Long-term thalidomide use in refractory cutaneous lesions of systemic lupus erythematosus

OBJECTIVE. To evaluate the efficacy of long-term thalidomide treatment in cutaneous lesions of systemic lupus erythematosus (SLE), not responsive to conventional therapy. PATIENTS AND METHODS. Were selected 18 SLE patients (ACR criteria) with active cutaneous lesions not responsive to chloroquine, photoprotectors and low doses prednisone and who presented good response to thalidomide but relapsed after withdrawal of the drug. All female patients had no risk of pregnancy. Thalidomide was reintroduced and maintained at low dose (25-100mg/day) for a minimum of 6 months. RESULTS. Eighteen patients (16 females) with mean age of 34.2yo (16-57y.o.) received thalidomide for 6-21 months (mean 8.5m). The mean dose of prednisone at beginning of study was 38.3


INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION INTRODUCTION
Thalidomide (α [N-phthalimido]-glutaramide) was synthesized in 1956 and sold as a sedative until 1961, when it was withdrawn from the market due to high teratogenicity and after having caused more than 10,000 cases of malformed babies 1 .
After withdrawal, thalidomide was used in many countries for the treatment of several inflammatory dermatoses such as lepra reaction 2,3 , actinic prurigo 4 , aphtae and aphtosis 5,6 , pyoderma gangrenosum 7 , Weber-Christian disease 8 prurigo nodularis 9 Langerhans cell histiocytosis 10 and discoid lupus erythematosus 11 .More recently, due to the immunomodulatory effect, thalidomide has been used to treat graft-versushost disease 12 and patients with human immunodefficience virus 13 .
Rubio & Gonzales in 1975 11 pioneered the use of thalidomide to treat patients with discoid lupus erythematosus (DLE), with good results.Thereafter, in literature, more than 200 patients with DLE have been treated with thalidomide, obtaining 90% of improvement.However, 70% of patients had recurrence of the lesions after stopping treatment [14][15][16][17][18][19][20] .Few cases of subacute cutaneous lupus erythematosus were treated with thalidomide  with good results 21,22 .Only three patients with SLE were treated with thalidomide until 1993 23 .
In 1993 we published the first paper showing good results using thalidomide in 23 patients with refractory cutaneous lesions to conventional treatment.Three patients had side effects needing to stop the drug.We found complete remission of cutaneous lesions in 18 out of 20 patients who could use thalidomide for more than one month, but we observed recurrence of lesions in thirty five percent of patients after stopping thalidomide 24 .
This study aimed to evaluate the efficacy of long-term use of thalidomide in low doses to treat SLE patients with cutaneous lesions refractory to conventional therapy.

PATIENTS AND METHODS PATIENTS AND METHODS PATIENTS AND METHODS PATIENTS AND METHODS PATIENTS AND METHODS
Eighteen patients from Rheumatology Outpatient Clinic at Hospital São Paulo/UNIFESP entered this open trial, after prior approval by the Committee of Clinical Research Ethic Control in anima nobile at Hospital São Paulo/UNIFESP.The following inclusion criteria were used:1) four or more ACR criteria for SLE classification 25 ; 2) cutaneous lesions refractory to conventional therapy (prednisone less than 0.5 mg/kg/day for at least 1 month, chloroquine diphosphate at a dose of 4mg/kg/day for at least 3 months, photoprotector creams); 3) previous success with thalidomide therapy but with relapse after drug withdrawal;4) no risk for pregnancy; 5) agreement in participating in the study.The following exclusion criteria were used: 1) risk of pregnancy; 2) low capacity for comprehension of possible side effects; 3) use of thalidomide for less than 6 months.
All patients enrolled were informed about the nature of study, possible side effects (specially teratogenicity) and instructed not to give the drug to anyone else.Thalidomide in 100mg tablets was provided by the Health State Bureau of São Paulo.The reintroduced dose ranged from 100 to 300mg/ day with gradual reduction depending on tolerance and clinical improvement.The prednisone dose was reduced as cutaneous lesions improved if the patient did not have other organs involvement.
Laboratory tests included full blood count, erythrocyte sedimentation rate, and urinalysis, performed every two months.Antinuclear antibodies were investigated at the beginning and at the end of the study by indirect immunofluorescence in mouse liver imprint.Antibodies to Sm, U1-RNP, SS-A/Ro, and SS-B/La were determined by double immunodifusion against calf spleen extract.Antibodies to native DNA were investigated by indirect immunofluorescence with Crithidia luciliae as substrate.
Statistical analysis for comparison of prednisone dose before and after long-term thalidomide therapy was performed by Wilcoxon's paired rank test.The significance level established was p<0.05.

RESULTS RESULTS
Eighteen patients participated in this study.Sixteen were female and two male, twelve white and six non-white.The mean age was 34.2 y.o., ranging from 16 to 57 years, and the mean disease duration was 7 years, ranging from 1 to 15 years.
Table 1 shows the initial and the final doses of thalidomide and prednisone for each one of the patients.The total dose of thalidomide ranged from 13,500 to 69,000mg (mean of 29,200mg).The dose of prednisone at the beginning of the study ranged from zero to 80 mg/day (mean of 38,3mg/day) and at the end of the trial had a mean of 9,7mg/day (ranging from zero to 20mg/day).The prednisone dose reduction for the whole group was statistically significant (p<0.05).Seventeen patients could reduce prednisone dose after the use of thalidomide.
All patients had previous treatment with thalidomide at 100 to 300mg/day, and presented recurrence of cutaneous lesions after stopping thalidomide.Then the drug was reintroduced with gradual reduction and maintenance at 25-100 mg/ day, with mean of 51mg/day, taken at night.The duration of thalidomide use ranged from 6 to 21 months with mean of 8.5 months.
Table 2 shows the kind of cutaneous lesions and the antinuclear antibodies presented by the patients when entered this study, the therapeutic response, and the side effects observed during the use of thalidomide.
Complete remission of cutaneous lesion in 13 patients (72%) and partial remission in the other 5 patients (28%) was obtained with maintenance dose.Figures 1-4 depict some of the lesions before (A) and after (B) thalidomide.
Side effects observed were: drowsiness in 7 patients (39%) and intestinal constipation in 5 cases (27%).One patient (5.5%) referred transient oliguria that did not recur after reintroduction of the drug.One patient (5.5%) referred paresthesia in hands, with normal electromyography, that was controlled with dose reduction.
The laboratory tests did not show significant difference during the trial.Seven of the female patients had tuba ligature, one had tuba obstruction owing to tuberculosis, two had hyste- As observed in discoid lupus erythematosus, the use of thalidomide, improves the majority of cutaneous lesions of SLE, but, the recurrence after withdrawal was frequently observed in our cases.On the other hand, the reintroduction and maintainance of low dose of thalidomide was sufficient to control the lesion in these patients.
Despite continuous interest in thalidomide, its mode of action is not totally known, with some studies with contradictory results.Thalidomide showed to inhibit IgM antibody formation in mice when fed before immunization with sheep erythrocytes 26 but, in experimental model of myasthenia gravis, it could not inhibit acethylcholine antibody formation 27 .The effect of thalidomide on chemotaxis and the capacity to generate superoxide anions of polymorphonuclear leukocytes is also contradictory 28 .More recently it was refered that thalidomide was associated with a decrease in CD4+ cells in 2 patients with erythema nodosum leprosum 29 , but not in healthy volunteers 30 .Reduced expression of integrin receptors in CD4 cells during thalidomide treatment was observed in laboratory animals 31 , but not in healthy volunteers 30 .Reduced expression of major histocompatibility complex class II antigens and ICAM-1 on keratinocytes from erythema nodosum leprosum lesions was observed during thalidomide treatment 32 .More recent studies have shown important role of TNF-α in the mode of action of thalidomide 28 , and it may be due to increased degradation of TNF-α mRNA 32,33 .
In relation to side effect, the teratogenicity is the biggest problem, but it can be used in patients without risk of pregnancy, such as men, posmenopaused or sterile women.Neuropathy remains the major complication of treatment with thalidomide, and it is mainly sensory.However, weakness and signs of pyramidal tract involvement may occur.Sensory symptoms may persist, and sometimes get worsen, after withdrawal of the drug and the pathologic findings suggest axonal neuropathy 34 .Although the frequency and the severity of neuropathy are not always found to be related to total dosage 34 , Wulff et al., confirmed that the neuropathy began after a total of 40-50g of thalidomide in most patients 35 .
Despite the increased use of thalidomide around the world, we worry about the possible side effects, mainly teratogenicity and neuropathy of this drug 36 , but we believe that more than prohibit their production, the governments need to do more restrict laws to permit their use.We do not agree that in the risk-benefit evaluation forgets the great benefit that this drug gives to some patients.The careful use of thalidomide and the search for derivatives with low toxicity seem important for many patients.Evidently thalidomide is not a first choice to treat cutaneous lesions of SLE patients, but we concluded that it is a good alternative for cases refractory to traditional treatment and may be used in patients without any risk of pregnancy, whose use of high dose of steroids or immunosuppressive drugs bring many side effect without the improvement that we observed with thalidomide.
We would like to remember that although the cutaneous lesions of SLE do not carry risk of life, it may bring many problems to the patients, mainly for female patients, since the SLE cutaneous lesions affect mainly face and arm.The patients lose self-esteem and have problem in work or social inter-personal relation-ship, worsening her quality of life.It is very important to continue looking for alternative therapy for SLE patients with cutaneous lesions refractory to the conventional treatment.

ACKNOWLEDGMENT ACKNOWLEDGMENT ACKNOWLEDGMENT ACKNOWLEDGMENT ACKNOWLEDGMENT
Acknowledgment to Special Research Foundation of the Brazilian Society of Rheumatology and CNPq (Brazil) for support this work.

mg/d and at the end was 9 .
7mg/d (p<0.05).Comple-mg/d and at the end was 9.7mg/d (p<0.05).Comple-mg/d and at the end was 9.7mg/d (p<0.05).Comple-mg/d and at the end was 9.7mg/d (p<0.05).Complemg/d and at the end was 9.7mg/d (p<0.05).Complete remission of cutaneous lesions was observed in te remission of cutaneous lesions was observed in te remission of cutaneous lesions was observed in te remission of cutaneous lesions was observed in te remission of cutaneous lesions was observed in thirteen patients (72%) and partial remission in thirteen patients (72%) and partial remission in thirteen patients (72%) and partial remission in thirteen patients (72%) and partial remission in thirteen patients (72%) and partial remission in five (28%).Side effects observed were: drow-five (28%).Side effects observed were: drow-five (28%).Side effects observed were: drow-five (28%).Side effects observed were: drowfive (28%).Side effects observedwere: drowsiness in eight patients, intestinal constipation in siness in eight patients, intestinal constipation in siness in eight patients, intestinal constipation in siness in eight patients, intestinal constipation in siness in eight patients, intestinal constipation in 5, transient oliguria in 1, paresthesia of hand 5, transient oliguria in 1, paresthesia of hand 5, transient oliguria in 1, paresthesia of hand 5, transient oliguria in 1, paresthesia of hand

Table 1 -Thalidomide and corticosteroid dose at the onset and completion of the trial
rectomy, one was sterile, two were menopaused, and three did not have sexual activities.