The feasibility and pharmacokinetic study of using loading dose methotrexate in rheumatoid arthritis patients.

INTERVENTION: All participants will receive triple disease‐modifying antirheumatic drugs (DMARDs) therapy with the drugs that are standard‐of‐care at the Royal Adelaide Hospital (RAH) (hydroxychloroquine, sulfasalazine, methotrexate) – the decision to initiate this therapy is not a part of this study. The intervention arm will receive a higher initial dose of methotrexate (50 mg once weekly subcutaneously) + oral sulfasalazine + oral hydroxychloroquine for the first 3 weeks, followed by standard dosing of methotrexate (20mg once weekly orally) + oral sulfasalazine + oral hydroxychloroquine for the next 3 weeks. The patient's adherence will be monitored through laboratory tests, patient's medical record and patient's self‐reported adherence. CONDITION: Inflammatory and Immune System ‐ Rheumatoid arthritis Rheumatoid arthritis; ; Rheumatoid arthritis INCLUSION CRITERIA: Patients attending the rheumatology clinic at the Central Adelaide Local Health Network (CALHN) who have active rheumatoid arthritis and for whom the decision has been made to commence methotrexate (and sulfasalazine and hydroxychloroquine) as triple DMARD therapy. The decision to use methotrexate is not part of this trial. It will be made according to clinical need and according to our standardised inclusion criteria for commencement of methotrexate therapy. These include: 1) ALT < 2 XULN 2) Calculated Creatinine Clearance > 60 mL/min (Cockcroft‐Gault) 3) Neutrophils within normal range 4) If a smoker, Pulmonary Function Tests will be conducted, and they must have FVC>70% predicted and DLCO> 60% predicted 5) At least 5 years since treatment for a malignancy (except non‐melanoma skin cancers) 6) Not pregnant (test is done as standard prior to MT Xcommencement) 7) Able to read English and/or good communication skills. 8) Age greate PRIMARY OUTCOME: Pharmacokinetic of methotrexate polyglutamate inside the red blood cell: the pharmacokinetic parameters for methotrexate polyglutamates inside red blood cell will be calculated via the Monolix software. The parameters for each polyglutamate (eg MTX‐Glu1, MTX‐Glu2 etc..) will be calculated individually, and also modelled together using multi‐compartmental analysis. The parameters of interest will be steady state concentration, half‐life, clearance, time to steady state (defined as 90% of the steady state concentration), area under the concentration time curve and time to detection of methotrexate polyglutamates in red blood cell. [The sample will only be drawn at one single timepoint for each week.; ; Baseline: The pre‐dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).; ; Week 1: The pre‐dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).; ; Week 2: The pre‐dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).; ; Week 3: The pre‐dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).; ; Week 6: The pre‐dose blood sample will be drawn on the day of clinic visit within 30 mins of subcutaneous dosing or at least 6 hours before the oral dosing (depending on whether the patient is taking oral or subcutaneous methotrexate).] Tolerance to, and safety of triple DMARD therapy that includes a methotrexate loading dose for initial treatment of RA. ; ; The patients will be presented with a list of possible side effects (such as upper and lower GI, rash, shortness of breath etc.) in the Vital Activities and Lifestyle Index (VALI) Follow‐up form. The patients will be asked to tick any side effect that they experienced with the dosing. Further assessment and review regarding the severity of side effect will be performed in the consultation process. The incidence and severity of Adverse Events (AEs)/Serious Adverse Events (SAEs) will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE) (Version 5).; ; Any change from baseline in physical examination findings, and from baseline in vital signs (Blood pressure and heart rate measured using a sphygmomanometer, respiratory rate using manual breath count and temperature by tympanic thermometer) will also be recorded.[Baseline, week 1, week 2, week 3 and week 6. ; ; The adverse events, physical examinations and vital signs related to the loading dose of methotrexate will be assessed as they are reported or observed and reviewed at baseline (30mins post‐dose), week 1 (pre‐dose and 30mins post‐dose), and week 2 (pre‐dose and 30mins post‐dose). ; ; For the standard dosing of methotrexate, the adverse events, physical examinations and vital signs will be assessed as they are reported or observed and reviewed at week 1 (pre‐dose), week 2 (pre‐dose), week 3 (pre‐dose) and week 6 (pre‐dose).] SECONDARY OUTCOME: Patients' attitude towards the methotrexate loading dose regimen as assessed by a study‐specific questionnaire.[Week 6 post‐commencement of intervention.] The feasibility to implement the methotrexate loading dose regimen as assessed by study‐specific questionnaires. ; ; The recruitment capability will be assessed as a composite outcome. We will assess and report:: ; i) the number of potential participants, ; ii) the number agreed to further contact/information about the study, ; iii) the number who consented to participation. ; iv) the recruitment rate and refusal rate for participation will be calculated. ; ; We will also assess and report the participants' retention rate and adherence to the intervention protocol. The retention rate will be defined as the number of participants who were retained or kept after consenting to participate in the study. We will also report participants attendance rate with regard to receiving their scheduled methotrexate loading dose and their attendance to the scheduled blood sampling.[At the conclusion of the study.] The patients' attitude towards the methotrexate loading dose regimen as assessed by using the Beliefs about Medicines Questionnaire (BMQ).[Week 6 post‐commencement of intervention.] The proportion of patients achieving low/minimal disease activity state as assessed using the Disease Activity Score 28‐joint count (DAS28) to intensive triple DMARD therapy (i.e. that includes a loading dose of methotrexate) and compare this to the controls (this study combined with historical controls) that were treated with ‘standard’ triple DMARD therapy at the rheumatology clinic at the Central Adelaide Local Health Network (CALHN).[At the conclusion of the study.] The time to achieve low/minimal disease activity state as assessed using the Disease Activity Score 28‐joint count (DAS28) to intensive triple DMARD therapy (i.e. that includes a loading dose of methotrexate) and compare this to the controls (this study combined with historical controls) that were treated with ‘standard’ triple DMARD therapy at the rheumatology clinic at the Central Adelaide Local Health Network (CALHN).[Baseline, week 1, week 2, week 3 and week 6 post‐commencement of intervention.] Treatment Satisfaction Questionnaire for Medication Version 2 (TSQM‐II)[Week 6 post‐commencement of intervention.]