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Letter to the Editor

Prolonged remission of rheumatoid arthritis withdexamethasone cyclophosphamide pulsetherapy: A case series

To The Editor

Rheumatoid arthritis is considered to be triggered by Th1

lymphocyte activation in genetically predisposed individuals.

It manifest as persistent inflammatory synovitis usually

involving the peripheral joints in a symmetrical manner.

Variousmedical treatments for rheumatoid arthritis including

methotrexate1 and biologics2 are helpful transiently but are

not able to produce prolonged or permanent remissions.

Dexamethasoneecyclophosphamide pulse (DCP) therapy has

been used widely to cure a large number of auto-immune

diseases like pemphigus3,4 systemic sclerosis,5 systemic lupus

erythematosus6 etc. with permanent remission.

Five patients having clinical and serological features of

rheumatoid arthritis or not responding to treatments were

included in this study. A written informed consent was taken

from all patients. Investigations included hemogram, LFT,

CRP, serum electrolytes, rheumatoid factor (RF), anti-CCP, and

urine analysis for RBC, X-rays chest, hands, shoulders, knees

and feet. These tests were done before starting the treatment

and every month before giving the pulse. Anti-CCP and RF

were repeated every 6e12 months. DCP therapy consists of

100 mg dexamethasone dissolved in 500 ml of 5% glucose

transfused in 1e1.5 h given on three consecutive days. On day

one, cyclophosphamide 500 mg was given in the drip. This

was called one pulse and is repeated every 28 days. In between

the pulses, cyclophosphamide 50 mg orally daily was given.

The whole treatment schedule was divided into four phases.

In phase I the patients continued other anti-rheumatic treat-

ment initially along with DCP therapy till the tenderness,

swelling and the stiffness subsided completely (when all the

anti-arthritic treatment was stopped completely). At this

point, the patients entered into phase II where he was given

compulsory 9 DCP pulses. In phase III, if the patients were still

free from pain in joints, the pulse was stopped, but cyclo-

phosphamide 50 mg daily was continued for another 9

months. At the end if there was no pain in the joints, cyclo-

phosphamide was also stopped and the patient entered into

phase IV. In this phase, the patients were followed-up every

six months with clinical examination for any relapse of

tenderness, swelling or morning stiffness and tests like ESR

Please cite this article in press as: Gupta R, Prolonged remissionmide pulse therapy: A case series, Indian Journal of Rheumatolo

and CRP were done. For those patients in reproductive age

group, azathioprine500 mg on day one of pulse and 100 mg

orally daily in between, in place of cyclophosphamide were

given.

1. Case reports

1.1. Case 1

A 60-year-old female presented with pain and swelling of

both elbows, wrists, both inter-phalangeal and meta-

carpophalangeal joints, knees, ankles and meta-

tarsophalangeal joints of 2 months duration with morning

stiffness of 15 min. Nimesulide 100 mg and paracetamol

1000 mg daily for 1 month showed no improvement. CRP

11mg/ml, ESR 47mmandRFwas 220 IU/mlwithnegativeANA.

At this juncture DCPwas started alongwith diclofenac sodium

200 mg daily. Chlorzoxazone 1.5 gm daily was added after 2

months. After 8 DCPs there was no pain in any joints when

diclofenac and chlorzoxazonewere stopped. Subsequently she

received 9 DCP in phase II and cyclophosphamide 50 mg daily

for another 9 months in phase III. There was no recurrence of

pain in joints during half yearly follow-up for the next 6 years

in phase IV. ESR, CRP and RF repeated every 6th months was

also normal.

1.2. Case-2

A 45-year-oldmale presentedwith pain in his right wrist, right

ankle, both shoulders and swelling and tenderness of left

wrist, all metacarpophalangeal joints and left ankle of 6

months duration. CRP 12.3 mg/ml, ESR 32 mm and RF were

240 IU/ml. X-rays of chest, hands and feet were normal.

Naproxen 500e750 mg daily for 5e6 weeks showed no effect

on pain and swelling. At this juncture DCP therapy was star-

ted. After 4th DCP there was no swelling and pain in any

joints. When naproxen was stopped. DCP was continued for

another 9 months without pain in joints. Cyclophosphamide

50mgwas also stopped after 9 months. Half yearly follow-ups

of rheumatoid arthritis with dexamethasone cyclophospha-gy (2014), http://dx.doi.org/10.1016/j.injr.2014.01.008

i n d i a n j o u rn a l o f r h e uma t o l o g y x x x ( 2 0 1 4 ) 1e32

for 6 years showed no recurrence. RF was negative with

normal ESR and CRP at the end of the 6 years.

1.3. Case-3

A 60-year-old female presented with pain and swelling of her

shoulders, wrists, inter-phalangeal, metatarsophalangeal and

hip joints of 4 year duration which used to improve with

ibuprofen, paracetamol taken off and on. There was a sudden

increase in pain in all the above joints with morning stiffness

of 1 h duration since 3 months. ESR was 37 mm with CRP

13 mg/ml, and RF 240 IU/ml. X-rays of both hands showed

rarified bone with degenerative changes. At this point DCP

therapy was started along with diclofenac sodium 100 mg

daily. Pain and morning stiffness of all joints disappeared

after 4th DCP when diclofenac sodium was stopped. DCP was

stopped after 9 months. Cyclophosphamide 50 mg daily was

continued for another 9 months. RF repeated after 6, 12 and 18

months was found negative with ESR 10 mm. X-rays of both

hands still showed decreased mineralization. There was no

pain or stiffness in any joints during next 5 years without any

treatment.

1.4. Case-4

A 30-year-old female presentedwith pain and swelling of right

2nd metacarpophalangeal joint, wrist and knee; left shoulder

and ankle; and bilateral inter-phalangeal joints and meta-

tarsophalangeal joints of 2 years duration with morning

stiffness of 2 hours duration. X-rays of all joints showed no

erosions. RF was 41.8 IU/ml, anti-CCP13.50 unit/ml with ESR

69 mm. and CRP 4.2 mg/l. She was started on methotrexate

20 mg and methylprednisolone 12 mg weekly, hydroxy-

chloroquine 400 mg and paracetamol 650 mg daily. Pain in all

joints disappeared in 15 days and stiffness in 1 month. During

the next 6 months methylprednisolone was tapered and

stopped. However, she developed pain in ankle and wrist

joints during next 7 days. Methotrexate was increased to

30 mg per week orally along with above-mentioned treatment

with increase in pain in most of the joints during next 5e6

months. At this point pulse therapy with azathioprine was

started. Pain and stiffness in all joints cleared completely after

4th pulse. She was given another 9 pulses without any pain.

Azathioprine 100 mg daily was continued for another 9

months without any pain. There was no recurrence of pain

during next 1-year follow-up.

1.5. Case-5

A 28-year-old female presented with pain and swelling of her

ankles, right knee and left shoulder of 2-year duration. X-rays

of ankles, knees, shouldersandpelvis showednoerosionswith

normal bone. ESRwas 39mm;CRP 11.3mg/ml andRF 85.14/ml,

ANA and anti-CCP (0.5 unit/ml) were negative. There was no

improvement with daily paracetamol 650 mg, methylpred-

nisolone 24 mg, chlorzoxazone 1.5 g, hydroxychloroquine

400 mg and methotrexate 15e30 mg given weekly in different

combination during 2 years duration. When presented, she

was on methotrexate 15 mg orally weekly etoricoxib 60 mg

daily, injection methylprednisolone 80 mg intramuscular

Please cite this article in press as: Gupta R, Prolonged remissionmide pulse therapy: A case series, Indian Journal of Rheumatolo

weekly. Her ESR was 81 mm with CRP 34.2 and RF 171.5 IU/ml

and anti-CCP 0.05 unit/ml. At this juncture. DAP therapy with

azathioprine was started, pain in all joints improved slowly

and cleared completely after 12th pulse. Slowly all the drugs

were withdrawn one by one and after 15th pulse she had no

pain and no drugs. She continued another 9 pulse. Azathio-

prine 100 mg was continued for another 9 months. There was

no pain during 1-year follow-up. At the end RF was 97.00/ml,

ESR-1 mm, CRP 1.50 and anti-CCP 0.50 unit/ml.

2. Discussion

Pulse therapy with methylprednisolone in rheumatoid

arthritis was used for the first time by Liebling et al in 1981.7

with clinical as well as serological improvement in favor of

methylprednisolone.

DCP has been found to put many auto-immune dis-

orders3e6 into permanent remission, that is why it has been

used in RA.

In the present series DCP/DAP therapy was found effective,

safe and devoid of much side effects. Usual side effects

include diffuse loss of hairs, occasional leucopenia and

cystitis. In long termsmany patientsmay get amenorrhea and

azoospermia. It was able to produce long term remissions

lasting even up to 6 years after complete stoppage of treat-

ment. However, the number of patients is too limited to draw

any conclusion.

It is hoped that if used properly it may be able to produce

prolonged and permanent remission in rheumatoid arthritis

too.

r e f e r e n c e s

1. Weinblatt WE, Weissman BN, Holdsworth DE, et al. Long-termprospective study of methotrexate in rheumatoid arthritis:conclusion after 132 months of therapy. J Rheumatol. 1998;25:238e242.

2. Weinblatt WE, Weissman BN, Holdsworth DE, et al. A trial ofetanercept, a recombinant tumor necrosis factor receptor: Fcfusion protein, in patients with rheumatoid arthritis receivingmethotrexate. N Engl J Med. 1999;340:253e259.

3. Pasricha JS, Gupta Ramji. Pulse therapy with dexamethasone e

cyclophosphamide in pemphigus. Indian J Dermatol VenereolLeprol. 1984;50:199e203.

4. Gupta Ramji. Prolonged remission of pemphigus induced bydexamethasone-cyclophosphamide pulse therapy. Indian JDermatol Venereol Leprol. 2007;73:121e123.

5. Gupta Ramji. Systemic sclerosis treated with dexamethasonepulse. Indian J Dermatol Venereol Leprol. 2003;69:191e192.

6. Gupta Ramji, Gupta Sarthak, Khera Vikas. Dexamethasonecyclophosphamide pulse therapy in systemic lupuserythematosus. A case report. J Dermatolog Treat. 2009;20:55e58.

7. Liebling MR, Leib E, Mclaughlin K, et al. Pulsemethylprednisolone in rheumatoid arthritis. A double-blindcrossover trial. Ann Intern Med. 1981;94:21e26.

Ramji Gupta*

Department of Dermatology, Indraprastha Apollo Hospital,

Sarita Vihar, New Delhi 110076, India

of rheumatoid arthritis with dexamethasone cyclophospha-gy (2014), http://dx.doi.org/10.1016/j.injr.2014.01.008

i n d i a n j o u r n a l o f r h e uma t o l o g y x x x ( 2 0 1 4 ) 1e3 3

Sarthak Gupta

National Institute of Arthritis and Musculoskeletal and Skin

Diseases, Bethesda, MD 20892, USA

*Corresponding author. M-54, Jal Vihar Road, Lajpat Nagar-II,

New Delhi 110024, India. Tel.: þ91 (0) 11 26347405.

E-mail addresses: drramjigupta@yahoo.co.in,

sarojramji@yahoo.com

Please cite this article in press as: Gupta R, Prolonged remissionmide pulse therapy: A case series, Indian Journal of Rheumatolo

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of rheumatoid arthritis with dexamethasone cyclophospha-gy (2014), http://dx.doi.org/10.1016/j.injr.2014.01.008