Immediate-release tofacitinib reduces insulin resistance in non-diabetic active rheumatoid arthritis patients: A single-center retrospective study

Abstract

Background: An increased risk of insulin resistance (IR) has been identified in rheumatoid arthritis (RA), a chronic inflammatory disorder with elevated levels of pathogenic cytokines. Biologics targeting proinflammatory cytokines can control the disease and improve insulin sensitivity in RA. Although Janus kinase (JAK) signaling can regulate cytokine receptors and participate in RA pathogenesis, it remains to be elucidated whether there is a reduction of IR in such patients under JAK inhibitor (JAKi) therapy.

Aim: To study the effect of JAKi treatment on the reduction of IR in RA patients with active disease.

Methods: A retrospective study was carried out from April 1, 2017 to March 31, 2021 in a population of non-diabetic patients with active RA who were undergoing tofacitinib (TOF) therapy with 5 mg twice-daily immediate-release formulation.

Results: Fifty-six RA patients, aged 30 years to 75 years (mean ± SD: 52.3 ± 11.1) with disease activity score 28 values ranging from 4.54 to 7.37 (5.82 ± 0.74), were classified into high-IR (> 2.0) and low-IR (≤ 2.0) groups based on their baseline homeostatic model assessment (HOMA)-IR levels. They had no previous exposure to JAKi, and received TOF therapy for no less than 6 mo. In 30 patients who were naïve to biologics, after a 24-week therapeutic period, the high-IR group showed reduced HOMA-IR levels (3.331 ± 1.036 vs 2.292 ± 0.707, P < 0.001). In another 26 patients who were exposed to tumor necrosis factor-α or interleukin-6 blockers, the high-IR group, despite having achieved a decrease but with lower magnitude than in naïve patients, showed reduced HOMA-IR levels (2.924 ± 0.790 vs 2.545 ± 1.080, P = 0.018).

Conclusion: In this retrospective study, reduced IR was achieved in non-diabetic active RA patients following 24 wk of TOF therapy.

Keywords: Diabetes mellitus; Insulin resistance; Janus kinase inhibitor; Rheumatoid arthritis; Tofacitinib.

Figure 1

Characteristics of homeostatic model assessment-insulin resistance levels in active rheumatoid arthritis patients naïve to biologic synthetic disease-modifying anti-rheumatic drugs. A: Positive correlation between 28-joint disease activity score 28 values and homeostatic model assessment (HOMA)-insulin resistance (IR) levels (P = 0.039) before tofacitinib (TOF) therapy; B: Serial calculations of HOMA-IR levels in 3 patients with high baseline IR at weeks 0, 4, 8, 12 and 24 after TOF therapy. There were significantly lower levels at week 24 as compared with those at week 0 (P < 0.01). HOMA-TR: Homeostatic model assessment-insulin resistance.

Figure 2

Homeostatic model assessment-insulin resistance and Quantitative Insulin Sensitivity Check Index levels in 30 active rheumatoid arthritis patients naïve to biologic agents before and 24 wk after tofacitinib therapy. A: Homeostatic model assessment (HOMA)-insulin resistance (IR) levels in all 30 patients at weeks 0 and 24 after tofacitinib (TOF) therapy (P < 0.001); B: HOMA-IR levels in the high-IR group with 18 patients at weeks 0 and 24 after TOF therapy (P < 0.001); C: HOMA-IR levels in the low-IR group with 12 patients at weeks 0 and 24 after TOF therapy; D: Quantitative Insulin Sensitivity Check Index (QUICKI) levels in all 30 patients at weeks 0 and 24 after TOF therapy (P < 0.001); E: QUICKI levels in the high-IR group with 18 patients at weeks 0 and 24 after TOF therapy (P < 0.001); F: QUICKI levels in the low-IR group with 12 patients at weeks 0 and 24 after TOF therapy. QUICKI: Quantitative Insulin Sensitivity Check Index; HOMA-TR: Homeostatic model assessment-insulin resistance.

Figure 3

Homeostatic model assessment-insulin resistance and Quantitative Insulin Sensitivity Check Index levels in 26 active rheumatoid arthritis patients exposed to biologic agents before and 24 wk after tofacitinib therapy. A: Homeostatic model assessment (HOMA)-insulin resistance (IR) levels in all 26 patients at weeks 0 and 24 after tofacitinib (TOF) therapy (P = 0.016); B: HOMA-IR levels in the high-IR group with 19 patients at weeks 0 and 24 after TOF therapy (P = 0.018); C: HOMA-IR levels in the low-IR group with 7 patients at weeks 0 and 24 after TOF therapy; D: Quantitative Insulin Sensitivity Check Index (QUICKI) levels in all 26 patients at weeks 0 and 24 after TOF therapy (P = 0.016); E: QUICKI levels in the high-IR group with 19 patients at weeks 0 and 24 after TOF therapy (P = 0.008); F: QUICKI levels in the low-IR group with 7 patients at weeks 0 and 24 after TOF therapy. QUICKI: Quantitative Insulin Sensitivity Check Index; HOMA-TR: Homeostatic model assessment-insulin resistance.