen

planopilaris with positive results in terms of decreasing any

associated erythema.



Melanoma

Solid tumours must develop their own blood supply by neo-

angiogenesis to grow and metastasize. As thalidomide inhibits

the processing of mRNA encoding peptide molecules for the

angiogenic substance, vascular endothelial growth factor, there

has been recent research studying its efficacy for tumours such

as melanoma. Thalidomide and pentoxifylline potentiate each

other’s antiangiogenic effect, as demonstrated in human

malignant melanoma cells in the cornea of Macaca arctoides mon-

keys.82 A phase I ⁄ II study of thalidomide and temozolomide

for metastatic melanoma was completed recently.83 Prelimin-

ary results have shown significant antitumour activity, even in

brain metastases.84

The complete results of the above preliminary study showed

that thalidomide and temozolomide were well tolerated and

had significant antitumour activity in patients with advanced

melanoma.85 Twelve patients with unresectable stage III or IV

melanoma without brain metastases were entered into four

treatment cohorts: level 1, temozolomide 50 mg m)2 daily

for 6 weeks followed by a 4-week break; and levels 2, 3 and

4, temozolomide 75 mg m)2 daily for 6 weeks followed by

breaks of 4, 3 and 2 weeks, respectively. Thalidomide was

started at 200 mg daily and increased to a maximum of

400 mg daily. There were one complete response and four

partial responses all at dose levels 2–4, and three of these

patients were over 70 years of age. The median duration of

response was 6 months (range 4–17+), and the median over-

all survival was 12Æ3 months (range 4–19+). All regimens

were well tolerated.

One study used low-dose thalidomide for several advanced

malignancies including melanoma and breast, ovarian and

renal cell cancer.86 Sixty-six patients with advanced measur-

able cancer (17 melanoma, 12 breast, 19 ovarian, 18 renal

cell cancer) received thalidomide 100 mg daily until disease

progression or unacceptable toxicity was encountered.

Although three of 18 patients with renal cell cancer showed

partial responses, no objective responses were seen in the

other tumour types. However, there were significant improve-

ments in appetite (P < 0Æ05) and sleeping (P < 0Æ05).

In another study, 20 patients with metastatic melanoma

without symptomatic brain metastases were administered tha-

lidomide 200 mg daily, with increments of 100 mg every

7 days to a maximum dose of 800 mg daily.87 Although none

of the patients had an objective response, seven patients

(35%) experienced stable disease for 12–32 weeks (median

16). The authors believed that the antiangiogenic property of

thalidomide is the basis of cytostatic activity in patients with

metastatic melanoma. Considering that metastatic melanoma

has very few therapeutic options, thalidomide seems to be a

promising avenue for further research.

Pyoderma gangrenosum

A 3-year-old girl with pyoderma gangrenosum refractory to

corticosteroids and clofazimine was given thalidomide

100 mg daily, leading to complete resolution.88 Another

patient was successfully treated with thalidomide 100 mg

daily, resulting in complete remission for 2 years, but cessa-

tion of therapy secondary to neuropathy led to immediate

relapse.89 After 6 months of therapy, one patient had healing

with scarring and no new lesions.90 One case of pyoderma

gangrenosum involving the penis refractory to high doses of

prednisolone improved within 5 days of thalidomide 100 mg

daily.91 A 47-year-old man with pyoderma gangrenosum

unresponsive to methylprednisolone had complete healing

after 10 weeks of thalidomide.92 Two patients with pyoderma

gangrenosum in association with Behcet’s syndrome were

given thalidomide 400 mg daily, later tapered to 50–100 mg

daily, which resulted in immediate, complete healing of skin

lesions and prevented the development of new mucocutaneous

lesions.93,94 Despite these case reports, thalidomide has not

been effective in our clinical experience. Most of our patients

have discontinued the medication after 3–4 months due to

lack of efficacy.

Contraindicated use

Toxic epidermal necrolysis

The pathogenesis of toxic epidermal necrolysis was believed to

be related to an increased level of TNF-a. Thalidomide was used

in a randomized, double-blind, placebo-controlled trial as tha-

lidomide is known as an inhibitor of TNF-a.95 Ten of 12

patients who received thalidomide 400 mg daily for 5 days

died, compared with only three of 10 who received placebo

(relative risk 2Æ78, P ¼ 0Æ03). The study was stopped prema-

turely because of excess mortality in the thalidomide group. It

was found that there was a paradoxical enhancement of TNF-aafter therapy with thalidomide. In diseases such as toxic epider-

mal necrolysis in which T-cell activation is involved in the path-

ogenesis, the use of thalidomide, which may stimulate T cells in

vivo, may further worsen the condition.96 Toxic epidermal nec-

rolysis was later found not to be related to TNF-a but to the sys-

tem of Fas receptors on keratinocytes.97 However, regardless of

the mechanism, thalidomide should not be used to treat toxic

epidermal necrolysis.

Adverse effects

Thalidomide is well-known for its side-effects of teratogenicity

and peripheral neuropathy, but it also has endocrine effects

and other more benign adverse effects (Table 7).

Teratogenicity

Birth defects are the most devastating adverse effect of thalido-

mide, which is classified as pregnancy category X. A single

dose of 100 mg within the first 35–50 days of pregnancy can

result in deformities.98 It is not known whether it has an

effect on spermatogenesis.21 Of 380 children born to thalido-

mide victims, 11 had congenital limb defects. This occurrence



was five times higher than in the general population. Further,

an Australia study by William McBride (who was the first to

report the association between thalidomide and phocomelia in

1961 in The Lancet) claimed that thalidomide altered DNA in

the sperm and egg cells of rats. In an open letter dated 30

August 1997 by Randy Warren, Chief Executive Officer, and

Giselle Cole, President, of TVAC, which can be found at

http://www.thalidomide.c./en/information/open_letter_2nd_

generation.html, it was stressed that these disabled children of

thalidomide victims were born as a result of some other unre-

lated genetic birth disorder. They mentioned that the media

falsely reported, for the sake of sensationalism, that thalido-

mide disabilities could be passed to their children or grand-

children. They also highlighted that William McBride was

discredited in 1982 for falsifying the results of his experi-

ments regarding the antinausea drug Debendox and was taken

off the Australian Medical Register in 1993. The TVAC has

been in communication with the British Thalidomide Society,

the FDA, and Celgene Corporation, and the TVAC is confident

that thalidomide has not doomed future generations.

The classification of the teratogenic effects are deformities

of the upper and lower extremities such as amelia; absence of

bones, phocomelia; abnormalities of the external ear such as

anotia and micro pinna; abnormalities of the eye such as

anophthalmos, with or without association with facial palsy;

and defects of the internal organs.99 At or shortly after birth,

the mortality rate is 40%.

The exact mechanism of action is still not known. It has

been proposed that the categories of thalidomide-induced

teratogenicity be divided into those affecting angiogenesis, cell

injury or death, chondrogenesis, DNA synthesis or gene tran-

scription, growth factors, or integrins.100

It has been theorized that thalidomide blocks a mesonephric

signal that is essential for normal limb growth.101 Elimination

of the mesonephros resulted in limb reduction defects similar

to those induced by thalidomide, and upper extremities were

more likely to have defects compared with lower extremities,

just as observed in thalidomide-induced teratogenicity. The

mesonephros also produces insulin-like growth factor, which

is important in normal limb initiation and development.102

Thalidomide-induced teratogenicity may be related to the anti-

angiogenic properties of thalidomide.103

Peripheral neuropathy

Peripheral neuropathy is the other well-known side-effect of

thalidomide. The neuropathy has no relation to the total

cumulative dose,13 and it can be slow to resolve or may be

irreversible.29 A 2-year prospective study monitoring 135

patients treated with thalidomide for different dermatological

diseases showed that the incidence rate of peripheral neuropa-

thy was greatest in the initial year of treatment (20%). The

risk was related to the daily dose regardless of duration of

therapy, with no neuropathy detected in those patients receiv-

ing 25 mg or less per day.104 In one study of patients with

neuropathy secondary to thalidomide for 4–6 years after end-

ing therapy, 25% had a full recovery, 25% had some improve-

ment, and 50% had no change.105 The incidence has been

reported to be from 0Æ5% to over 70%, with the elderly and

women being at a higher risk.106

Neuropathy usually first presents as symmetrical painful

paraesthesias of the hands and feet with sensory loss in the

lower extremities. Muscle weakness or cramps may or may

not be present, and pyramidal tract signs and carpal tunnel

syndrome may occur.107 A high incidence of ‘tightness around

the feet’ has been reported.108 After discontinuing thalido-

mide, muscle weakness improves rapidly, but sensory deficits

may improve slowly, worsen, or stay the same.109

Biopsy findings show loss of large-diameter fibres without

segmental demyelination and increased numbers of small

fibres from regeneration.110 Electrophysiological studies show

axonal neuropathy with reduced sensory nerve action potential

amplitude and increased latency in somatosensory-evoked

potentials.111

Miscellaneous side-effects

The most common side-effect is sedation, which diminishes

over time. Other common side-effects are rash, constipation

and dizziness. Uncommon side-effects include headache,

hypotension, oedema, neutropenia, increased appetite, mood

changes, nausea, pruritus and weight gain.

Another adverse event in patients treated with thalidomide

is thromboembolic complications, such as deep vein thrombo-

sis and pulmonary embolism.112 A review of data from Med-

Watch, the FDA’s spontaneous reporting programme, and

Table 7 Side-effects

Serious

TeratogenicityCommon

SedationConstipation5

Rash153

Peripheral neuropathy

ThromboembolismDizziness99

Uncommon

Amenorrhoea116

Oedema5

Neutropenia7

Bradycardia

Dry mouth and skin4

Pruritus6

Headache21

Hypotension

Increased appetiteMood changes

Male sexual dysfunction117

Nausea5

TachycardiaWeight gain



phase II and III clinical trials involving patients with multiple

myeloma, renal cell cancer, melanoma and other cancers,

revealed that events occurred after a mean of 2 months of tha-

lidomide therapy, at a reported rate of 0–43% of treated

patients, with a marked incidence when chemotherapy was

given with thalidomide. In a group of 521 patients who

received thalidomide and chemotherapy without venous

thrombosis prophylaxis, 16% developed thrombotic events; of

60 patients who received thalidomide with dexamethasone,

15% developed thrombotic events; and among 326 patients

who received thalidomide monotherapy, 5% developed

thrombotic events. It has been suggested that there is a high

rate of thromboembolic events in cancer patients treated with

thalidomide because thalidomide may alter tumour cell inter-

actions with coagulation factors; generate procoagulant factors;

activate platelets or vascular endothelium; increase thrombo-

genicity of endothelial cells through increased secretion of IFN

by T-helper 1 cells; and induce increases in integrin levels

which, combined with chemotherapy-induced endothelial

damage, might lead to tumour cell adhesions and platelet

clumps that can be thrombogenic. Thrombotic events have

also been reported in lupus patients who had antiphospholipid

antibodies.113 Some clinicians recommend a coagulation

assessment of patients before starting thalidomide, and limited

evidence suggests that with the addition of warfarin prophy-

laxis, patients may be safely continued on thalidomide after

having thalidomide-associated thrombotic events.114

Rarely, thalidomide depresses thyroid function, stimulates

adrenocorticotrophic hormone and prolactin production, and

causes hypoglycaemia.115 Thalidomide has also been reported

to cause amenorrhoea116 and male sexual dysfunction.117

Thalidomide may also cause dermatological side-effects.

Cases of exfoliative118 and erythrodermic119 reactions, allergic

vasculitis and thrombocytopenic purpura,120 toxic epidermal

necrolysis121 and psoriasis exacerbation122 have been reported.

Patients with HIV receiving thalidomide may be more likely

to experience hypersensitivity reactions (Fig. 6).123 In a

open-label clinical trial of 87 patients with multiple myeloma,

subjects were treated with thalidomide alone (50 patients) or

thalidomide and dexamethasone (37 patients).124 Skin reac-

tions occurred in 46% of patients taking thalidomide and in

43% of those taking thalidomide and dexamethasone. These

eruptions included maculopapular, morbilliform, seborrhoeic

or nonspecific dermatitis. Three patients developed severe skin

reactions (erythema multiforme, exfoliative erythroderma and

toxic epidermal necrolysis) that required hospitalization and

termination of thalidomide.

Monitoring guidelines

Thalidomide should be carefully selected for appropriate

patients, and for those who are of childbearing age both

counselling and contraceptives should be offered. British

guidelines for the use of thalidomide include informed con-

sent being obtained in every case and routine dispensing of

information leaflets.125 Women of childbearing potential

should have a negative pregnancy test 2 weeks prior to start-

ing treatment, along with appropriate contraceptive advice.

Baseline nerve conduction studies (NCS) are recommended to

monitor for the subclinical development of peripheral neuro-

pathy. Sensory nerve action potential amplitudes should be

measured in at least three peripheral nerves, usually the med-

ian, radial and sural nerves. Falls of 30–40% should lead to a

review of thalidomide use, and a fall from baseline values of

> 40% on repeat testing should lead to discontinuation of the

therapy. After every 10 g cumulative dose or every 6 months,

follow-up testing is recommended. However, NCS every

6 months are not practical in the U.K. If any symptoms

develop between tests, patients should stop thalidomide

immediately and seek medical advice.

To prevent teratogenic exposure,125 the manufacturer of

thalidomide has created a comprehensive programme to con-

trol prescribing, dispensing and use of the drug, known as the

System for Thalidomide Education and Prescribing Safety

(S.T.E.P.S.TM),126 which is now running in the U.K. Its main

goal is to prevent fetal exposure to thalidomide.

The three-step approach is to: control access to the drug;

educate and register prescribers, pharmacists and patients; and

monitor compliance. Prescribers are sent information about

Fig 6. A human immunodeficiency virus-positive man with total

body erythematous macules following the use of thalidomide to treat

oral aphthous ulcers.



the S.T.E.P.S.TM programme, devised by Celgene Corporation,

the manufacturer of thalidomide. If they are interested in par-

ticipating, they must agree to: (i) give comprehensive patient

counselling on the risks and benefits of thalidomide; (ii) give

appropriate contraception counselling and pregnancy testing;

(iii) have patients complete informed consent forms and sub-

mit them to the Slone Epidemiologic Unit; (iv) complete and

submit the prescriber section of the patient-monitoring sur-

vey; (v) prescribe no greater than 28 days of therapy without

refills; and (vi) tell patients to return unused thalidomide

to the pharmacy.126 Pharmacies must also register in the

S.T.E.P.S.TM programme to dispense thalidomide.

To receive the medicine, women of childbearing potential

must agree to use two forms of reliable contraception.126 Only

women who are postmenopausal, who have undergone a hys-

terectomy, or who have not had menses for at least 24 con-

secutive months are considered sterile. Women must use

contraception for 4 weeks before the start of therapy and for

4 weeks after ending therapy. Those who wish to be abstinent

must remain so during this same period.

Women must also agree to undergo pregnancy testing before

and during treatment.126 This is required every week for the

first month and monthly afterwards in women with regular

menstrual cycles and every 2 weeks in those whose cycles are

irregular. Pregnancy testing must also be done if a patient misses

her cycle or there is any abnormality in menstrual bleeding. To

encourage compliance with the pregnancy-testing requirement,

women should receive no more than a 1-week supply for each

of the first 4 weeks. If pregnancy does occur during therapy,

thalidomide must be stopped immediately, and the prescriber

and patient must meet to discuss the implications.126 Celgene

Corporation must be informed immediately. The patient must

be referred to a board-certified obstetrician ⁄gynaecologist who

has training in reproductive toxicity.

Male patients must receive oral and written warnings of the

risk of possible contraception failure and the need to use con-

doms. All patients must agree not to donate blood or share

thalidomide with others.

Patients and prescribers must both sign a four-copy informed

consent form. They must also complete frequent follow-up

questionnaires (every month for women and every 3 months

for men). The surveys have questions about demographics,

knowledge of the teratogenic risks of thalidomide, sexual activ-

ity, use of contraception, and not sharing thalidomide.

A questionnaire was completed by 17 of 19 dermatologists

concerning thalidomide usage and monitoring practices in

Wales.127 Eleven of the 17 respondents had prescribed tha-

lidomide to a total of 40 patients, but only two dermatologists

gave information leaflets and only five obtained written con-

sent. Seven women of childbearing potential were taking tha-

lidomide, but none had had baseline pregnancy tests. Four

dermatologists ordered baseline NCS, and nine ordered these

studies during treatment. Unfortunately, despite two published

guidelines for the use of thalidomide, it appears that many

prescribers are unaware of the monitoring guidelines and risks

of thalidomide.

Drug interactions

Thalidomide enhances the activity of alcohol, barbiturates,

chlorpromazine and reserpine.106 It raises serum levels of acet-

aminophen and increases its toxicity.29 It antagonizes acetyl-

choline, histamine, prostaglandins and serotonin in vitro. Other

drugs that cause sedation, neuropathy, or decrease the efficacy

of oral contraceptives should be used carefully if thalidomide

is added to the patient’s regimen.

Conclusions

Thalidomide is an effective medication for ENL as well as sev-

eral other dermatological diseases refractory to conventional

therapies. However, the adverse effects of teratogenicity and

peripheral neuropathy have to be considered before starting

thalidomide. In appropriately selected patients, thalidomide

can be an extremely efficacious medication.

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