Thalidomide Is an Adjunct Therapy for the Refractory Systemic Juvenile Idiopathic Arthritis Patients in a Tertiary Hospital Study ()
1. Introduction
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood and an important cause of short and long-term disability [1] . JIA is defined by the International League of Associations for Rheumatology (ILAR) as arthritis of unknown etiology beginning before the sixteenth birthday and persisting for at least six weeks with other known conditions excluded [2] .
Worldwide incidence of JIA ranges from 0.8 to 22.6 per 100,000 children per year with the prevalence ranges from 7 to 401 per 100,000 children [3] . The exact incidence and prevalence of JIA data is not available in our country. A study conducted in a semi-urban area of Bangladesh showed prevalence of JIA as 60.5 per 100,000 children [4] .
JIA is classified into seven subgroups according to International league of association for rheumatology (ILAR) 2001 classification. sJIA is one of the subgroups of JIA [5] . Sjia constitute 5% - 15% of all JIA cases [6] . A study conducted by Islam MI et al. at Bangabandhu Sheikh Mujib Medical University over a decade showed sJIA constitutes 17% of total JIA patients [7] .
Systemic JIA has 2% - 4% overall mortality rate and accounts for 2/3rd of all death among children with arthritis [8] .
Though exact cause is not known, hypothesis exists that abnormalities in innate immunity plays a major role in pathogenesis of sJIA. The cytokines playing important role are IL-1, IL-6, TNF-alpha and IL-18 which are secreted from T lymphocytes, macrophage, and monocyte [9] .
Systemic JIA is most difficult to treat among all arthritis. About 50% of children with sJIA do not respond to drug that work for others subtype of JIA [10] .
Thalidomide is an immunomodulating agent which reverses many of the cytokine’s disturbances. Also it is a remission producing, corticosteroid sparing agents in refractory sJIA patients [11] . It was observed that a quite good number of refractory sJIA patients were attending in the Paediatric Rheumatology and Immunology clinic in Paediatric Department of BSMMU. These patients were not improved to traditional treatment like MTX and other drugs.
So, this study was aimed to evaluate the efficacy of thalidomide in refractory sJIA patients who didn’t respond to traditional DMARDS.
2. Methods and Materials
This was a prospective interventional study carried out in the Paediatric Rheumatology and Immunology follow-up clinic run by the Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from January 2019 to July 2020. There were 29 refractory sJIA patients, were registered in this clinic, among them four patients did not complete their regular follow-up and subsequently excluded from the study. Informed written consent was taken from parents, and Institutional Review Board Clearance Certificate (NO. BSMMU/2019/2714) was taken before enrollment of the study. Data were collected in a semi-structured pretested questionnaire which included demographic information, detailed history, physical examination and laboratory findings including CBC with ESR, urine R/M/E, serum aminotransferase and serum creatinine. After confirmation of diagnosis, sJIA patients are treated with MTX by sub cutaneous route at a dose 15 mg/m2 body surface area for at least 6 months along with steroid and other adjuvant drugs. If patients failed to respond in six months then they were considered as refractory sJIA patient. Subsequently these patients were added thalidomide at a dose of 3 - 5 mg/kg/day along with MTX. Efficacy of thalidomide was assessed by using JADAS 27 criteria at 12th week and 24th week of treatment. At the same time adverse events of thalidomide were also assessed. For statistical analysis, Chi-square and paired t-test were done for qualitative and quantitative data respectively.
3. Results
A total of 25 patients completed the study. Amongst them, 64% were female and 36% were male and M:F ratio was 1.77:1. Age range of the patients was 4 - 14 years. The mean age at disease onset was 5.45 years. Disease duration at presentation was 1 to 3 year in the majority (92%) of cases. The mean dose of steroid was 0.52 ± 0.33 mg/kg/day at the beginning of the study. (Table 1)
All patients presented with arthritis and fever. Along with fever 96% presented with lymphadenopathy, 88% presented with rash. Hepatomegaly and splenomegaly were present in 84% & 80% of cases respectively. (Table 2)
Significant improvement of Hb% and ESR level were observed from baseline to subsequent follow up. The others parameter like total count of WBC, neutrophil count, platelet count were also decreased significantly from baseline to 12th week and 24th week follow up. (Table 3)
All the parameters of JADAS-27 includes physician VAS, parents/patients VAS, active joints count and ESR improved significantly from baseline to 12th week and 24th week follow up. Statistical analysis was done using student paired t test. (Table 4)
Table 5 shows that few adverse effects occurred during 24 weeks of Thalidomide therapy. Somnolence developed in 28% and 24% cases at 12th week and 24th week respectively. Hb was low in 4% of cases at 24th week follow up. Neutropenia was present in 4% case.
The improvement of total score of JADAS-27 was 77.51% at 12th week and 97.52% at 24th week (Figure 1). Improvements were statistically significant (p value < 0.001).
It was possible to taper the dose of steroid during follow up at 12th week but significant reduction was possible at 24th week (Figure 2).
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Table 1. Baseline demographic characteristics of cases (n = 25).
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Table 2. Baseline clinical characteristics of cases (n = 25).
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Table 3. Changes in the laboratory parameters from baseline to follow up among study participants (n = 25).
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Table 4. Changes in the JADAS-27 variable from baseline to follow up among study participant (n = 25).
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Table 5. Number of adverse clinical and laboratory events during follows up period.
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Figure 1. Changes in the total JADAS-27 from baseline to follow up among study participants (n = 25).
4. Discussion
Systemic arthritis has a variable disease course. sJIA is the most difficult to treat among all arthritis. In most severe cases of sJIA up to 2/3rd of children experience chronic arthritis and approximately 50% develop significant joint disabilities despite of available traditional treatment. About 50% of children with sJIA
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Figure 2. Dose of steroid from baseline to follow up among study participants (n = 20).
do not respond to drugs that work for other subtypes of JIA. In a study by Islam, et al. found thalidomide was shown efficacious for treating refractory sJIA.
There was 73% improvement of arthritis from baseline to 12 months follow up [12] .
The present study has shown the efficacy of thalidomide therapy in 25 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. Among the patients 16 were female and 9 were male, the ratio being 1.77:1. This study showed mean physician VAS at baseline was 7.8 cm which was almost similar to the study done by Islam, et al. [12] . At 12th week and 24th weeks of treatment, mean physician VAS were improved significantly. At 12th and 24th week of follow up mean joints count reduction were significant (p value < 0.001). Our study showed mean normalized ESR at baseline was 5.14, which was similar to Carrasco et al. study. At 12th and 24th weeks, the ESR was significantly reduced compared to baseline in our study. The percentage of improvement of Physician VAS, Parents/patients VAS, active joints count and ESR at 12th and 24th week were significant observed in this study.
García-Carrasco, et al. reported three cases of recalcitrant sJIA that improved dramatically after treatment with thalidomide. An Indian study with three children with refractory sJIA also reported improvement after treatment with thalidomide [11] . Steroid sparing effect of Thalidomide was observed in the Lehmanet, et al. study where they discontinued prednisolone at 13 patients out of 20 after 24th week of treatment which was also matched with the present study [13] .
Tolerability of thalidomide is generally found to be better with single night time administration. Some adverse effects were noted during 24 weeks treatment with Thalidomide. Among the adverse effects somnolence, anemia and neutropenia were found during follow up.
5. Conclusion
Significant improvement in all the variables of JADAS in refractory sJIA patients were found after thalidomide therapy during follow-up. Somnolence, paresthesia, constipation was found as a side effects in a small number of patients.
Limitation of Study
This is single center study with small study population.
Data Collection Sheet
Principle Investigator: Dr. Md. Taiyabur Rahman, MD (Phase B Resident).
Place of Study: Paediatric Rheumatology and Immunology Clinic and Inpatient, Department of Paediatrics, BSMMU.
ID No: Date:
Name: Age:
Father’s Name: Contact Number:
Address:
Section A:
Section B:
Past Treatment History:
Present Treatment History:
Dose of Prednisolone:
Information of Physical Examination:
Anthropometric Information:
Locomotors System:
Laboratory Investigations:
Presence of Common Drug Related Adverse Events: