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Leflunomide, an Isoxazole
derivative, is a disease-modifying anti-rheumatic drug
(DMARD). Its active metabolite A-77 I726 inhibits
pyrimidine synthesis, thereby reducing the proliferation
of T-lymphocytes, down-regulating autoimmune response
[1]. Although, it has been found to be as effective as
methotrexate in patients with polyarticular JIA [2,3],
it has been infrequently used in children. We used
leflunomide in 4 patients of systemic onset juvenile
idiopathic arthritis (SOJIA) who did not respond to MTX
and could not afford TNF-α
blockers.
Case Report
Case 1: A five-year-old girl
presented with history of moderate grade fever two
spikes per day and swelling, pain and morning stiffness
of multiple joints for two months. There was no history
of loose stool, dysuria, rash or eye pain. On
examination, she had multiple significant
lymphadenopathy and hepatomegaly with no subcutaneous
nodules, enthesitis or uveitis. Her bilateral ankles,
knee, wrist, metacarpophallangeal (MCP) and proximal
interphalangeal (PIP) joints were swollen and tender
(active joints 26). Investigations revealed hemoglobin,
total leukocyte count, erythrocyte sedimentation rate
(ESR) and C reactive protein (CRP) of 8.6 g/dL, 8750/mm3,
12 mm first hour and 2.4 mg/dL, respectively. Rheumatoid
factor (RF) and antinuclear antibody (ANA) were
negative. Liver function tests (LFT), kidney function
tests (KFT), and serum immunoglobulin levels were
normal. She was diagnosed as a case of SOJIA and was
given injection methotraxate (MTX) 10 mg/m2/
week, S.C. and oral prednisolone 2 mg/kg/day in 4
divided doses. After 2 weeks, patient responded and
prednisolone was tapered over next two weeks. She had
eight relapses over next five years, first occurring
after six months of initial therapy. Each flare-up was
associated with fever, lymphadenopathy,
hepatosplenomegaly, active joints ranging from six to
eighteen, and raised acute phase reactants. Each time
prednisolone was added in the dose of 2 mg/kg/day for
2-3 weeks and then tapered over next 2-3 weeks. In the
third relapse MTX was increased to 15 mg/m2/week
subcutaneous and hydroxychloroquine (HCQS) at 5mg/kg/day
was added. The last of these flares occurred at ten-
and-a-half years of age when thalidomide 100 mg once
daily (OD) was added to MTX, HCQS and prednisolone. She
responded and prednisolone was tapered to 2.5 mg/day
over next two weeks. While on MTX, prednisolone (2.5 mg
OD), HCQS and thalidomide, she developed another relapse
within 4 weeks with six active joints. She also
developed side-effects of steroid in the form of
cushingoid features; hirsutism and growth failure
(height gain of 3 cm in 1 year). At the age of 13,
leflunomide was added to these drugs and after eight
weeks patient had no active joint disease. All other
drugs were withdrawn over next four months. She has been
in remission for last 21 months with normal clinical and
biochemical parameters.
Case 2: A nine-year-old boy
was diagnosed as SOJIA at six year of age on the basis
of two months history of fever, pain and swelling of
multiple joint and examination showing 18 active joints
(bilateral knees, ankles, wrists, elbows and all PIPs),
without enthesitis or uveitis. Investigations revealed
ESR of 50 mm, CRP of 12 mg/dL, positive RF, negative ANA
and normal LFT and KFT. After three weeks of MTX (15
mg/m2 /week,
subcutaneous) and prednisolone (2 mg/kg /day), there was
partial response (active joints, 8) and prednisolone was
tapered over next three weeks to 2.5 mg OD. Over next
one year, he had four flare-ups requiring prednisolone
to be increased in each flare. He also developed growth
failure, hirsutism and cushingoid features. He was given
a trial of thalidomide and HCQS for three months but
showed no response. The active joint count persistently
remained four. Thalidomide and HCQS were stopped and
leflunomide was added to MTX and low dose prednisolone.
After three months of leflunomide therapy, there was no
active joint disease and acute phase reactants were
normal. MTX and prednisolone were withdrawn over next
three months. He has been in remission for last 18
months on leflunomide alone.
Case 3: A three-year-old boy
was diagnosed at one year of age as a case of SOJIA on
the basis of fever, hepatosplenomegaly, lymphadenopathy,
morning stiffness, and pain and swelling of multiple
joints without enthesitis. He had 28 active joints
(bilateral knees, ankles, wrists, elbows, all MCPs,
PIPs).His ESR was 34 mm while RF and ANA were negative.
Injection MTX and prednisolone in the doses as in case 2
were started. He responded partially over 3 weeks and
prednisolone was tapered to 2.5mg/day over next 3 weeks.
After six months he had 12 active joints, raised ESR (28
mm) and Leflunomide was started. After three months, all
his joints were normal. Over next three months MTX and
prednisolone were withdrawn. At present, he is in
remission for past thirteen months.
Case 4: A three-year-old boy
was diagnosed at one-and half-years of age as SOJIA on
the basis of 3 months history of fever, pain, swelling
and morning stiffness of ankles and knees, cervical
lymphadenopathy and hepatosplenomegaly. His ESR was 80
mm, and CRP 2.5 mg/dL. RF and ANA were negative. He was
started on injection MTX and prednisolone in the same
dose as case 2. Over next three weeks, swelling and
tenderness decreased and steroids were tapered. He took
four months to respond completely (all joints, ESR and
CRP were normal). Over the next one year, he relapsed
five times, requiring high dose prednisolone each time.
In the second relapse, HCQS and in the third relapse,
thalidomide was added. He also developed cushingoid
features, hirsutism, and gained only 2 cm of height in a
year. At fifth relapse, leflunomide was added. He
started responding and all his joints were normal over
next six weeks. HCQS, thalidomide, prednisolone and MTX
were withdrawn gradually over the next six months. He
continues to be in remission for last six months.
The scores of Visual analogue scale
for pain (VAS), Physician global assessment (Phy GA) and
Parents general evaluation (PGE) before and after
starting leflunomide in these 4 patients are depicted in
the Table I.
TABLE I Characteristics of SOJIA Patients Before and on Leflunomide Therapy
|
Case |
Age
(y)/Sex |
Total duration of disease ( y) |
|
Before starting leflunomide |
After starting leflunomide |
|
|
|
No. |
Active |
ESR |
VAS |
PhyGA |
PGE |
Response |
Remission |
No. |
ESR |
Side |
|
|
|
of
|
joint |
|
|
|
|
time |
period
|
of |
|
effects |
|
|
|
flares |
count |
|
|
|
|
(mo) |
(mo) |
flares |
|
|
|
1 |
13/F |
8 |
9 |
4 |
42 |
7 |
5 |
6 |
2 |
21 |
0 |
8 |
2 LRTI |
|
2 |
9/M |
3 |
4 |
4 |
120 |
5 |
6 |
8 |
3 |
18 |
0 |
10 |
3 LRTI |
|
3 |
3/M |
2 |
0 |
12 |
54 |
8 |
6 |
7 |
3 |
13 |
0 |
14 |
Nil |
|
4 |
3/M |
1.5 |
5 |
6 |
34 |
6 |
5 |
7 |
2 |
6 |
0 |
2
|
Diarrhea |
|
Leflunomide
dose: For case 1 and 2 100 mg OD for 2 days then
10 mg OD. For case 3 &4 100mg OD for 1 day then
10 mg alternate day. Visual analogue scale (
VAS), Physicians Global Assessment (Phy GA), and
Parents General Assessment (PGA), are in scale
of 0 to 10 (higher the score worse is the pain
or disease activity, Active joint count, VAS,
Phy GA and PGE were zero in patients on
leflunomide. LRTI: Lower respiratory tract
infection. |
Discussion
Methotrexate has been the mainstay of
treatment in most patients of JIA. In a few of the
polyarticular and SOJIA patients there might be
insufficient response or repeated disease flares,
adversely affecting the functional activity, growth and
development. Treatment of such patients poses a medical
challenge in a resource limited country where
biologicals are non-affordable.
Leflunomide has been widely used in
adults but not in children. In adults it has been found
to be equally efficacious as sulphasalazine and
methotrexate, and delays radiological progression [4].
In the three studies conducted in children so far, it
has been found to be as effective as methotrexate in
polyarticular JIA patients [2,3,5]. Commonly reported
side-effects of leflunomide were diarrhea, abdominal
pain, anorexia, gastritis, rashe, headache, and raised
transaminases [4,5]. In our four patients of SOJIA, the
clinical response to leflunomide was found to be good
and we were able to withdraw other DMARDs and
prednisolone. The response time ranged from two to three
months. The side-effects encountered were mild such as
lower respiratory tract infections and diarrhea.
Leflunomide may serve as an option in poor patients not
responding to other drugs. However, well planned
randomized controlled trials are required in various
subsets of JIA to define the rightful place of
leflunomide.
Contributors credit: TPY, AJ and
VD: conceived, collected the data and drafted the paper;
TPY has revised the manuscript to its final form and
will act as guarantor.
Funding: None; Competing
interest: None stated.
References
1. Fox RI. Mechanism of action of
leflunomide in rheumatoid arthritis, J Rheumatol
(Suppl.) 1998;53:20-6.
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Jung LK, Saurenmann RK, Lahdenne P, et al.
Leflunomide or methotrexate for juvenile rheumatoid
arthritis. NEJM. 2005;352:655-66.
3. Silverman E, Spiegel L, Hawkins D,
Petty R, Goldsmith D, Schanberg L, et al. Long
term open label preliminary study of safety and efficacy
of leflunomide in patients with polyarticular-course in
juvenile rheumatoid arthritis. Arthritis Rheum.
2005;52:554-62.
4. Osiri M, Shea B, Robinson V,
Suarez-Almazor M, Strand V, Tugwell P, et al.
Leflunomide for the treatment of rheumatoid arthritis: A
systematic review and meta-analysis. J Rheumatol.
2003;30:1182-90.
5. Foeldvari I, Wierk A. Effectiveness
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