1 Background Systemic Juvenile Idiopathic Arthritis (sJIA) is a distinct subtype of Juvenile Idiopathic Arthritis characterized by systemic inflammation, quotidian fever, evanescent rash, arthritis, and elevated inflammatory markers. Driven by innate immune dysregulation, it involves elevated IL1 and IL6 levels. Tocilizumab, an IL6 receptor antagonist, has shown efficacy in controlling disease activity, tapering glucocorticoids, and improving quality of life. Methotrexate, a conventional DMARD, is widely used in JIA, especially for arthritis. However, data comparing Tocilizumab monotherapy with combination therapy using Methotrexate in sJIA is limited. This randomized control trial aims to evaluate whether Methotrexate adds clinical benefit in paediatric sJIA management.
2 Rationale of Study The prevalence of systemic Juvenile Idiopathic Arthritis appears to be higher in India compared to Western countries. The 2024 EULAR/PReS management guidelines for sJIA suggest a limited role for Methotrexate, despite it being one of the oldest and most commonly used DMARDs in earlier treatment protocols. While Tocilizumab has emerged as a key therapeutic agent in sJIA, the clinical benefit of combining it with Methotrexate remains uncertain. There is a paucity of comparative data evaluating the effectiveness of Tocilizumab alone versus in combination with Methotrexate. This gap in evidence forms the basis of the present study.
3 Methodology a) Study Design This will be a hospital-based open label randomized control trial.
b) Place of Study Department of Paediatric Medicine of IPGMER and SSKM Hospital, a tertiary care centre in West Bengal.
c) Period of Study 18 months.
d) Study Population Children under 12 years of age who are admitted in the department of paediatric medicine with systemic Juvenile Idiopathic Arthritis.
e) Expected Sample Size 30 participants (15 in each group). This is a pilot study. Enrolment ratio 1 Alpha error 0.05 Power 80 percent
f) Sampling Method The total population will be randomized into two groups using a computer-generated random sequence number. The allocation ratio will be 1 is to 1, and concealment will be performed using sequentially numbered opaque sealed envelopes.
g) Laboratory Investigations as applicable Complete hemogram with peripheral blood smear Serum electrolytes including sodium, potassium, calcium, phosphate Renal function test ie urea, creatinine PT, INR, APTT Liver function test C reactive protein (CRP) Erythrocyte Sedimentation Rate (ESR) Serum Ferritin Serum Triglyceride Blood culture Mantoux test Anti-nuclear antibody (ANA) Rheumatoid Factor, Anti-citrullinated peptide antibody (ACPA) Anti-neutrophil cytoplasmic antibody (ANCA) Ultrasound of affected joints in case of arthritis
h) Parameters to be Studied Name, age, sex, geographic location as demographic data Age of onset of sJIA symptoms Family history of autoimmune or rheumatologic diseases Presence of systemic features at baseline like fever, rash, hepatomegaly or splenomegaly, lymphadenopathy, serositis Presence of arthritis (active joint count at the time of diagnosis) Laboratory findings at baseline and follow-up Treatment received after diagnosis of sJIA Response to treatment at 6 months and 12 months with mention of treatment regimen and total duration Course of disease from diagnosis until current follow-up
4 Work Plan The study will be conducted after approval by the Institutional Ethics Committee and registration with Clinical Trial Registry India (CTRI). All new patients aged less than 12 years with systemic JIA who attend the Paediatric OPD and are admitted to the Paediatric Medicine ward, in the presence of the principal investigator (myself), will be included after applying inclusion and exclusion criteria. Enrolment will continue until 6 months before the end of the study period. Written informed consent and assent will be obtained from parents/ guardians and children. A pre-designed proforma will be used to record history, examination findings, lab investigations, and treatment course. At the first visit, detailed history and clinical examination will be done. A study proforma will be filled including demographic details, baseline disease activity, inflammatory markers such as ESR, CRP and Ferritin, previous medications and steroid use. The study population will be randomized into two groups using a computer-generated sequence with a 1 is to 1 allocation. Group A will receive Tocilizumab alone. Group B will receive Tocilizumab with Methotrexate. Both groups will be started on high dose glucocorticoids at 2 milligrams per kilogram per day, tapered to a low dose equal to or below 0.2 milligrams per kilogram per day over 3 months and preferably stopped by 6 months as per EULAR/ PReS 2024 guidelines. Tocilizumab dosing, frequency, and tapering will also follow EULAR/ PReS 2024 guidelines. Methotrexate will be given at a dose of 10 to 15 milligrams per square meter once weekly either orally on empty stomach or subcutaneously, along with folic acid as per IAP Standard Treatment Guidelines 2022. Patients will be assessed every two weeks for the first 3 months and monthly thereafter. Clinical activity will be monitored using the JADAS score. Steroid use (cumulative dose) will be tracked. Adverse events including infections, cytopenias and hepatotoxicity will be recorded. Frequency of disease flares and repeat inflammatory markers will be documented. Proportion of children achieving CID off steroids at 6 months will be analyzed. If children in Group A experience two consecutive flares, Methotrexate will be added and the study will be terminated for that individual but their data will still be included. In case of complications such as Macrophage Activation Syndrome, high dose intravenous methylprednisolone at 30 milligrams per kilogram (maximum 1 gram per infusion) will be administered. Weight, height and BMI will be assessed using WHO growth charts for children under 5 and IAP growth charts for children over 5. Ultrasound of affected joints will be done in case of arthritis. All laboratory and radiological investigations will be performed by the institutional laboratory.
5 Expected Outcome of the Proposed Study A higher percentage of CID may be achieved at 6 months in the combination group compared to monotherapy. Flares may be more frequent in the monotherapy group during follow-up. Cumulative dose of steroid may be higher in the monotherapy group. Slightly more adverse events may occur in the combination group.
6 Outcome Definitions Parameters and Variables ILAR Criteria for sJIA Diagnosis Arthritis in one or more joints with or preceded by fever of at least 2 weeks that is documented to be daily for at least 3 days, along with one or more of the following a Evanescent rash b Generalized lymph node enlargement c Hepatomegaly or splenomegaly d Serositis
Exclusions include 1 Psoriasis or family history of psoriasis 2 Arthritis in HLA B27 positive males after 6th birthday 3 Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with inflammatory bowel disease, or acute anterior uveitis, or history of one of these disorders in first degree relative 4 Presence of IgM rheumatoid factor on at least 2 occasions 3 months apart
Clinically Inactive Disease (CID) Single point in time measure defined as absence of any sJIA manifestations including normal ESR or CRP. Physician global assessment must be less than or equal to 10 on a 0 to 100 visual analogue scale equivalent to less than 1 on a 0 to 10 scale.
Remission Defined as maintenance of CID over a period of at least 6 months regardless of treatment status.
High Disease Activity High spiking fever, widespread polyarthritis, pain score above 6 to 7 out of 10 on VAS, pericarditis and signs of impending MAS such as elevated liver enzymes or high serum ferritin.
Juvenile Arthritis Disease Activity Score (JADAS) Composite disease activity score includes 1 Physician global assessment on 0 to 10 VAS 2 Parent or patient global well-being on 0 to 10 VAS 3 Active joint count 4 ESR normalized to a 0 to 10 scale Maximum score is 40 Lower scores indicate lower disease activity A score below or equal to 1 indicates inactive disease
Macrophage Activation Syndrome (MAS) A rare but potentially fatal complication marked by high fever, lymphadenopathy, hepatosplenomegaly, encephalopathy. Lab findings include thrombocytopenia, leukopenia, elevated liver enzymes, LDH, ferritin, triglycerides. Patients may have purpura, mucosal bleeding, elevated fibrin split products and prolonged PT and APTT. ESR is low due to hypofibrinogenemia and liver dysfunction, helping to distinguish it from a flare. International criteria for MAS in sJIA: Ferritin above 684 nanograms per milliliter and Any two of the following: Thrombocytopenia less than or equal to 181 times 10 to the power 9 per liter Elevated liver enzymes ie AST above 48 units per liter Triglycerides above 156 milligrams per deciliter Fibrinogen less than or equal to 360 milligrams per deciliter |