Novel Adverse Effect: Tofacitinib Associated Hypoglycaemia in a Non-diabetic Patient with Rheumatoid Arthritis

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that significantly impacts quality of life, particularly in elderly patients. ¹ The hallmark of RA is systemic inflammation, which damages joints and causes extra-articular symptoms such as cardiovascular illness, negatively affecting morbidity and mortality. ² Advancements in therapeutic approaches have led to better control of disease activity and prevention of systemic complications, thereby enhancing the overall clinical outcomes in patients with RA. ³ The development of disease-modifying anti-rheumatic medications, which include biologic Disease-Modifying Anti- Rheumatic Drugs (DMARDs), and Targeted Synthetic (Ts) (DMARDs), produced the most encouraging outcomes. ⁴ RA patients exhibiting moderate to high disease activity are increasingly managed with Janus kinase (JAK) inhibitors, a subclass of Ts DMARDs, reflecting a shift towards precision-targeted therapeutic strategies, which include tofacitinib, baricitinib and upadacitinib. ⁵ The US Food and Drug Administration (FDA) authorised tofacitinib in November 2012, and the European Medicines Agency approved it in March 2017 for the treatment of RA. ⁶

Case Description

A 68-year-old female with a two-year history of RA presented with progressive joint pain affecting both small and large joints, significantly limiting her mobility. On admission, her Disease Activity Score 28 exceeded five, indicating high disease activity. She had been stable on methotrexate (MTX) 10 mg weekly and hydroxychloroquine (100 mg daily) prior to hospitalisation.

On examination, she was bed-bound with marked joint inflammation, particularly in the knees, wrists and ankles. Laboratory investigations revealed a normal complete blood count, an elevated erythrocyte sedimentation rate (ESR) of 110 mm/h and liver and kidney function tests were normal. She was administered a depot preparation of methylprednisolone to control inflammation at the time of admission and was initiated on tofacitinib (11 mg once daily) while continuing MTX and hydroxychloroquine.

Hyperglycaemia was anticipated following the initiation of depot preparation of methylprednisolone and General Random Blood Sugar (GRBS) was monitored daily. However, no significant rise in blood glucose was observed. By the second day of tofacitinib therapy, she developed persistent symptomatic hypoglycaemia. Given the temporal association, tofacitinib was suspected as the likely cause and was withdrawn, after which the patient’s glucose levels returned to normal. Given her age, comorbidities and previous intolerance to higher doses of MTX, a cautious approach was opted, and she was continued at 10 mg MTX weekly, and the dose of hydroxychloroquine was increased to 100 mg twice daily to enhance therapeutic efficacy. A course of oral deflazacort (18 mg/day) was initiated and tapered over more than six weeks. The patient showed marked clinical improvement with this adjusted regimen. At follow-up, the patient remained in clinical remission with no evidence of disease flare. Therefore, she was maintained on MTX 10 mg once weekly and hydroxychloroquine 100 mg twice daily.

Investigations

From the above graph, it is noted that on Day 1, the patient was assessed and depot preparation of methylprednisolone, hydroxychloroquine and MTX were given. Tofacitinib was initiated on Day 2, following which GRBS, showed a downward trend. On Day 6, dechallenging of the suspected drug tofacitinib was done and on Day 7, there was a significant improvement in GRBS level.

	TOFACITINIB
Day 1	Day2	Day 3	Day 4			Day 5		Day 6	Day 7
Hb-11 g/dL Total count-10,000cells/mm3 Platelet-2 lakhs cells/mm3						Hb-10 g/dL Total count-9000cells/mm3 Platelet-1.78 lakhs cells/mm3
GRBS-102 mg/dL	GRBS-110 mg/dL	GRBS-90 mg/dL	82 mg/dL	62 mg/ dL	57 mg/dL	65 mg/dL	91 mg/dL	142 mg/dL	120 mg/dL
Creatinine 0.77 mg/dL Urea- 24 mg/dL Sodium-132 mmol/L Potassium-4.1 mmol/L			Creatinine 0.74 mg/dL Urea-34 mg/dL Sodium-130 mmol/L Potassium-3.8 mmol/L
LFT- normal
ESR-111 mm/hr
ESR-Erythrocyte sedimentation rate LFT-Liver function test

Discussion

Tofacitinib is an oral Ts DMARD that inhibits JAKs involved in inflammatory signalling pathways. This JAK inhibitor was authorised by the FDA in April 2012 and is recommended for the treatment of ulcerative colitis, psoriatic arthritis, polyarticular course juvenile idiopathic arthritis, and RA. ⁷ Tofacitinib is prescribed for adults with moderate to severe RA who are either nonresponsive to or have developed sensitivity to one or more DMARDs. ⁸ Tofacitinib can be used as a monotherapy for RA or in combination with conventional DMARDs or first-line treatment MTX. ⁸ A prevalent characteristic of human diseases such as diabetes, hyperlipidaemia, metabolic syndrome, fatty liver and obesity is insulin resistance (IR), which is characterised by a blockage of tissues to the action of insulin upon the uptake, metabolism or storage of glucose. ⁹ Tofacitinib, a JAK inhibitor primarily targeting JAK1 and JAK3, has been rarely associated with hypoglycaemia despite it not being a commonly reported adverse effect. One proposed mechanism involves improved insulin sensitivity through suppression of pro-inflammatory cytokines such as Interleukin-6 (IL-6) and Tumor Necrosis Factor-Alpha (TNF-α), which can reduce IR and lower blood glucose, particularly in patients with marginal glucose control or reduced caloric intake. ¹⁰ Additionally, partial inhibition of JAK2 may impair counterregulatory hormone signalling (e.g., growth hormone and catecholamines), potentially blunting physiological responses to hypoglycaemia, such as gluconeogenesis and glycogenolysis. ¹¹ In elderly or malnourished individuals, tofacitinib may also contribute indirectly via drug-drug or drug-food interactions and appetite suppression, further decreasing glucose availability.^12,13 This case highlights the potential complications associated with combination therapy in RA management, particularly in older patients. The dose of hydroxychloroquine remained unchanged throughout the period when hypoglycaemia was noticed. While Hydroxychloroquine (HCQ) is known to improve insulin sensitivity and has been associated with hypoglycaemia even in non-diabetic individuals,^14–16 the absence of dose escalation in our patient makes it a less likely sole contributor to the observed event.

There is limited but emerging evidence suggesting that tofacitinib may improve insulin sensitivity, ¹⁷ and isolated pharmacovigilance reports have noted hypoglycaemia in patients on tofacitinib. ¹⁸ However, no studies to date have confirmed a synergistic glucose-lowering interaction between tofacitinib and hydroxychloroquine.

The patient’s clinical improvement following the withdrawal of tofacitinib suggests that careful monitoring is essential when introducing new therapies. Although hypoglycaemia with tofacitinib has been documented in diabetic patients ¹⁹ but this case is distinctive as it highlights hypoglycaemia in a non-diabetic patient. According to the World Health Organisation (WHO) assessment scale, this Adverse Drug Reaction (ADR) caused due to tofacitinib was found to be probable.^20,21 An ‘probable’ classification indicates that there is a plausible period correlation between the delivery of the drug and the development of hypoglycaemia, that the reaction improves when the drug is stopped (dechallenged), and that there is no other plausible explanation. Considering the clinical setting, this categorisation supports a strong suspicion of causality even though hypoglycaemia is not a frequently reported side effect of tofacitinib. This case reinforces the importance of individualised treatment strategies and ongoing assessment in managing RA effectively.

Conclusion

In conclusion this report cites the importance of ADR, which is exhibited as hypoglycaemia in non-diabetic patients. Tofacitinib causes hypoglycaemia in diabetic patients, but in this case, we have reported hypoglycaemia induced by tofacitinib in a non-diabetic patient. This report will be of much clinical relevance.