Comparative Study of Leflunomide Plus Methotrexate Versus Methotrexate Monotherapy in Refractory Polyarticular Juvenile Idiopathic Arthritis Patients

Study design:

Randomized control trial, Open level, Parallel design

Place of study:

Department of Pediatric Rheumatology Division (OPD clinic and Inpatient), Department of Paediatrics, Bangladesh Medical University

Study period:

From March, 2024 to January, 2026.

Study Population:

All diagnosed cases of Refractory Polyarticular Juvenile Idiopathic Arthritis (JIA) according to ILAR, 2001 unresponsive to methotrexate (at standard dose of 15mg/m² body surface area at least 3-6 months) as monotherapy or together with low dose steroid as bridge therapy who attended Paediatric Rheumatology Division (OPD clinic and inpatient), Department of Paediatrics of BMU, during the study period were the study population.

Sampling method:

Purposive sampling was done.

Sample size: 50

Inclusion criteria:

All diagnosed cases of Refractory Polyarticular Juvenile Idiopathic Arthritis (JIA) according to ILAR, 2001 unresponsive to methotrexate (at standard dose of 15mg/m² body surface area at least 3-6 months) as monotherapy or together with low dose steroid as bridge therapy who attended Paediatric Rheumatology Division (OPD clinic and inpatient), Department of Paediatrics of BMU, during the study period.

Exclusion criteria:

1. A patient with prior or current infectious disorders, including active/latent tuberculosis, and/or H/O chronic or recurrent severe infections, including opportunistic infections.
2. A patient with leucopenia (White blood cell count < 3000/mm3), neutropenia (Neutrophil count < 1000/mm3) and thrombocytopenia (Platelet count < 100000/mm3).
3. Serum creatinine > upper limit of normal reference range.
4. Alanine aminotransaminase (ALT) more than 2 times of upper normal limit.
5. All diagnosed cases of refractory polyarticular JIA who did not give the consent during the study period.

Study variables:

Clinical characteristic variables

• Age
• Gender
• Age at disease onset
• Age group
• Disease duration
• Physician global assessment 0-10cm VAS
• Parent/ patient global assessment 0-10 cm VAS
• Active joint count (0-27 joints)

Laboratory variables:

• CBC with ESR
• S.ALT
• S. creatinine
• Urine RME

Outcome variables:

For Efficacy:

1. Improvement according to JADAS-27 criteria
2. Functional improvment by CHAQ-B (DI)

For Safety:

1. Any infection and allergies
2. Raised liver enzyme
3. Hematological abnormalities (Hb, Total count, Differentials, Platelet count).
4. Raised S. Creatinine.

Study Procedure:

In this randomized control trial 50 diagnosed cases of refractory polyarticular JIA fulfilling inclusion criteria according to ILAR, 2001 were evaluated. The children with acute infections, chronic kidney disease, chronic liver disease, and any lymphoproliferative disorders and children or parents who were unwilling to give their consent were exluded from study.

After having approval by the Institutional Review Board(IRB), BMU, documented informed consent were taken from all patients or parents or care-givers and assent were taken from participants above 7 years of old after informal assessment in clinic.

A predesigned questionnaire was filled out for all patients completed for each patient by interviewing them from their parents and also from their medical records. At BMU, each outpatient and inpatient is assigned a Paediatric Rheumatology and Immunology Clinic (PRIC) number and provided with a record book in which clinical complaints, examination findings, investigation results, disease status, treatment details, and follow-up plans are systematically documented at every visit. The same information is simultaneously entered into a web-based database (paedrhum.com) for secure electronic storage.

Following enrollment in the study, patients were allocated by simple randomization using random allocation software version 2.0 into experimental group and control group. 25 patients were taken in each group. Comprehensive medical history were taken including age at presentation, age at diagnosis, initial clinical presentation, use of sterod, NSAID and DMARDs. A full physical examination will be performed including tender joints, swollen joints, limitation of movement in joints, lymphadenopathy, skin rash, hepatomegaly and/or splenomegaly and serositis will be assessed. Baseline investigations were done including Hb%, total leukocyte count (TLC), differential count (DC), platelet count (PLT), ESR, serum ALT, serum creatinine, Rheumatoid factor, antinuclear antibody, chest X-ray, routine and microscopic examination of urine.

Disease activity were evaluated using a standardized questionnaire containing JADAS-27 (Juvenile Arthritis Disease Activity score in 27 joints) - ankles, knees, hips, meta- carpophalangeal joints (from first to third), proximal interphalangeal joints, wrists, elbows and cervical spine which include number of joint with active disease (swollen joints, tender joints and restriction of movement), physician and patient global assessment of disease activity and acute phase reactant (ESR).

Global assessment of disease activity by physician and patient/parent were done by using visual analog scale (VAS). A 0- 10 cm horizontal line were taken to represent the status of global assessment of disease activity. The line begins at zero indicating disease activity absent and the extreme ends of the line is 10 cm which indicates the activity of disease is maximum (100%). From the initial visit to follow up visit VAS were assessed by the investigator and opinion were taken from the rheumatology team. When a patient marked the line at 7 cm point of the VAS, it was assessed as 70% of disease activity, subsequently 5 cm and 3 cm were indicated 50% and 30% of disease activity.

ESR which was converted to a scale from 0 to 10 by following formula - {ESR (mm in 1st hour) - 20}/10

**ESR with values < 20 mm in 1st hour were converted to 0 and values >120 mm in 1st hour were converted to 10.

A global score of 0 to 57 was obtained by calculating the JADAS-27 as the arithmetic sum of the scores of its four components. A JADAS-27 score of higher than 8.5 is indicative of high disease activity, whereas a score of 3.9 to 8.5 indicates moderate disease activity, 1.1 to 3.8 indicates low disease activity and ≤1 indicates no disease activity.

Functional assessment was done by CHAQ-B (DI) which has eight functional domains: dressing and personal care, rising from a seated position, eating, walking, personal hygiene, reaching, gripping, and daily activities. Each domain consists of several items scored on a 4-point scale ranging from 0 (no difficulty) to 3 (unable to perform). For scoring, the highest item score within each domain was used, and the average of these scores generated the Disability Index, which represented the overall degree of functional impairment.

All patients of experimental group were given leflunomide along with existing methotrexate. Leflunomide will be prescribed as once daily oral dose before meal on weight based 10mg for patients 10 to <20kg, 15mg for patients 20-40kg and 20mg for patients >40kg (Rabinovich, 2024, p. 1466). Every medication were purchased from a single pharmaceutical company. Along with leflunomide, all the study participants of this group received MTX subcutaneously at a dose of 15 mg/m2/ week in a single weekly dose. Participants of control group were given existing MTX subcutaneously at a dose of 15 mg/m²/ week in a single weekly dose at night. Considering high disease activity level, steroids were continued at low bridging dose at 0.5-1mg/kg/day and then it was stopped by gradually tapering in both group. Nonsteroidal anti-inflammatory drugs were continued as necessary (Chickermane and Khubchandani, 2013).

All the participants received calcium and vitamin D combination along with folic/folinic acid routinely at the dose of 1000 mg calcium and 400 vitamin D daily and folic/folinic acid 5 mg once weekly. No other conventional or biological DMARDS were used in both group and no other DMARDs except methotrexate will not also be given before leflunomide.

Blood was drawn from the patients by venipuncture for the following baseline laboratory tests: Complete Blood Count (CBC) with ESR, Serum ALT, Serum Creatinine, Rheumatoid factor, antinuclear antibody, CXR, Mantoux test, HBsAg, routine and microscopic examination of urine were done.

All lab tests were completed from BMU. CBC with ESR and routine and microscopic examination of urine were done from Clinical pathology Department. S.ALT, S.Creatinine were done in the Department of Biochemistry and HBsAg was performed in the Department of Virology, BMU. X-ray chest was performed in the Department of Radiology and Imaging, BMU.

All the patients were followed up initially at 6th, 12th and then at 24th weeks to assess clinical and laboratory status of disease activity and to identify any adverse effects.

Along with clinical follow up, investigations including Hb%, TLC, DC , PLT, ESR , serum ALT, serum creatinine, urine R/E were done at scheduled follow up. According to JADAS-27 criteria baseline measurements were compared with those obtained at the 6th weeks, 12th weeks and 24th weeks follow up.

Continuous communication were maintained with study subjects by cell phone to ensure drug adherence and follow-up visits. Patients who developed serious medication-associated adverse reactions like organ involvement or patients requiring hospital admission were discontinued from therapy.