Comparison of Effectiveness and Safety of Tofacitinib Versus Upadacitinib as Add-on to Methotrexate in Rheumatoid Arthritis

This study will be conducted in the Department of Pharmacology in collaboration with Rheumatology Department of Shaikh Zayed Medical Complex, Lahore.

The study population will consist of adult patients with diagnosis of RA on the basis of EULAR 2010 Classification Criteria: Moderate to severe disease activity indicated by DAS28 >3.2 and those with Inadequate response to methotrexate (MTX) characterized by Persistent active disease on ≥12 weeks of MTX treatment.

Sample size was estimated considering the following clinically significant variables: infection rate, thrombotic events, and cessation of treatment as a result of remission according to scientific publications. The maximum sample size was estimated among these methods in order to have adequate power.

If infection rate was considered as a key safety parameter, and taking into account the event rates of 0.7 and 1.2 per 100 patient-years for Tofacitinib and Upadacitinib, respectively22, the sample size would be 116 patients (58 per group) at 95% confidence interval and 80% power. In the case of thrombotic events with an assumed event rate of 0.2 and 0.4 per 100 patient-years23, the required sample size would be 100 patients (50 per group) at 95% confidence interval and 90% power.

Adult patients aged ≥18 years, regardless of gender will be included in the study. Whereas the following patients will not be included:

• Other autoimmune rheumatic disorders (SLE, psoriatic arthritis, AS, etc.)
• Administration of any biologic DMARD in the previous three months
• History of a serious infection (e.g., active tuberculosis or sepsis)
• Previous or existing history of recurrent infections or immunosuppressive status
• History of any malignancy in the last five years.
• Current chemotherapy, radiotherapy or intake of any genotoxic drug
• Severe liver impairment (e.g., ALT/AST >3× ULN)
• Severe renal impairment (e.g., estimated GFR <30 mL/min)
• Severe Haematological Abnormalities: Hb <8 g/dL, TLC <3,000 /mm³, Platelets <100,000 /mm³
• Past or present deep vein thrombosis or pulmonary embolism
• Pregnant or lactating women
• Women of reproductive age who are not practicing adequate contraception measures

Data collection procedure:

After the Evaluation by rheumatologist and prescribing the tofacitinib or Upadacitinib, an informed consent will be taken from the patient. Baseline investigations and history will be taken and added to the data collection sheet (Attached at the end). Patients will be followed vigilantly and then the clinical evaluation & biochemical investigations will be recorded at 3 months and 6 months.

Statistical Analysis:

All analyses will be conducted according to the ITT principle. A per protocol analysis will also be performed as sensitivity analysis. Two-sided p ≤ 0.05 will be considered statistically significant.

Continuous variable will be presented as mean±SD/median (IQR) and categorical variables will be presented as frequency (%).

Comparison of proportion between groups will be performed using the Chi-square/Fisher's exact test and effect sizes will be calculated as Risk difference, relative risk (RR) with 95% confidence interval.

Change in DAS28 will be compared by using Independent sample t-test/Mann Whitney-U test. Repeated measures analysis (mixed model/ANOVA) will be used to see the groups and time effect simultaneously. ACR responses will be analyzed by using Chi-square test Comparison of incidence rate between groups will be performed using Chi-square/Fisher's exact test and rates will be presented as proportion and/or incidences per 100 patient years.

Inclusion criteria

• • Adult patients aged ≥18 years, regardless of gender

Exclusion criteria

• • Other autoimmune rheumatic disorders (SLE, psoriatic arthritis, AS, etc.)

• Administration of any biologic DMARD in the previous three months
• History of a serious infection (e.g., active tuberculosis or sepsis)
• Previous or existing history of recurrent infections or immunosuppressive status
• History of any malignancy in the last five years.
• Current chemotherapy, radiotherapy or intake of any genotoxic drug
• Severe liver impairment (e.g., ALT/AST >3× ULN)
• Severe renal impairment (e.g., estimated GFR <30 mL/min)
• Severe Haematological Abnormalities: Hb <8 g/dL, TLC <3,000 /mm³, Platelets <100,000 /mm³
• Past or present deep vein thrombosis or pulmonary embolism
• Pregnant or lactating women
• Women of reproductive age who are not practicing adequate contraception measures