prolong remission of psoriasis with azathioprine pulse therapy

Prolong remission of psoriasis with azathioprine pulse therapy

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Original Article

Prolong remission of psoriasis with azathioprinepulse therapy

Ramji Gupta*

Consultant Dermatologist, Department of Dermatology, Indraprastha Apollo Hospital, Sarita Vihar,

New Delhi 110076, India

a r t i c l e i n f o

Article history:

Received 21 May 2014

Accepted 19 July 2014

Available online xxx

Keywords:

Azathioprine pulse therapy

APT

Psoriasis

Prolong remission

* 47-C Pocket B Siddhartha Extension, NewE-mail address: [email protected]

Please cite this article in press as: Gupta(2014), http://dx.doi.org/10.1016/j.apme.2

http://dx.doi.org/10.1016/j.apme.2014.07.0050976-0016/Copyright © 2014, Indraprastha M

a b s t r a c t

Background: Various therapies used for the treatment of psoriasis though are able to pro-

duce remission but relapses remain the common problem. Treatment with Azathioprine

Pulse Therapy (intermittent high dose (IHD) and continuous low dose (CLD) azathioprine)

can produce prolonged and durable remission in psoriasis was observed.

Methods: Sixty patients with psoriasis were treated with monthly IHD azathioprine (500 mg

on 3 consecutive days), CLD azathioprine (100 mg orally) was given daily in between IHD.

The entire treatment schedule was divided into four phases. During phase I, treatment

with IHD and CLD azathioprine was continued till complete clearance of lesions, when

patients proceeded to phase II while continuing treatment with IHD and CLD. After

continued remission for a period of 9 months, treatment with IHD was stopped, but CLD

was continued (Phase III). After 9 months of phase III treatment, CLD was also withdrawn,

and patients were followed-up without any treatment (Phase IV).

Results: Forty five patients completed treatment and are in remission without any

treatment.

Conclusions: Out of 45 patients in phase IV, 25 patients are in continuous remission for more

than 3 years (maximum 93 months), 9 are in remission for 1e3 years, while 11 are less than

1 year in continuous remission after all treatment was stopped. Thus azathioprine pulse

therapy regimen produced prolonged remission in psoriasis.

Copyright © 2014, Indraprastha Medical Corporation Ltd. All rights reserved.

1. Introduction

Various therapies used to treat psoriasis, clear the lesions but

are unable to prevent relapse. Psoriasis is known to be caused

by activated T lymphocyte cells which produce cytokines.

Cytokines lead to the proliferation of keratinocytes

Delhi 110014, India. Teln.

R, Prolong remission o014.07.005

edical Corporation Ltd. A

responsible for development of psoriasis lesions.1 Azathio-

prine is known to suppress activated T lymphocyte cells

which in turn stop production of cytokines which ultimately

stop the proliferation of keratinocytes responsible for devel-

opment of psoriasis. To achieve clearance of the lesions as

well as prolong period of remission an arbitrarily designed

regimen of azathioprine was studied2 in the management of

.: þ91 11 26347405.

f psoriasis with azathioprine pulse therapy, Apollo Medicine

ll rights reserved.

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http://dx.doi.org/10.1016/j.apme.2014.07.005



Fig. 2 e Histopathology of psoriasis plaque e (H & E £10).


psoriasis. Azathioprine was used as intermittent high dose

(IHD) azathioprine (500 mg on 3 consecutive days, repeated

every month on the same date) with continuous low dose

(CLD) azathioprine (100 mg orally) given daily in between IHD.

The entire treatment was divided into four phases.3,4

During phase I, treatment with IHD and CLD azathioprine

was continued till clearance of lesions. Once the lesions

cleared completely patient would proceed to phase II, while

continuing IHD and CLD azathioprine. After the patient had

remained lesions free for a period of 9months, treatmentwith

IHD azathioprine was stopped, but CLD azathioprine

continued (Phase III). Subsequently, after 9months of phase III

treatment with no recurrence, CLD azathioprine was also

withdrawn and patients were followed-up without any

treatment (Phase IV). This entire treatment is known as

Azathioprine Pulse Therapy (APT) regimen. Initially to clear

the lesion fast and in patients of pustular psoriasis, eryth-

rodermic psoriasis and extensive plaque psoriasis, metho-

trexate 15 mg per week5 and topical coal tar 6% with salicylic

acid 3%6 was also used in phase I as azathioprine takes few

weeks to start action.

2. Materials and method

Diagnosis of psoriasis was made clinically (Fig. 1); histopathol-

ogy was done in some patients only (Fig. 3). Laboratory evalu-

ation included hemoglobin, total and differential leukocyte

counts, platelet counts, erythrocyte sedimentation rate, blood

urea, creatinine, SGOT, SGPT and alkaline phosphatase. These

investigations were undertaken before starting treatment and

regularly before giving IHD. Psoriasis Area Severity Index (PASI)

was charted in each patient. TPMT enzyme screening was not

done initially due to its unavailability but later on done in every

patient when it became available. Patient having PASI more

than 8was includedwhile patient with active systemic disease

like hepatitis, cirrhosis of liver; acute and chronic nephritis,

malignancy, pregnant women, lactating mother and children

were excluded from the study. Informed written consent was

taken from each patient. Ethical approval was obtained from

the Institution Ethics Committee of Prayatna.

In addition to azathioprine, most patients also received

topical coal tar 6% with salicylic acid 3% ointment and

Fig. 1 e Psoriasis axilla before treatment.

Please cite this article in press as: Gupta R, Prolong remission o(2014), http://dx.doi.org/10.1016/j.apme.2014.07.005

methotrexate 15 mg weekly during phase I to assist in fast

symptom control.

3. Statistical analysis

On the basis of available data, an analysis was done in the

study period. Mean duration of remission is 40.14 ± 22.56

(17.58e62.70) months.

4. Results

Sixty patients (54 psoriasis vulgaris, 4 pustular and 2 eryth-

rodermic) between 25 and 72 years of age with 2e50 years

disease duration were included in the study. The average PASI

score was 19.60 ± 7.64. Before coming to us most of the pa-

tients had taken methotrexate, coal tar and PUVA with re-

lapses at variable interval. All previous treatments were

stopped for four weeks before commencing azathioprine

pulse therapy. In addition to APT, 28 patients also received

topical coal tar 6% ointment and oral methotrexate 15 mg per

Fig. 3 e Psoriasis axilla after treatment.




Table 1 e Details of patient in remission.

Time No of patients

3 yrs and above (up to 93 months) 25

1e3 years 9

Less than 1 yr 11

Total 45

a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1e4 3

week during phase I which varies from 2 to 9 weeks. 45 pa-

tients completed the therapy and are in phase IV (Fig. 2).

The duration of continuous remission in 25 patients is

more than 3 years (maximum 93 months), in 9 patients 1e3

years and in 11 patients less than 1 year. Mean duration of

remission is 40.14 ± 22.56 months (Table 1).

4.1. Relapse

Seven patients relapsed after being in phase IV for 7e23

months. 3 patients were restarted on APT and are in phase IV

from 10 to 42 months. Remaining 4 patients were lost to

follow-up.

4.2. Side effects

Common side effects seen were nausea and vomiting in 18

patients, which was controlled with ranitidine, weakness and

fatigue in 4 patients, giddiness in 2 patients, loss of appetite,

sleeplessness and generalized malaise in 1 patient each. Liver

function tests were elevated in 8 patients in phase I and 5

patients in phase II. Leucopenia was seen in 3 patients in

phase I, which returned to normal in 3 weeks after stopping

azathioprine. Lee et al7 have also reported similar transient

side effects in long term use of azathioprine (Table 2).

5. Discussion

It is usually believed that complete and durable remission of

psoriasis is extremely difficult to obtain. Our present findings

and earlier published report3,4 suggest that it may be possible

to induce long term remission by azathioprine pulse therapy

regimen.

Table 2 e Side effects of APT.

Phase I Phase II Phase III Phase IV

Liver function tests

(SGOT, SGPT,

alkaline phosphatase)

8 5

Leucopenia 3

Nausea and vomiting 5 2

Nausea 1

Weakness 4

Giddiness 2

Restlessness 2

Uneasiness 1

Loss of appetite 1

Hair loss 1


Systemic azathioprine has been extensively investigated for

the treatment of psoriasis. In 1961 Kravetz and Balsam8 first

time used azathioprine in psoriasis; they used 2 mg/kg daily in

12 patients, 1e4 courses with improvement. Majority of them

developed relapse within 1.5e6 months after the last dose. In

1970Greaves andDawber9 used 2.5mg/kg/day for 6weeks in 10

patients with 25% clearance of the lesions in 5 patients in 2e6

weeks. Relapse was seen 1 month after stoppage of azathio-

prine. Fledges and Barnes10 in 1974 used 2.5 mg/kg/day in 10

patients for 4½ months to 5½ years with almost complete

clearance of skin lesions in 6 patients. Azathioprine was dis-

continued after remission lasting for 1 year. However all

developedrelapseafter stoppageof treatment. In1974DuVivier

et al11 used 100e300mg azathioprine daily for 2e24weekswith

75e100% clearance of psoriasis lesions withmaintenance dose

of 75e200mgdaily in 13out of 29patients.Onepatientwhowas

free of the lesions developed relapse 6 months after complete

stoppage of azathioprine. Lee et al7 used 200e300 mg azathio-

prine daily for 12e24 months in psoriatic arthritis with

improvement with few transient side effects.

Azathioprine in high dose in pulse form (800 mg daily on 3

consecutive days repeated every month and 200 mg daily in be-

tween for 12e24months) has recently been evaluated in limited

patients with Wegner's granulomatosis and lupus nephritis12,13

with very few side effects. The present study lies in using

azathioprine pulse therapy in this particular dosage schedule.

In summary, treatment with azathioprine pulse therapy

regimen can induce durable clinical remission in patients

with psoriasis with an acceptable safety profile. More studies

using this regimen by other investigators will further confirm

our findings.

Conflicts of interest

The author has none to declare.

Acknowledgment

Author thanks Mr. Anil Gupta, Center for Social Medicine and

Community Health, Jawaharlal Nehru University, New Delhi,

India for statistical assistance.

r e f e r e n c e s

1. Das RP, Jain AK, Ramesh V. Current concepts in thepathogenesis of psoriasis. Indian J Dermatol. 2009;54:7e12.

2. Gupta R. Azathioprine pulse therapy in the treatment ofpsoriasis. J Pak Assoc Dermatol. 2013;23:120e125.

3. Gupta R. Can psoriasis be cured. Delhi Med Assoc News Bull.May 10, 2013;10:22.

4. Gupta R. Prolong remission of psoriasis with azathioprinepulse therapy. Indian J Dermatol. 2014 [in press].

5. Roenigk Jr HH, Auerbach R, Maibach HI, Weinstein GD.Methotrexate in psoriasis: revised guidelines. J Am AcadDermatol. 1988;19:145e156.

6. Lebwohl M, Abel E, Zanolli M, Koo J, Drake L. Topical therapyfor psoriasis. Int J Dermatol. 1995;34:673e684.


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7. Lee JCT, Gladman DD, Schentag CT, Cook RJ. The long-termuse of azathioprine in patients with psoriatic arthritis. J ClinRheumatol. 2001;7:160e165.

8. Kravetz RE, Balsam T. Treatment of psoriasis withmercaptopurine. Arch Dermatol. 1961;84:597e600.

9. Greaves MW, Dawber R. Azathioprine in psoriasis. Br Med J.1970;2:237e238.

10. Feldges DH, Barnes CG. Treatment of psoriatic arthropathywith either azathioprine or methotrexate. Rheumatol Rehabil.1974;13:120e124.


11. Du Vivier A, Munro DD, Verbov J. Treatment of psoriasis withazathioprine. Br Med J. 1974;1:49e51.

12. Benenson E, Fries JWU, Heilig B, Pollok M. High-doseazathioprine pulse therapy as a new treatment option inpatients with active Wegener's granulomatosis and lupusnephritis refractory or intolerant to cyclophosphamide. ClinRheumatol. 2005;24:251e257.

13. Aries PM, Hellmich B, Reinhold-Keller E, Gross WL. High-doseintravenous azathioprine pulse treatment in refractoryWegener's granulomatosis. Rheumatology. 2004;43:1307e1308.































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prolong remission of psoriasis with azathioprine pulse therapy

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