Background/Purpose

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are associated with an increased risk of diabetes mellitus (DM). Disease-modifying anti-rheumatic drugs, including methotrexate (MTX), may exert protective metabolic effects conducive to reduced incidence of DM. Whether MTX mitigates metabolic risk factors in non-diabetic RA and PsA patients has not been determined unequivocally. In this study we assessed metabolic parameters in RA or PsA patients during the first six months of MTX therapy.

Methods

Newly diagnosed, MTX-naïve RA (2010 ACR/EULAR criteria) and PsA (CASPAR criteria) patients were included between December 2012 and June 2013. Patients with DM or hypothyroidism were excluded. The initial assessment included DAS28ESR, BMI, fasting plasma glucose and insulin, HbA_1c, TSH, triglycerides, HDL, LDL and urate. Disease activity and the metabolic parameters were followed 1, 2, 3 and 6 months after MTX initiation. Uninterrupted MTX treatment with dose escalation according to the treat to target approach was required. HOMA-IR (glucose (mM) x insulin (μU/ml)/22.5), HOMA-B (20 x insulin (μU/ml)/[glucose (mM)-3.5]) and QUICKI ([log₁₀glucose (mg/dl) + log₁₀insulin (μU/ml)]^-1) were used as surrogate indices of insulin sensitivity and β-cell function. ANOVA or the Kruskal-Wallis test, followed by an appropriate post hoctest was used to establish statistical significance.

Results

Inclusion criteria were fulfilled by 16 RA and 10 PsA patients (16 female, 10 male). Mean age was 52.5±12.2 (range: 27-76), BMI 28.4±4.8 kg/m² (range: 19.7-39.4) and the initial DAS28ESR 5.23±1.27 (range: 2.95-7.71). Eighteen patients had prediabetes according to the American Diabetes Association criteria (HbA_1c: 5.7-6.4%), while 11 patients had insulin resistance as assessed by HOMA-IR (>2.5). After six months of MTX (±methylprednisolone) therapy remission or low disease activity (DAS28ESR<3.2) was achieved in 76%. BMI, fasting plasma glucose, insulin, triglyceride, cholesterol or urate levels remained unaltered. Conversely, HbA_1c (%) decreased in a time-dependent manner from the baseline value of 5.80±0.29% to 5.55±0.31% (n=26, P=0.017) at 6 months. HbA_1c (%) was reduced in 17 out of 26 patients. The decrease in HbA_1c (%) was especially pronounced in patients without insulin resistance at inclusion (5.82±0.35% vs. 5.42±0.32%, P=0.013, 12 out of 14 patients). Overall, the number of patients with prediabetes was reduced from 18 to 8. HOMA-IR, HOMA-B and QUICKI remained unaltered in patients receiving MTX or MTX and methylprednisolone, indicating co-therapy with methylprednisolone did not impair insulin sensitivity.

Conclusion

MTX reduces serum HbA_1c in non-diabetic RA or PsA patients during the initial 6 months of treatment. As assessed by HbA_1c MTX also reduces the prevalence of prediabetes, consistent with the notion that MTX protects against the development of DM. According to recent data HbA_1c is not only an established predictor of CV risk in diabetic patients, but also an independent CV risk predictor in non-diabetics. Taken together, our findings support a possible role of MTX in reducing DM and CV risk in RA as well as PsA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-reduces-the-frequency-of-prediabetes-in-patients-with-rheumatoid-arthritis-or-psoriatic-arthritis/