Efficacy and Safety of Thalidomide as Adjunct Therapy in Refractory Systemic Juvenile Idiopathic Arthritis Patients

About 50% of systemic onset juvenile idiopathic arthritis (sJIA) patients run a recalcitrant disease course and resistant to the conventional disease modifying anti inflammatoy drugs (DMARDs), ultimately resulting in permanent disability from joint destructions. Thalidomide has been reported as an effective and safe drug in the management of systemic JIA due to its immunomodulatory properties. This was an interventional study, aimed to evaluate the efficacy of thalidomide in refractory JIA patients. Twenty five systemic JIA patients who were refractory to conventional DMARDs were included in this study. These patients were prescribed thalidomide at a dose of 2-3mg/kg/day for 12 months. Efficacy of thalidomide was assessed by using Wallace criteria at 6 month and 12 month of thalidomide treatment. Active arthritis was improved in 55% and 73% of the patients at 6 and 12 month of thalidomide treatment respectively. Fever and rash subsided in 72.8% and 81.2% of patients respectively at 12 month of follow up. Hepatosplenomegaly and lymphadenopathy regressed in 100% of patients at 12 th month follow up. ESR was also improved in 50% and 68.2% cases at 6 and 12 months respectively. Few minor side effects were observed like transient elevation of liver enzyme and somnolence in this study. It may be concluded that thalidomide is safe and effective in refractory JIA patients.


Introduction
Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of children and is a very important cause of short and long term morbidity and disability. 1 It is characterized by idiopathic peripheral arthritis with an immunoinflammatory pathogenesis possibly activated by contact with external antigens. 2 is classified into seven subgroups according to International league of associations for rheumatology (ILAR) 2001 classification. 3ystemic onset JIA (sJIA) is one of the seven subtypes, incidence of which was found in 10-20% cases. 4Recently, a study done in Bangladesh found that 14% of patients had sJIA in their study.5 Besides, an Indian and a Canadian study found 7.7 and 4.4 % of sJIA patients respectively in their series. 6,7Systemic JIA has 2-4% overall mortality rate and accounts for two third of all deaths among children with arthritis.About 50% of these patients run a recalcitrant disease course and resistant to the conventional disease modifying anti rheumatic drugs (DMARDs), ultimately resulting in permanent disability from joint destructions and local growth deformities. 8alidomide is a unique anti-inflammatory agent that suppresses angiogenesis, cellular adhesion molecule expression and production of tumor necrosis factor-α and interleukin-6.It also inhibits leucocyte chemotaxis and decrease the CD4/CD8 ratio. 9Thalidomide, once discarded as a potent teratogen, has been reported effective in the management of sJIA due to its immune modulatory properties. 10Sedation, somnolence, myalgia, constipation, neutropenia and anaphylaxis were found as common side effects of thalidomide therapy in different studies. 10,6Till date, so far no study has been done on efficacy of thalidomide therapy in refractory sJIA patients in Bangladesh.The aim of this study was to evaluate the efficacy of thalidomide in refractory sJIA patients.

Materials and Methods
This was an interventional study carried out in the Paediatric Rheumatology follow-up clinic run by the Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from July 2013 to December 2014.There were 72 sJIA patients, who were registered in the paediatric rheumatology follow up clinic during study period.Amongst them, 25 were identified as refractory sJIA patients, and were enrolled in the current study.Three patients did not complete their regular follow-up visit, and were subsequently excluded from the study.
After obtaining informed consent from patients/parents, data were collected in a questionnaire.The data included demographic information, detailed history, physical examination and laboratory findings including CBC with ESR, serum aminotransferase and serum creatinine.
The study subjects were administered methotrexate (MTX) by sub cutaenous route at a dose 15 mg/m 2 body surface area/week for at least 6 months along with steroid (starting at 0.5 to 1 mg/kg/day and gradually tappering dose).As no satisfactory improvement occured, hydroxychloroquine at a dose of 5 to 6 mg/kg/day was added for another 3 months.
Working definition of Refractory sJIA patients who were treated with two conventional DMARDs in appropriate dose along with other adjuvant therapy for at least 6 months and failed to achive a remission according to Wallace criteria 11 were considered as refractory sJIA patient.Subsequently these patients were prescribed thalidomide at a dose of 2-3mg/kg/day for 12 months.Methotrexate and hydroxychloroquine were also continued during this period.Efficacy of thalidomide was assessed by using Wallace criteria 11 at 6 th month and 12 th month of thalidomide treatment.At the same time adverse events of thalidomide if any were also looked for.For statistical analysis, Chi-square and paired t-test were done for qualitative and quantitative data respectively.

Results
A total of 22 patients completed the study.Amongst them, 82% were male and 18% were female, M: F ratio was 5.25:1.Age range of the patients was 5.5 year to 15 year and most of the patients were in the age group of 6-10 year.Disease duration at presentation was more than 12 months in the majority (68%) of cases.The mean dose of steroid was 0.635±0.123mg/kg at the beginning of the study (table I).

Discussion
Systemic arthritis has a variable disease course.Among about the half of the patients, the disease is characterized by monocyclic or intermittent course with relapses followed by remission.Remaining half of the patients, the disease follows an unremitting course. 11Persistently active systemic JIA represents a major challenge to paediatric rheumatologists.Traditional diseasemodifying anti-rheumatic drugs have limited benefit in this type of JIA. 12 In a study, thalidomide was shown efficacious for treating refractory sJIA. 10The present study have also shown the efficacy of thalidomide therapy in 22 patients who were nonresponsive to traditional DMARDs.Before starting thalidomide they were offered biological therapy, but due to economic constraint they could not afford that.Boys and girls ratio was 5.25: 1 which was different from other established study 9 where boys and girls ratio was nearly 1: 1.This may be due to the fact that boys get more preference and attention by the male dominating society in Bangladesh and are taken to health service facilities early.Another study from Bangladesh also showed similar findings where M:F ratio among JIA patients were 2:1. 13e number of patients with active arthritis were significantly improved at 6 th month (54.55%) and 12 th month (73%) of follow-up when compared with time of enrollment (p <0.001).Systemic features like fever, rash, lymphadenopathy, hepatosplenomegaly were also significantly improved in this study.Normalisation of acute phase reactant (ESR) was found in 68.2% cases.These findings were almost similar with Lehman et al's results. 10García-Carrasco et al reported three cases of recalcitrant sJIA that improved dramatically after treatment with thalidomide. 14n Indian study with three children with refractory sJIA also reported improvement after treatment with thalidomide. 6se of steroid was reduced significantly in this study and two of our patients were able to discontinue prednisolone, whereas 6 (out of 13) patients were able to discontinue prednisolone in Lehman et al study. 10The difference may be explained by the facts that, perhaps severity of the disease at presentation might have been different in this study.Delay in diagnosis and treatment before seeking medical services might have also influenced the outcome.
Thalidomide is a well-known teratogen which was withdrawn from market in 196 15 but this risk is not a problem in this study population.Tolerability of thalidomide is generally found to be better with single night time administration.Thalidomide is a cheap and available drug in comparison to other biological agents. 6mmon side effects in this study included transient elevation of aminotransferase in two cases and somnolence in three cases.Short lived paresthesia (tingling, numbness) were found during initial period of therapy in another study. 10o neurotoxicity amongst the cases of this study was to be found though in literature neurotoxicity/ paraesthesia is commonly found. 1

Conclusion
Beneficial effects of thalidomide in sJIA patients as adjunct therapy were found in this study amongst the patients, who were non responsive to traditional DMARDs.So, it may be concluded from this study that thalidomide may be used in children with sJIA who have failed to conventional therapy.Though the adverse effects of this drug were minimal, use of this drug in children should be carefully supervised.

Table I :
Baseline demography of cases (n= 25)

Table IV :
Improvement According to Wallace Criteria from Baseline to Follow up (n=25) th month of treatment (p <0.001).It was possible to taper the dose of steroid during follow up at 6 month and 12 month but significant reduction was possible at 12 month (table IV).