Home            Past Issues            About IP            About IAP           Author Information            Subscription            Advertisement              Search  

   
Case Report

Indian Pediatr 2012;49: 750-752

Leflunomide in Systemic Onset Juvenile Idiopathic Arthritis


Afsana Jahan, Vivek Dewan and Tribhuvan Pal Yadav

From Department of Paediatrics, Post Graduate Institute of Medical Education and Research, Dr Ram Manohar Lohia hospital, New Delhi, India.

Correspondence to: Dr Tribhuvan Pal Yadav, H 1571 GF Chittaranjan Park, New Delhi 110 019, India.
Email: tribhuvanpal@gmail.com

Received: January 5, 2012;
Initial review: January 30, 2012;
Accepted: April 21, 2012.

 


Methotrexate, the mainstay of treatment in Juvenile idiopathic arthritis, might not be effective in a few patients of polyarticular and systemic onset juvenile idiopathic arthritis. Use of biologicals like TNF-
α blockers, the next line of preferred drugs is constrained by the high cost. We successfully used leflunomide in four patients.

Key words: Systemic onset juvenile idiopathic arthritis, leflunomide.


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.

2. Silverman E, Mouy R, Spiegel L, 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 of leflunomide in patients with juvenile idiopathic arthritis in clinical practice. J Rheumatol. 2010;37:1763-7.

 

Copyright 1999-2012  Indian Pediatrics