Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

Table 1 Studies on effects of anti-tumor necrosis factor therapies on insulin resistance in non-diabetic rheumatoid arthritis patients

No.	Source	Character	Cases, n, drug (s)	Clinical feature (s)	Duration	Effects on IR	Ref.
1	2004, Austria	mAb	2 IFX	Non-diabetic	4 or 8 mo	Improved HOMA-IR only in high-IR group	[67]
2	2005, Greece	mAb	28 IFX	Non-diabetic	6 mo	Improved HOMA-IR only in high-IR group	[68]
3	2006, Spain	mAb	27 IFX	Non-diabetic	2 h after infusion	Improved HOMA-IR	[69]
4	2007, Netherlands	mAb	5 IFX	Non-diabetic	6 wk	Improved insulin sensitivity1	[70]
5	2007, Denmark	mAb	9 ADA	Non-diabetic, high IR	8 wk	Ineffective HOMA-IR	[71]
6	2007, China	mAb	19 IFX	Non-diabetic	14 wk	Improved HOMA-IR	[72]
7	2007, Turkey	mAb	7 IFX	Non-diabetic	5-15 mo	Improved HOMA-IR	[73]
8	2008, Spain	mAb	21 IFX	Non-diabetic	24 wk	Improved HOMA-IR	[74]
9	2008, Italy	mAbs, sTNFRFP, Mixed	20 ETA, 18 IFX, Total 38	Non-diabetic	24 wk	Improved HOMA-IR	[63]
10	2011, Spain	mAbs, rsTNFRFP, Mixed	8 ADA, 6 IFX, 2 ETA, Total 16	Non-diabetic	12 mo	Ineffective HOMA-IR	[64]
11	2012, United Kingdom	mAbs, rsTNFRFP, Mixed	49 IFX, 11 ADA, 1 ETA, Total 61	Non-diabetic	12 wk	Improved HOMA-IR in high-IR group	[65]
12	2012, Greece	mAbs, rsTNFRFP, Mixed	20 IFX, 11 ETA, 1 ADA, Total 32	Non-diabetic	6 mo	Improved HOMA-IR in high-IR, non-obese group	[66]
13	2019, Italy	mAbs, rsTNFRFP, Separated	11 IFX, 12 ETA, 10 ADA, Total 33	Non-diabetic, non-obese	24 wk	Improved HOMA-IR in individual group of all TNF blockers	[75]
14	2020, Netherlands	mAb	28 ADA	Non-diabetic	6 mo	Ineffective HOMA-IR, improved-β-cell function	[76]
15	2020, Taiwan	rsTNFRFP	30 ETA	Non-diabetic, non-obese	24 wk	Improved HOMA-IR in high-IR group	[77]

¹Measurement by hyperinsulinemic euglycemic glucose clamp only. ADA: Adalimumab; ETA: Etanercept; IFX: Infliximab; IR: Insulin resistance; mAb: monoclonal antibody; rsTNFRFP: Recombinant soluble tumor necrosis factor-α receptor fusion protein; TNF: Tumor necrosis factor; HOMA: Homeostasis model assessment.

Table 2 Studies on effects of non-tumor necrosis factor-targeted therapies on insulin resistance in rheumatoid arthritis patients

No.	Source	Drug	Cases, n	Clinical features	Duration	Effects on IR	Ref.
1	2010, Germany	TCZ	11	Non-diabetic	3 mo	Improved HOMA-IR	[116]
2	2012, United Kingdom	ABA	7	Non-diabetic, active disease	12 wk	Ineffective HOMA-IR	[65]
3	2013, United Kingdom	TCZ	221	Active disease	24 wk	Improved HOMA-IR	[117]
4	2013, United Kingdom	TCZ	62	Active disease, JRA children	6 wk	Improved HOMA-IR in high-IR group	[118]
5	2015, Italy	ABA	15	Non-diabetic, active disease	6 mo	Improved ISI, ineffective β-cell functions	[119]
6	2015, Taiwan	TCZ	24	Active disease	24 wk	Improved HOMA-IR	[120]
7	2015, Greece	TCZ	19	Active disease	6 mo	Ineffective HOMA-IR	[121]
8	2017, France	TCZ	15	Active disease	6 mo	Ineffective HOMA-IR	[122]
9	2019, Spain	TCZ	50	Non-diabetic	1 h after 1st infusion	Improved HOMA-IR	[123]
10	2019, France	Other1, TNFi	107, 96	Active disease	24 wk	Improved leptin/adiponectin ratios in other group than TNFi group	[124]
11	2020, France	TCZ	77	Active disease	12 mo	Ineffective HOMA-IR	[125]

¹No. 10 study including other non-tumor necrosis factor-targeted agents, like abatacept and tocilizumab. ABA: Abatacept; IR: Insulin resistance; ISI: Insulin sensitivity index; JRA: Juvenile rheumatoid arthritis; TCZ: Tocilizumab; TNFi: Tumor necrosis factor inhibitor; HOMA: Homeostasis model assessment.

Table 3 Studied effects on diabetes mellitus by applying anti-tumor necrosis factor- and non-tumor necrosis factor- targeted agents for treating patients with rheumatology disorders

No.	Source	Drug	Mechanism	PN	Clinical feature(s)	Duration	Effect on IR or diabetic status	Ref.
1	2005, United States	ETA	rSTNFRFP	10	Type II DM, obese	4 wk	Ineffective IS	[147]
2	2007, INC	ANA	IL-1Ra	34	Type II DM	13 wk	Reduced HbA1C and increased insulin secretion at 13 wk, reduced insulin doses at 39 wk	[156]
3	2009, United States	RTX	CD20 mAb	49	Type I DM, recent	1 yr	Reduced HbA1C/insulin doses and higher 2 h C-peptide AUC at 1 yr, no differences at 30 mo	[150]
4	2011, United States	ABA	CTLA4-Ig	73	Type I DM, recent	2 yr	Higher 2 h C-peptide AUC	[155]
5	2011, United States	TNFi	ETA, IFX	8	Type II DM	10 yr	Reduced HbA1C and fasting glucose levels	[148]
6	2011, Japan	TCZ	IL-6R mAb	10	Type II DM	6 mo	Reduced HbA1C and use of antidiabetic drugs	[110]
7	2012, INC	CAN	IL-1 mAb	151	Type II DM	4 wk	Increased insulin secretion (ISR relative to glucose at 0 to 0.5 h)	[157]
8	2012, INC	CAN	IL-1 mAb	372	Type II DM	4 mo	Ineffective HbA1C, fasting glucose and insulin levels	[158]
9	2012, INC	GEV	IL-1 mAb	81	Type II DM	13 wk	Reduced HbA1C, increased IS and insulin secretion at single i.v. groups (0.03, 0.1 mg/kg)	[159]
10	2013, INC	ANA	IL-1 Ra	25	Type I DM, recent	9 mo	Ineffective 2 h C-peptide AUC	[160]
11	2013, INC	CAN	IL-1 mAb	45	Type I DM, recent	I yr	Ineffective 2 h C-peptide AUC	[160]
12	2014, INC	CAN	IL-1 mAb	14	Type II DM	24 wk	Reduced HbA1C at single i.v. 1.5 and 10 mg/kg groups	[161]
13	2015, Netherlands	ANA	IL-1Ra	14	Type I DM	1 wk	Reduced HbA1C, insulin doses and fasting glucose levels, increased IS	[162]
14	2015, Italy	ANA	IL-1Ra	2	Type II DM	6 mo	Reduced HbA1C and fasting glucose levels, reduced or off antidiabetic therapeutics	[145]
15	2015, Italy	ANA	IL-1Ra	3	Type II DM	6 mo	Reduced HbA1C and fasting glucose levels	[146]
16	2015, Germany	BER	IL-1 mAb	7	Type II DM	60 d	Increased insulin secretion	[163]
17	2016, Switzerland	GEV	IL-1 mAb	15	Type I DM	1 yr	Ineffective 2-h C-peptide AUC	[164]
18	2016, Switzerland	CAN	IL-1 mAb	6	Type II DM	24 wk	Reduced HbA1C	[165]
19	2017, Japan	RTX	CD20 mAb	3	Type II DM, insulin RS	6-16 mo	Reduced HbA1C and insulin doses, disappearance of IR antibody	[151]
20	2018, United States	RIL	IL-1R-Ig	13	Type I DM, recent	26 wk	Higher 2 h C-peptide AUC	[166]
21	2019, Italy	ANA	IL-1Ra	17	Type II DM	6 mo	Reduced HbA1C	[167]
22	2019, Italy	ANA	IL-1Ra	15	Type II DM	6 mo	Increased IS, improved β-cell function, decreased glucagon levels	[168]
23	2020, United States	TOF	JAKi	634	Type I, II DM	9 mo	DM treatment (insulin/non-insulin) intensification lowest in using TOF	[178]

ABA: Abatacept; ADA: Adalimumab; ANA: Anakinra; AUC: Area under the curve; BER: Bermekimab; CAN: Canakinumab; DM: Diabetes mellitus; ETA: Etanercept; GEV: Gevokizumab; IFX: Infliximab (a TNF mAb); Ig: Immunoglobulin; INC: International countries; Insulin RS: Insulin resistance syndrome; IR: Insulin receptor; IS: Insulin sensitivity; ISR: Insulin secretion rate; i.v.: Intravenous; JAKi: Janus kinase inhibitor; mAb: Monoclonal antibody; PN: Patient numbers; Ra: Receptor antagonist; RIL: Rilonacept; rSTNFRFP: Recombinant soluble tumor necrosis factor-α receptor fusion protein; TCZ: Tocilizumab; TNFi: Tumor necrosis factor inhibitor; TOF: Tofacitinib; RTX: Rituximab; HbA1c: Hemoglobin A1c; IL: Interleukin.

Table 4 Studies and case reports on effects of anti-tumor necrosis factor and non-tumor necrosis factor-targeted therapies on insulin resistance or diabetes in ankylosing spondylitis and psoriatic arthritis/psoriasis patients

No.	Source	Drug	Case, n disease	Clinical feature(s)	Duration	Effect on IR or DM status	Ref.
1	2005, Greece	IFX	17, AS	Non-DM	6 mo	Reduced HOMA-IR in high-IR group	[68]
2	2007, Italy	ETA	9, PsO	Non-DM	24 wk	Reduced HbA1C and insulin levels	[188]
3	2009, Brazil	ETA	1, PsO	Type II DM	7 h	Hypoglycemic episode	[189]
4	2009, United States	ETA	1, PsO	Type II DM	20 mo	Reduced HbA1C and fasting glucose levels, discontinuing insulin use	[190]
5	2010, Brazil	TNF blocker1	18, PsA	Non-DM	6 mo	No changes in fasting glucose levels	[191]
6	2010, Brazil	TNF blocker1	37, AS	Non-DM	6 mo	No changes in fasting glucose levels	[191]
6	2011, United States	ADA	54, PsO	DM 13%, PsA 41%	16 wk	Ineffective changes in fasting glucose levels in DM	[192]
7	2012, Spain	IFX	30, AS	Non-DM	120 min	Reduced HOMA-IR	[196]
8	2014, Turkey	IFX	30, AS	Non-DM	12 wk	Ineffective HOMA-IR	[197]
9	2017, United States	ETA	1, PsA	Type II DM, obesity	12 wk	Reduced HbA1C and fasting glucose levels, discontinuing insulin use	[193]
10	2018, Taiwan	UST	93, PsO	Obesity 45%	24 wk	Increased fasting glucose levels	[207]
11	2018, United States	IXE	2328, PsO	DM 9%, PsA 24%	12 wk	No changes in fasting glucose levels	[202]
12	2019, Germany	SEC	828, PsO	DM 10%, PsA 19%	52 wk	No changes in fasting glucose levels	[204]
13	2019, INC	APR	1089, PsA/O	DM 9%	52 wk	Reduced HbA1C, improvement highest in HbA1C no less than 6.5%	[210]
14	2019, Italy	APR	1, PsO	Type II DM, obesity	6 mo	Reduced HbA1C and fasting glucose levels, discontinuing insulin use	[211]
15	2020, Italy	APR	113, PsA/O	DM, 25%	52 wk	Reduced fasting glucose levels	[212]
16	2020, INC	TOF	474, PsA	MetS, 42%	6 mo	No increased blood glucose levels, hyperglycemic event and diabetic occurrence	[217]
17	2021, Taiwan	TOF	5, PsA	Non-DM, non-obese, high-IR	12 wk	Reduced HOMA-IR	PS

¹Tumor necrosis factor blocker in No. 5 and 6 including adalimumab, etanercept and infliximab. ADA: Adalimumab; APR: Apremilast; AS: Ankylosing spondylitis; ETA: Etanercept; IFX: Infliximab; INC: International countries; IR: Insulin resistance; IXE: Ixekizumab; MetS: Metabolic syndrome; PS: Present study; PsA: Psoriatic arthritis; PsO: Psoriasis; Ref.: Reference; SEC: Secukinumab; TNF: Tumor necrosis factor; TOF: Tofacitinib; UST: Ustekinumab; HbA1c: Hemoglobin A1c; HOMA: Homeostasis model assessment.