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Association of Rheumatoid Arthritis with Diabetic Comorbidity: Correlating Accelerated Insulin Resistance to Inflammatory Responses in Patients

Authors Verma AK, Bhatt D, Goyal Y, Dev K, Beg MMA , Alsahli MA, Rahmani AH

Received 6 October 2020

Accepted for publication 10 December 2020

Published 12 April 2021 Volume 2021:14 Pages 809—820


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Scott Fraser

Amit K Verma,1,* Deepti Bhatt,1,* Yamini Goyal,1,* Kapil Dev,1 Mirza Masroor Ali Beg,2 Mohammed A Alsahli,3 Arshad Husain Rahmani3

1Department of Biotechnology, Jamia Millia Islamia, New Delhi, India; 2Department of Biochemistry, Maulana Azad Medical College, New Delhi, India; 3Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia

*These authors contributed equally to this work

Correspondence: Amit K Verma
Department of Biotechnology, Jamia Millia Islamia, 413, Medical Biotechnology Lab, Srinivasa Ramanujan Block, Mujeeb Bagh, New Delhi, 110025, India
Email [email protected]

Abstract: Over the past two decades, with advancement of medical research and technology, treatments of many diseases including chronic disorders like rheumatoid arthritis (RA) have been revolutionized. Treatment and management of RA has been refined by advances in understanding its pathologic mechanisms, the development of drugs which target them and its association with various other chronic comorbidities like diabetes. Diabetes prevalence is closely associated with RA since elevated insulin resistance have been observed with RA. It is also associated with inflammation caused due to pro-inflammatory cytokines like tumour necrosis factor α and interleukin 6. Inflammation encourages insulin resistance and also stimulates other factors like a high level of rheumatoid factor in the blood leading to positivity of rheumatoid factor in RA patients. The degree of RA inflammation also tends to influence the criticality of insulin resistance, which increases with high activity of RA and vice versa. Markers of glucose metabolism appear to be improved by DMARDs like methotrexate, hydroxychloroquine, interleukin 1 antagonists and TNF antagonist while glucocorticoids adversely affect glycemic control especially when administered chronically. The intent of the present review paper is to understand the association between RA, insulin resistance and diabetes; the degree to which both can influence the other along with the plausible impact of RA medications on diabetes and insulin resistance.

Keywords: rheumatoid arthritis, diabetes, myocardial infarction, tumor necrosis factor α, interleukin 6


Rheumatoid arthritis (RA) is a systemic, inflammatory and chronic autoimmune disorder that causes symmetrical polyarthritis of small as well as large joints, usually between the ages of 30 and 50 years.1 Various genetic and environment risk factors have been found to influence the disease susceptibility. Researchers have demonstrated that genetic variation accounts for 50 to 60% of the RA risk development.2

While RA affects nearly 1% of the world’s adults,3 its association with other chronic disorders like diabetes has been widely explored upon in recent years with the advancement in medical research and technology. Dougados et al performed the first population-based cross-sectional observational study (n=4586) to evaluate various comorbidities in RA patients from five distinct continents and confirmed the high prevalence of comorbidities in RA patients.4 Studies reported that RA enhances the atherosclerotic cardiovascular disorder risk among RA patients.5–7 Adipokines also play a key role in cardiovascular and atherosclerosis risk among patients with RA.8 Although the number of people with diabetes is much more than RA (463 million in 2019) and continues to increase due to the challenges of modern lifestyle,9 however their interdependence cannot be rejected. In fact, around 90% of all diabetes cases related to type 2 diabetes (T2D)10 and recent research reveals the progression of RA with insulin resistance, advancing into T2D. Further, diabetes being a chronic disease has been found to be associated with the increased risk and complication of several cardiovascular diseases, chronic kidney disease, and other diseases like blindness resulting in an increase in morbidity and mortality among diabetic patients.11

The association of RA with diabetes has been identified in several cases, and anomalies are linked with RA in the metabolism of glucose, primarily insulin resistance which may develop into T2D.12 Numerous findings supported a higher chance of diabetic prevalence in people with RA, whereas some studies reported conflicting results in their association.13–15 Tumor necrosis factor-α (TNF-α) and interleukin 6 (IL6) were observed to be associated with pathogenesis of diabetes, insulin resistance and RA.15 The intent of the present review paper is to understand the association between RA, insulin resistance and diabetes; the degree to which they can influence each other along with the plausible impact of RA medications on diabetes and insulin resistance.

Rheumatoid Arthritis (RA)

Rheumatoid arthritis is a chronic disorder and the strongest genetic risk factor linked to its onset and progression are (HLA)-DRB1*01, *04, and *10 alleles, particularly for anti-citrullinated protein antibody (ACPA) positive RA.16 Mostly HLADRB1 gene variants linked with RA have indistinguishable sequence of amino acids among peptide binding groove, known as shared epitope (SE).17 Environmental factors like smoking and infection can also have an impact on the development, progression and severity of RA.18,19 RA patients have higher rheumatoid factor (RF) titers, that are auto-antibodies against Fc portion of immunoglobulin G (IgG), expected to have extra articular manifestations involving rheumatoid vasculitis, rheumatoid nodules, and hematologic, cardiovascular, pleuropulmonary, digestive, neurologic, cutaneous, and ocular complications.20–22 RA may become more complex by vasculitis with systemic manifestations.23,24

In the pathophysiology of RA, B lymphocytes, T lymphocytes, and coordinated communication of pro-inflammatory cytokines play significant roles.25,26 Pro-inflammatory cytokines such as TNF-α and IL6 influenced RA pathogenesis.27,28 Vascular endothelial growth factor (VEGF), IL1 and IL17 also have an important influence on RA. The multifaceted interaction of cytokines and effector cells results in joint damage which is initiated at synovium or synovial membrane. Local activation and/or recruitment of plasma cells, macrophages, mastocytes, B lymphocytes, T lymphocytes, and angiogenesis causes synovitis. Synovial lining turns to hyperplastic and synovial membrane enlarges and create villi structures. Pannus or osteoclast-rich area of synovium damages the bone and cartilage degrades over time by the enzymes released by chondrocytes, neutrophils, and synoviocytes.25

Rheumatoid Arthritis and Insulin Resistance

Insulin Resistance

Insulin sensitivity occurs due to biological effects in the insulin responsive tissue mainly adipose, liver, and striated muscle tissue. Decreased insulin sensitivity is also called insulin resistance (IR) and it is usually classified as decreased suppression of hepatic glucose production, reduced lipolysis rate among adipose or fat tissue and impaired clearance of glucose in striated muscle or through reduced joint action on complete body glucose disposal.29 IR plays a key role in metabolic syndrome’s pathophysiology and it is linked with a twofold increase in cardiovascular disease risk.30 There are several methods present which depict the relationship between insulin and fasting blood sugar. Among all methods, homeostatic model assessment for insulin resistance (HOMA-IR) is a low cost, fast, and accurate method and it is based on statistics for assessing IR and function of β cells (Figure 1).31

Figure 1 Processes applied to determine insulin sensitivity and insulin resistance.

Notes: Data from Nicolau et al.127

Association of IR and RA

IR prevalence has been observed to be greater in people with RA (58% and 51% in long-standing and early RA, respectively) in comparison with normal people (19%).32–34 Insulin resistance in RA partially causes obesity by increasing fat mass, disease activities, and occurrence of RF. Insulin resistance can also be linked significantly with some inflammation markers such as C-reactive protein (CRP) and TNF (Figure 2).32,35

Figure 2 Commonality between pathophysiology of rheumatoid arthritis and insulin resistance.

Abbreviations: TNF, tumor necrosis factor; IL, interleukin.

Notes: Adapted from Wasko MC, Kay J, Hsia EC, Rahman MU. Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: risk reduction in a chronic inflammatory disease. © 2011 the American College of Rheumatology.15

According to a study by Shahin et al, insulin resistance is more serious and critical in people experiencing high disease activity than in people experiencing medium disease activity. Measured disease activity by disease activity score 28 (DAS28), people with DAS28 >5.5 exhibit high disease activity and people with DAS28 ≥3.6 or DAS28 ≤5.5 exhibit medium disease activity.36 Insulin resistance is not associated with all rheumatic disease or all inflammatory cytokines.34,37 For example, insulin resistance is not associated with inflammation severity among individuals with systemic lupus erythematosus (SLE), regardless of alike concentration of TNF serum that is observed in people with RA.37 Obesity was the main factor for insulin resistance in the case of SLE and serum IL6 in the case of RA.37 Giles et al reported that insulin resistance in RA was correlated with prednisone therapeutic technique, level of CRP and positivity of RF. However, it was not correlated with serum IL6 determined at a particular time.34 People having a low level of IL6 exhibited higher insulin resistance in comparison with sex and age coordinated study controls having a similar level of IL6. The inconsistency between high insulin resistance and a low level of IL6 indicates that the main factors that are responsible for insulin resistance are incidence of noninflammatory factors.34 Other researchers also reported that longterm exposure to increased IL6 level induced insulin resistance, which suggests different processes responsible for insulin resistance in RA and SLE. Hence, inflammation can encourage insulin resistance and also stimulate other factors like positivity of RF.38

Association of RA and Diabetes

The worldwide diabetes prevalence is 463 million (9.3% in 2019), predicted to increase more than 10% by 2045.39 In a British cohort study, 11,158 RA patients were tracked for 24 years (1986–2010), rate of incidence of diabetes was 6.3 per 1000 person-years.40 After adjusting body mass index (BMI), age, sex, consumption of alcohol, history of smoking, glucocorticoid therapeutic technique and related comorbidities, HR of development of diabetes in people with RA in comparison with gender and age matched healthy controls was 0.94 with 95%CI: 0.84–1.06. Therefore, lifestyle factors such as smoking, alcohol consumption, and high BMI (or obesity) were found to be mainly responsible in developing diabetes among RA patients.40 Su et al reported that the main reason for mortality in RA patients is cardiovascular disease. Along with diabetes, hyperlipidemia and hypertension are important and the main cardiovascular disease risk factors. Their study revealed that hyperlipidemia or hypertension elevates the diabetes risk among RA patients. Presence of both hyperlipidemia and hypertension increase the hazard rate of diabetes by 23-fold. All these risk factors can also be associated with a sedentary lifestyle.41 Crepaldi et al reported that diabetes was associated with higher disease activity in RA patients whereas hyperlipidemia was associated with lower disease activity.42 A study projected that T1D approximately affects 2.8% of total RA patients. High prevalence of T1D was found among people with RA having ACPA with OR: 7.3 and 95%CI: 2.7–20.2.43 The correlation between T1D and RA recommends the presence of common susceptible genes like T cell activation RhoGTPase activating protein (TAGAP) gene, protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene, HLA-DRB1 gene, KIAA1109/TENR/IL2/IL21 genes and cytotoxic T lymphocyte associated protein 4 (CTLA-4) gene.44–48 But no polymorphism with IL6 gene is linked with T1D or RA.49 Association of T2D and RA is very complex and debatable high levels of IL6 or CRP encourage T2D development.50 Study of 114,342 US women did not observe a difference in T2D incidence among women with RA and without RA.51

In another prevalent study, significance of T2D was moderately higher among 28,208 RA patients (10.4%) in comparison to healthy individuals (7.6%) with P-value=0.01.14 Data comparison of people with and without RA taken from the ORALE (Outcome of Rheumatoid Arthritis Longitudinal Evaluation) and (SAHS) San Antonio Heart Study, demonstrated the higher significance of T2D in people with RA (16.1%) compared to people without RA (9.5%), P-value <0.001. But, in age-stratifying sampling this variation between data was eliminated (age ≥55 years; 22.8% vs 20.1%; P=0.7 and age <55 years; 8.3% vs 6.7%; p=0.5).52 Moreover, after adjusting for age, sex, glucocorticoid treatment, the cohort study from Canada of 490,751 individuals reported that T2D risk was higher in RA patients (n=48,718) in comparison with controls (442,033) with HR: 1.5; 95%CI: 1.4–1.5.51 Another study also reported the significant risk of T2D in patients with RA and association of glucose metabolism imbalance and uncontrolled disease activity. This study found that out of 439 RA patients, 31 developed T2D after 12 months of prospective follow-up.53 Ruscitti et al performed a cross-sectional study and found elevated prevalence of impaired fasting glucose and T2D among RA patients in Italian population in comparison with gender and age-matched controls. They also observed that cardiovascular risk factors like high blood pressure and RA-specific characteristics like duration of disease, and exposure to corticosteroids were considerably associated with abnormal glucose metabolism whereas disease activity, increasing erythrocyte sedimentation rate, and serum triglyceride levels were not associated with impaired fasting glucose among RA patients.54

A case-controlled study from Taiwan highlighted the chances of development of RA in diabetes patients. In 1416 RA patients and 7080 controls it was found that the odds ratio of development of RA after diagnosis of diabetes was higher in females with OR: 1.46 and 95%CI: 1.24–1.72 but not in males with OR: 1 and 95%CI: 0.72–1.37.55 In contrast, another case–control study from Taiwan with 600,695 participants reported that the T2D risk was greater in males with RA (OR: 1.68; 95%CI: 1.53–1.84) in comparison to females with RA (OR: 1.46; 95%CI: 1.39–1.54).41 In a cohort study with 48,718 RA patients, RA was shown to be associated with increased diabetes risk.13

People with RA showed association with several other diabetes risk factors like obesity, lifestyle, glucocorticoid therapeutic technique which encourage T2D development in RA patients. Several research-based results support the correlation of diabetes and RA, and their associated impact on development, progression, and the severity of both.

Effect of RA Medication on Insulin Resistance

RA Medications and Diabetes: Glucocorticoids

Glucocorticoids (GC) deteriorate glucose tolerance through various pathways by inhibiting glucose uptake in the adipose tissue and increasing hepatic gluconeogenesis.56 GCs were found to be associated with different levels of dysfunction of β cells, decrease in the insulin sensitivity as well as reduced β cell function as they function through the GC receptors found on pancreatic β cells (Table 1).57 Patients with RA cured by oral GC therapy is a vital risk factor of diabetes. Every 5 mg rise in current dose of oral GC was found to be linked with 25–30% increased diabetes risk. It was also found that GC dosages, which were within the preceding six-months were related to current diabetes risk.58 In a cross-sectional analysis of patients with RA, treatment with GCs decreased fasting insulin sensitivity59,60 and likely to project development of T2D.61,62 A single blind randomized controlled study was performed among 41 early active RA patients who were administered prednisolone 60 or 30 mg/day for seven days. In active RA patients, improvement in disease activity was observed in short periods of treatment with 30 or 60 mg/day prednisolone and this treatment did not deteriorate glucose tolerance.63 Lillegraven et al12 reported that patients with RA having prescribed doses of GCs (7.5 mg daily or more) had a hazard ratio of 2.33 95%CI: 1.68–3.22 incidence of diabetes than in patients without oral GC prescription. Short-term GC therapy, even in high doses in active RA patients does not tend to have an adverse effect on glucose tolerance. Whereas chronic GC therapy is linked with impaired glucose tolerance and with a non-negligible risk of T2D development. Thus, the European League Against Rheumatism (EULAR) suggests that patients be weaned off GC therapy as soon as possible to avoid IR worsening and ultimately T2D developing.64

Table 1 Effect of RA Medication on Diabetes and Insulin Resistance

Diseasemodifying Antirheumatic Drugs (DMARDs)

DMARDs are immunomodulators and immunosuppressants and classified either as biological DMARDs (bDMARDs) or conventional DMARDs (cDMARDs).65 Radner et al showed that out of 3920 multimorbid patients with RA, 59.9% received synthetic DMARDs (sDMARDs), 32.7% bDMARDs only, 54.8% used corticosteroids and 51.1% used concomitant nonsteroidal anti-inflammatory drugs (NSAIDs).66

Biological Disease-modifying Antirheumatic Drugs (bDMARDs)

bDMARDs are very specific and target particular pathways of the immune system.65

TNF Antagonists

TNF antagonists decreases pro-inflammatory cytokines levels in synovial membrane and systemic circulation.67 TNF antagonists reduce C-reactive protein in RA patients and also modify the well-known cardiovascular risk factors, involving lipid metabolism and insulin resistance.68–70 Insulin sensitivity is improved with TNF antagonists in animal studies.71 TNF antagonist’s treatment in RA patients improves insulin sensitivity68,70,72–76 and changes the lipid profile.70 TNF inhibitors significantly reduced the diabetes risk in RA patients when adjusted for covariates like BMI and disease activity.12

Stagakis et al77 performed a cohort analysis in patients with RA with anti-TNF agents (etanercept, n=1; adalimumab, n=11; infliximab, n=49), and found that 12 weeks after the anti- TNF treatment, patients having high IR displayed considerable decrease in HOMA-IR with P<0.001 and rise in quantitative insulin sensitivity check index (QUICKI) (P<0.001). Lillegraven et al78 examined the relationship of exposure of DMARDs with incidence diabetes in a large multicenter prospective cohort study of 21,775 patients with RA and found reduction in the risk of developing diabetes in patients with RA treated by TNF-inhibitors after controlling for disease activity, BMI and steroid use.

Interleukin 1β Antagonist

Interleukin 1β (IL1β) is a pro-inflammatory cytokine, which is involved in chronic inflammatory disease like RA, cardiovascular disease and T2D.79 Diabetes incidences were reduced by IL1 antagonist in animal models,80,81 as this cytokine plays a modulatory role either in insulin sensitivity, function of pancreatic β cell, or immune system function. Larsen et al82 demonstrated that blocking with anakinra (recombinant human IL1 receptor antagonist) leads to improvement in secretory function of β cells and glycemia and decreased markers of systemic inflammation in double-blind, placebo-controlled, parallel-group analysis with 70 people with T2D, who were given either once-daily 100 mg anakinra (Kineret) or placebo in the morning for 13 weeks. Several studies confirmed the vital role of IL1 in the β-cell mass maintenance, suggesting the processes lead to improvement of glucose after anakinra treatment are complex and possibly mediated by a double effect on both β-cell function and IR.82–88 Ruscitti et al performed an open-label, randomized, parallel-group trial in RA patients with T2D and suggested that IL1 inhibition by anakinra may facilitate therapeutic targeting of RA as well as T2D and use of only a single agent may be beneficial in management of both metabolic and inflammatory disorder.89 Studies suggested that inflammatory mechanisms of T2D could be exaggerated by RA and on this basis, single therapy/treatment that manages both disorders RA and T2D seems to be a promising treatment for enhancing the care of patients with T2D and RA.85,90,91

Interleukin 6 Antagonist

IL6 is an important component in chronic inflammation, and it is excessively expressed at inflammation sites. Similar to TNF and IL1, IL6 triggers the production of acute phase protein.92,93 It stimulates particular antibody‐mediated immune response like differentiation of B lymphocytes and activation of T lymphocytes.94 Many evidences have recommended that IL6 is an important component in rheumatoid inflammation.95 Studies reported that acute infusion of IL6 elevates the muscle sensitivity to insulin through AMP-activated protein kinase activation.96 Chronic increase of circulating IL6 level, higher than acute secretion of IL6, has null or weak effect in vivo in muscle, while it can contribute to whole body IR, mainly in adipose and liver tissue. IL6 can also be indirectly engaged in IR through its effect on metabolism of lipids. IL6 also encourages lipolysis in the culture of adipose and adipocyte tissue.97–99 In mice, chronic overexpression of levels of IL6 in skeletal muscle cause reduced body weight, inflammation of liver, hypoglycemia, incongruous hyperinsulinemia, hypoadiponectinemia, and reduced insulin stimulated glucose transfer to muscles.100

Tocilizumab (TCZ) (humanized monoclonal antibody against IL6 receptor) is an efficient therapy for RA.101,102 Schultz et al conducted a study on 11 RA patients without diabetes, where intravenous TCZ (8 mg per kg of body weight) was administered every four weeks to study insulin sensitivity and significant decrease was found in HOMA-IR after three months of treatment.103 In another study on 24 RA patients, when treated with intravenous TCZ dose (4 mg/kg) once monthly for the first three months and then 8 mg/kg once monthly, they observed significant decrease in HOMA-IR at week 24.104 Inhibition of IL6 can be a helpful strategy in reducing IR and decreasing the risk of T2D development.

Conventional DMARDs (cDMARDs)


Initially hydroxychloroquine (HCQ) was used as antimalarial drug, but now it is extensively used in treating systemic inflammatory conditions like RA and SLE. HCQ decreases diabetes risk through improving the function of pancreatic β cells and insulin sensitivity,105,106 which can be independent of anti-inflammatory activities. A large US-wide observational cohort analysis performed by Ozen et al107 found that diabetes incidences were increased in RA patients and HCQ was linked with decreased risk of diabetes among RA patients. Several studies found that HCQ reduced incidence of diabetes risk among RA patients.108–110 Earlier observational findings showed that HCQ ever use was associated with 38–71% decrease in diabetes risk in comparison with never used108,110 and current use was related to a 46% decrease in diabetes risk in comparison to any nonbiological non-MTX DMARD use.109 Mean decrease was observed in HbA1c of 0.66% (95%CI: 0.26–1.05) between pre-HCQ use and post-HCQ use.111 Findings of Desai et al112 showed a 33% decrease in incidences of diabetes risk with HCQ monotherapy (HR: 0.66; 95%CI: 0.45–0.98). Most of the previous studies advocate the positive effects of HCQ on glucose metabolism with favorable alterations in insulin clearance, release, and sensitivity.


Methotrexate (MTX) is suggested as first-line drug by EULAR and American College of Rheumatology (ACR) in early and established RA management.113,114 In a cross-sectional analysis of 387 patients with RA, it was found that metabolic syndrome was uncommon in patients with MTX therapy. However, risk of metabolic syndrome is not affected by preceding use of MTX and current use of GCs, other biologic agents and DMARDs. Use of MTX was observed to be related to lower fasting blood sugar level.115 A study by Dessein et al116 demonstrated that MTX had a beneficial impact on insulin sensitivity and in insulin resistance through QUICKI and HOMA and suggested this effect may be caused due its anti-inflammatory activity. Although they also suggested that the chances of this effect are partly arbitrated by other activities of classical drugs which encourage lipid profile remission or other areas cannot be excluded. Other study also revealed negative association between metabolic syndrome and use of MTX.117 Solomon et al109 conducted a reterospective cohort analysis on patients with RA and found that risk of T2D was not lower with MTX therapy in comparison to other DMARDs, after adjusting for confounders.

A new guideline formulated by the ACR for RA treatment, addressed use of biologicals in the clinical management of high risk populations and vaccine usage for infections such as herpes zoster, influenza and hepatitis B among patients receiving or starting antirheumatic drugs.118 The patients in which monotherapy with conventional DMARDs fails and those who were having continuous medium to high disease activity should be given treatment with combination therapy.119 EULAR recommended suggestions for management of CVD risk among RA patients.64 These recommendations consisted of the necessity of cardiovascular examination among RA patients and insufficiency of classic tables for CVD risk stratification when utilized in RA patients, particularly those having long-term disease (>10 years).120 Current evidence proposed that testing persons for high diabetes risk may decrease cardiovascular mortality.121

Janus Kinase Inhibitors

Janus kinase inhibitors (JAKi) are a novel category of oral medications counteracting JAK activation and JAKs are cytoplasmic enzymes which have control of several biological functions such as inflammatory cascade activation among cells of the immune system.122 They play a vital role in immune responses and are associated with various receptors of cytokine. Hence, JAKinhibition seemed to be a potential therapeutic strategy in autoimmune disorders like RA.123 Several oral JAKi like upadacitinib, tofacitinib, peficitinib, and baricitinib have been approved for the treatment of immune mediated disorders such as RA.124 Fujita et al observed that the JAKi drug baricitinib was efficient in the treatment of RA complicated by T1D and systemic sclerosis.125 Trivedi et al reported that JAKi drugs like barcitinib and ruxolitinib were effective for human consumption for the treatment and prevention of T1D.126


RA is an inflammatory chronic autoimmune disorder that may be linked with several abnormalities in glucose metabolism, primarily insulin resistance, which may develop into T2D. Environmental factors like smoking and infections may affect the progression, development, and severity of RA and onset of T2D in RA-affected persons. Numerous studies report that insulin resistance prevalence is greater in people with RA in comparison to normal people. Insulin resistance in RA partially causes obesity by increasing fat mass, disease activities and occurrence of factors of RA. Similarly, lifestyle factors such as smoking, alcohol consumption and high BMI (or obesity) are mainly responsible in the development of diabetes among RA patients. RA patients showcased association with several other diabetes risk factors like obesity, lifestyle, glucocorticoid therapeutic technique, which encourage T2D development in RA patients. Several studies reported significant association between development of T2D and RA whereas in contrast, some studies did not find any considerable association with T2D development and RA. Markers of glucose metabolism appear to be improved by DMARDs like methotrexate, hydroxychloroquine, IL1 antagonists and TNF antagonist while glucocorticoids adversely affect glycemic control, especially when administered chronically. Therefore, optimal drug selection for RA treatment may be helpful in attaining the treatment targets for diabetes to reduce the incidence of diabetes risk among RA patients. Although many studies reveal the chance of diabetes onset among people with RA. However, studies also suggest, administering combination drug therapy to RA patients, vaccine usage for treating infections among patients taking antirheumatic drugs, examining and monitoring cardiovascular conditions among RA patients with high diabetic risk may reduce the onset of diabetes risk and morbidity among patients.


ACPA, anti-citrullinated protein antibody; ACR, American College of Rheumatology; BMI, body mass index; CRP, C-reactive protein; CVD, cardiovascular disease; DAS28, disease activity score including 28-joints; EULAR, European League Against Rheumatism; IL6, interleukin-6; RA, rheumatoid arthritis; RF, rheumatoid factor; T2D, type 2 diabetes; TNF, tumor necrosis factor; IR, insulin resistance; HOMA, homeostatic model assessment; SLE, systemic lupus erythematosus; ORALE, outcome of rheumatoid arthritis longitudinal evaluation; SAHS, San Antonio heart study; GC, glucocorticoids; HCQ, hydroxychloroquine; TCZ, tocilizumab; MTX, methotrexate; HLA, human leukocyte antigen; SE, shared epitope; VEGF, vascular endothelial growth factor; T1D, type 1 diabetes; TAGAP, T cell activation RhoGTPase activating protein; PTPN22, protein tyrosine phosphatase nonreceptor type 22; CTLA-4, cytotoxic T lymphocyte associated protein 4; IL1β, interleukin 1β; QUICKI, quantitative insulin sensitivity check index.

Ethics Approval

The current review does not require ethical approval.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.


The current review did not receive funds from any outside source.


The authors of the current review report no conflicts of interest in this work.


1. Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR. Kelley’s Textbook of Rheumatology E-Book. Elsevier Health Sciences; 2012.

2. MacGregor AJ, Snieder H, Rigby AS, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000;43(1):30–37. doi:10.1002/1529-0131(200001)43:1<30::AID-ANR5>3.0.CO;2-B

3. Kahlenberg JM, Fox DA. Advances in the medical treatment of rheumatoid arthritis. Hand Clin. 2011;27(1):11–20. doi:10.1016/j.hcl.2010.09.002

4. Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73(1):62–68. doi:10.1136/annrheumdis-2013-204223

5. Dessein PH, Norton GR, Woodiwiss AJ, Joffe BI, Wolfe F. Influence of nonclassical cardiovascular risk factors on the accuracy of predicting subclinical atherosclerosis in rheumatoid arthritis. J Rheumatol. 2007;34(5):943–951.

6. Solomon DH, Kremer J, Curtis JR, et al. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann Rheum Dis. 2010;69(11):1920–1925. doi:10.1136/ard.2009.122226

7. Nurmohamed MT, Kitas G. Cardiovascular risk in rheumatoid arthritis and diabetes: how does it compare and when does it start? Ann Rheum Dis. 2011;70(6):881–883. doi:10.1136/ard.2010.145839

8. Dessein PH, Tsang L, Solomon A, Woodiwiss AJ, Millen AME, Norton GR. Adiponectin and atherosclerosis in rheumatoid arthritis. Mediators Inflamm. 2014;2014:1–10 doi:10.1155/2014/358949

9. Goyal Y, Verma AK, Bhatt D, Rahmani AH, Dev Y, Dev K. Diabetes: perspective and challenges in modern era. Gene Rep. 2020;20:100759. doi:10.1016/j.genrep.2020.100759

10. IDF Diabetes Atlas. 9th ed. Brussels, and Belgium; 2019. Available from: Accessed February 27, 2021.

11. Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: a review of current evidence. Diabetologia. 2019;62(1):3–16. doi:10.1007/s00125-018-4711-2

12. Lillegraven S, Greenberg JD, Reed GW, et al. Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis. PLoS One. 2019;14(1):e0210459. doi:10.1371/journal.pone.0210459

13. Solomon DH, Love TJ, Canning C, Schneeweiss S. Risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis and psoriasis. Ann Rheum Dis. 2010;69(12):2114–2117. doi:10.1136/ard.2009.125476

14. Han C, Robinson DW, Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006;33(11):2167–2172.

15. Wasko MC, Kay J, Hsia EC, Rahman MU. Diabetes mellitus and insulin resistance in patients with rheumatoid arthritis: risk reduction in a chronic inflammatory disease. Arthritis Care Res. 2011;63(4):512–521. doi:10.1002/acr.20414

16. Huizinga TWJ, Amos CI, van der Helm-van Mil AHM, et al. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 2005;52(11):3433–3438. doi:10.1002/art.21385

17. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30(11):1205–1213. doi:10.1002/art.1780301102

18. Klareskog L, Padyukov L, Alfredsson L. Smoking as a trigger for inflammatory rheumatic diseases. Curr Opin Rheumatol. 2007;19(1):49–54. doi:10.1097/BOR.0b013e32801127c8

19. Getts MT, Miller SD. 99th dahlem conference on infection, inflammation and chronic inflammatory disorders: triggering of autoimmune diseases by infections. Clin Exp Immunol. 2010;160(1):15–21. doi:10.1111/j.1365-2249.2010.04132.x

20. Gabriel SE, Crowson CS, Kremers HM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003;48(1):54–58. doi:10.1002/art.10705

21. Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis. 2003;62(8):722–727. doi:10.1136/ard.62.8.722

22. Hochberg MC, Johnston SS, John AK. The incidence and prevalence of extra-articular and systemic manifestations in a cohort of newly-diagnosed patients with rheumatoid arthritis between 1999 and 2006ʹ. Curr Med Res Opin. 2008;24(2):469–480. doi:10.1185/030079908X261177

23. Turesson C, Weyand CM, Matteson EL. Genetics of rheumatoid arthritis: is there a pattern predicting extraarticular manifestations? Arthritis Care Res. 2004;51(5):853–863. doi:10.1002/art.20693

24. Carl Turesson GS, Jacobsson L, Bergström U, Truedsson L, Sturfelt G. Predictors of extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol. 2000;29(6):358–364. doi:10.1080/030097400447552

25. Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2(6). doi:10.1038/nrd1109

26. Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370(9602):1861–1874. doi:10.1016/S0140-6736(07)60784-3

27. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–442. doi:10.1038/nri2094

28. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423(6937):356–361. doi:10.1038/nature01661

29. Roden M, Petersen K, Shulman G. Insulin resistance in type 2 diabetes. In: Textbook of Diabetes. John Wiley & Sons, Ltd; 2016:174–186.

30. Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol. 2010;56(14):1113–1132. doi:10.1016/j.jacc.2010.05.034

31. Katsuki A, Sumida Y, Gabazza EC, et al. Homeostasis model assessment is a reliable indicator of insulin resistance during follow-up of patients with type 2 diabetes. Diabetes Care. 2001;24(2):362–365. doi:10.2337/diacare.24.2.362

32. Chung CP, Oeser A, Solus JF, et al. Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis. 2008;196(2):756–763. doi:10.1016/j.atherosclerosis.2007.01.004

33. Mirjafari H, Farragher TM, Verstappen SM, et al. Seropositivity is associated with insulin resistance in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register (NOAR): an observational study. Arthritis Res Ther. 2011;13(5):R159. doi:10.1186/ar3476

34. Giles JT, Danielides S, Szklo M, et al. Insulin resistance in rheumatoid arthritis: disease-related indicators and associations with the presence and progression of subclinical atherosclerosis. Arthritis Rheum. 2015;67(3):626–636. doi:10.1002/art.38986

35. Dessein PH, Joffe BI. Insulin resistance and impaired beta cell function in rheumatoid arthritis. Arthritis Rheum. 2006;54(9):2765–2775. doi:10.1002/art.22053

36. Shahin D, Eltoraby E, Mesbah A, Houssen M. Insulin resistance in early untreated rheumatoid arthritis patients. Clin Biochem. 2010;43(7–8):661–665. doi:10.1016/j.clinbiochem.2010.01.012

37. Chung CP, Oeser A, Solus JF, et al. Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. Arthritis Rheum. 2008;58(7):2105–2112. doi:10.1002/art.23600

38. Bordon Y. IL-6, the resistance fighter. Nat Rev Immunol. 2014;14(5). doi:10.1038/nri3670

39. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. doi:10.1016/j.diabres.2019.107843

40. Dubreuil M, Rho YH, Man A, et al. Diabetes incidence in psoriatic arthritis, psoriasis and rheumatoid arthritis: a UK population-based cohort study. Rheumatology. 2014;53(2):346–352. doi:10.1093/rheumatology/ket343

41. Su -C-C, Chen I-C, Young F-N, Lian I-B. Risk of diabetes in patients with rheumatoid arthritis: a 12-year retrospective cohort study. J Rheumatol. 2013;40(9):1513–1518. doi:10.3899/jrheum.121259

42. Crepaldi G, Scirè CA, Carrara G, et al. Cardiovascular comorbidities relate more than others with disease activity in rheumatoid arthritis. PLoS One. 2016;11(1):e0146991. doi:10.1371/journal.pone.0146991

43. Liao KP, Gunnarsson M, Källberg H, et al. Specific association of type 1 diabetes mellitus with anti-cyclic citrullinated peptide-positive rheumatoid arthritis. Arthritis Rheum. 2009;60(3):653–660. doi:10.1002/art.24362

44. Dieudé P, Teixeira VH, Pierlot C, Cornélis F, Petit-Teixeira E, ECRAF. Testing for linkage and association with rheumatoid arthritis a ptpn22 promoter polymorphism reported to be associated and linked with type 1 diabetes in the Caucasian population. Ann Rheum Dis. 2008;67(6):900–901. doi:10.1136/ard.2007.077180

45. Vaidya B, Pearce SH, Charlton S, et al. An association between the CTLA4 exon 1 polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies. Rheumatology. 2002;41(2):180–183. doi:10.1093/rheumatology/41.2.180

46. Eyre S, Hinks A, Bowes J, et al. Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease. Arthritis Res Ther. 2010;12(5):R175. doi:10.1186/ar3139

47. Chatzikyriakidou A, Voulgari PV, Lambropoulos A, Georgiou I, Drosos AA. Validation of the TAGAP rs212389 polymorphism in rheumatoid arthritis susceptibility. Joint Bone Spine. 2013;80(5):543–544. doi:10.1016/j.jbspin.2013.01.008

48. Hollis-Moffatt JE, Chen-Xu M, Topless R, et al. Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 locus in Caucasian sample sets: confirmation of association of rs6822844with rheumatoid arthritis at a genome-wide level of significance. Arthritis Res Ther. 2010;12(3):R116. doi:10.1186/ar3053

49. Xu W-D, Zhou M, Peng H, Pan H-F, Ye D-Q. Lack of association of IL-6 polymorphism with rheumatoid arthritis/type 1 diabetes: a meta-analysis. Joint Bone Spine. 2013;80(5):477–481. doi:10.1016/j.jbspin.2012.11.005

50. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286(3):327–334. doi:10.1001/jama.286.3.327

51. Solomon Daniel H, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107(9):1303–1307. doi:10.1161/01.CIR.0000054612.26458.B2

52. Del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001;44(12):2737–2745. doi:10.1002/1529-0131(200112)44:12<2737::AID-ART460>3.0.CO;2-%23

53. Ruscitti P, Ursini F, Cipriani P, et al. Poor clinical response in rheumatoid arthritis is the main risk factor for diabetes development in the short-term: a 1-year, single-centre, longitudinal study. PLoS One. 2017;12(7):e0181203. doi:10.1371/journal.pone.0181203

54. Ruscitti P, Ursini F, Cipriani P, et al. Prevalence of type 2 diabetes and impaired fasting glucose in patients affected by rheumatoid arthritis. Medicine. 2017;96(34):e7896. doi:10.1097/MD.0000000000007896

55. Lu M-C, Yan S-T, Yin W-Y, Koo M, Lai N-S, Pietropaolo M. Risk of rheumatoid arthritis in patients with type 2 diabetes: a nationwide population-based case-control study. PLoS One. 2014;9(7):e101528. doi:10.1371/journal.pone.0101528

56. Burt MG, Roberts GW, Aguilar-Loza NR, Frith P, Stranks SN. Continuous monitoring of circadian glycemic patterns in patients receiving prednisolone for COPD. J Clin Endocrinol Metab. 2011;96(6):1789–1796. doi:10.1210/jc.2010-2729

57. Raalte DHV, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest. 2009;39(2):81–93. doi:10.1111/j.1365-2362.2008.02067.x

58. Movahedi M, Beauchamp ME, Abrahamowicz M, et al. Risk of incident diabetes mellitus associated with the dosage and duration of oral glucocorticoid therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2016;68(5):1089–1098. doi:10.1002/art.39537

59. Hoes JN, van der Goes MC, Van Raalte DH, et al. Glucose tolerance, insulin sensitivity and -cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids. Ann Rheum Dis. 2011;70(11):1887–1894. doi:10.1136/ard.2011.151464

60. Dessein PH, Joffe BI, Stanwix AE, Christian BF, Veller M. Glucocorticoids and insulin sensitivity in rheumatoid arthritis. J Rheumatol. 2004;31(5):867–874.

61. van Tuyl LHD, Boers M, Lems WF, et al. Survival, comorbidities and joint damage 11 years after the COBRA combination therapy trial in early rheumatoid arthritis. Ann Rheum Dis. 2010;69(5):807–812. doi:10.1136/ard.2009.108027

62. Wolfe F, Michaud K. Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize ra patients with fibromyalgia. J Rheumatol. 2004;31(4):695–700.

63. den Uyl D, van Raalte DH, Nurmohamed MT, et al. Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: balance between diabetogenic effects and inflammation reduction. Arthritis Rheum. 2012;64(3):639–646. doi:10.1002/art.33378

64. Peters MJL, Symmons DPM, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010;69(2):325–331. doi:10.1136/ard.2009.113696

65. Benjamin O, Bansal P, Goyal A, Lappin SL. Disease Modifying Anti-Rheumatic Drugs (DMARD). In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.

66. Radner H, Yoshida K, Hmamouchi I, Dougados M, Smolen JS, Solomon DH. Treatment patterns of multimorbid patients with rheumatoid arthritis: results from an international cross-sectional study. J Rheumatol. 2015;42(7):1099–1104. doi:10.3899/jrheum.141534

67. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol. 2001;19:163–196. doi:10.1146/annurev.immunol.19.1.163

68. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, et al. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis’. Clin Exp Rheumatol. 2006;24(1):83–86.

69. Popa C, Netea MG, Radstake T, et al. Influence of anti-tumour necrosis factor therapy on cardiovascular risk factors in patients with active rheumatoid arthritis. Ann Rheum Dis. 2005;64(2):303–305. doi:10.1136/ard.2004.023119

70. Tam L-S, Tomlinson B, Chu TT, Li TK, Li EK. Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis. Clin Rheumatol. 2007;26(9):1495–1498. doi:10.1007/s10067-007-0539-8

71. Araújo EP, De Souza CT, Ueno M, et al. Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes. Endocrinology. 2007;148(12):5991–5997. doi:10.1210/en.2007-0132

72. Rosenvinge A, Krogh-Madsen R, Baslund B, Pedersen BK. Insulin resistance in patients with rheumatoid arthritis: effect of anti-TNFalpha therapy. Scand J Rheumatol. 2007;36(2):91–96. doi:10.1080/03009740601179605

73. Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis. 2005;64(5):765–766. doi:10.1136/ard.2004.026534

74. Yazdani-Biuki B, Stelzl H, Brezinschek HP, et al. Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab. Eur J Clin Invest. 2004;34(9):641–642. doi:10.1111/j.1365-2362.2004.01390.x

75. Seriolo B, Paolino S, Ferrone C, Cutolo M. Effects of etanercept or infliximab treatment on lipid profile and insulin resistance in patients with refractory rheumatoid arthritis. Clin Rheumatol. 2007;26(10):1799–1800. doi:10.1007/s10067-007-0702-2

76. Oguz FM, Oguz A, Uzunlulu M. The effect of infliximab treatment on insulin resistance in patients with rheumatoid arthritis. Acta Clin Belg. 2007;62(4):218–222. doi:10.1179/acb.2007.035

77. Stagakis I, Bertsias G, Karvounaris S, et al. Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Res Ther. 2012;14(3):R141. doi:10.1186/ar3874

78. Lillegraven S, Greenberg JD, Reed GW, et al. OP0161 use of TNF inhibitors is associated with a reduced risk of diabetes in RA patients. Ann Rheum Dis. 2013;72(Suppl 3):A106–A107. doi:10.1136/annrheumdis-2013-eular.366

79. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117(14):3720–3732. doi:10.1182/blood-2010-07-273417

80. Eizirik DL, Mandrup-Poulsen T. A choice of death–the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia. 2001;44(12):2115–2133. doi:10.1007/s001250100021

81. Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia. 1996;39(9):1005–1029. doi:10.1007/BF00400649

82. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517–1526. doi:10.1056/NEJMoa065213

83. Park YJ, Warnock GL, Ao Z, et al. Dual role of interleukin-1β in islet amyloid formation and its β-cell toxicity: implications for type 2 diabetes and islet transplantation. Diabetes Obes Metab. 2017;19(5):682–694. doi:10.1111/dom.12873

84. Dinarello CA, Donath MY, Mandrup-Poulsen T. Role of IL-1beta in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes. 2010;17(4):314–321. doi:10.1097/MED.0b013e32833bf6dc

85. Giacomelli R, Ruscitti P, Alvaro S, et al. IL-1β at the crossroad between rheumatoid arthritis and type 2 diabetes: may we kill two birds with one stone? Expert Rev Clin Immunol. 2016;12(8):849–855. doi:10.1586/1744666X.2016.1168293

86. Matsumoto S, Takita M, Chaussabel D, et al. Improving efficacy of clinical islet transplantation with iodixanol-based islet purification, thymoglobulin induction, and blockage of IL-1β and TNF-α’. Cell Transplant. 2011;20(10):1641–1647. doi:10.3727/096368910X564058

87. Ruscitti P, Cipriani P, Cantarini L, et al. Efficacy of inhibition of IL-1 in patients with rheumatoid arthritis and type 2 diabetes mellitus: two case reports and review of the literature. J Med Case Rep. 2015;9(1):123. doi:10.1186/s13256-015-0603-y

88. Ruscitti P, Ursini F, Cipriani P, et al. IL-1 inhibition improves insulin resistance and adipokines in rheumatoid arthritis patients with comorbid type 2 diabetes: an observational study. Medicine. 2019;98(7):e14587. doi:10.1097/MD.0000000000014587

89. Ruscitti P, Masedu F, Alvaro S, et al. Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): a multicentre, open-label, randomised controlled trial. PLOS Med. 2019;16(9):e1002901. doi:10.1371/journal.pmed.1002901

90. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107. doi:10.1038/nri2925

91. Zatterale F, Longo M, Naderi J, et al. Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol. 2020;10. doi:10.3389/fphys.2019.01607

92. Ishihara K, Hirano T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev. 2002;13(4–5):357–368. doi:10.1016/s1359-6101(02)00027-8

93. Prowse KR, Baumann H. Interleukin-1 and interleukin-6 stimulate acute-phase protein production in primary mouse hepatocytes. J Leukoc Biol. 1989;45(1):55–61. doi:10.1002/jlb.45.1.55

94. Kishimoto T. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther. 2006;8(Suppl 2):S2. doi:10.1186/ar1916

95. Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther. 2006;8(Suppl 2):S3. doi:10.1186/ar1917

96. Geiger PC, Hancock C, Wright DC, Han D-H, Holloszy JO. IL-6 increases muscle insulin sensitivity only at superphysiological levels. Am J Physiol Endocrinol Metab. 2007;292(6):E1842–E1846. doi:10.1152/ajpendo.00701.2006

97. Trujillo ME, Sullivan S, Harten I, Schneider SH, Greenberg AS, Fried SK. Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro. J Clin Endocrinol Metab. 2004;89(11):5577–5582. doi:10.1210/jc.2004-0603

98. Petersen EW, Carey AL, Sacchetti M, et al. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab. 2005;288(1):E155–E162. doi:10.1152/ajpendo.00257.2004

99. Fève B, Bastard J-P. The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2009;5(6):305–311. doi:10.1038/nrendo.2009.62

100. Franckhauser S, Elias I, Rotter Sopasakis V, et al. Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia. 2008;51(7):1306–1316. doi:10.1007/s00125-008-0998-8

101. Yazici Y, Curtis JR, Ince A, et al. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis. 2012;71(2):198–205. doi:10.1136/ard.2010.148700

102. Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66(9):1162–1167. doi:10.1136/ard.2006.068064

103. Schultz O, Oberhauser F, Saech J, et al. Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS One. 2010;5(12):e14328. doi:10.1371/journal.pone.0014328

104. Chen D-Y, Chen Y-M, Hsieh T-Y, Hsieh C-W, Lin -C-C, Lan J-L. Significant effects of biologic therapy on lipid profiles and insulin resistance in patients with rheumatoid arthritis. Arthritis Res Ther. 2015;17(1):52. doi:10.1186/s13075-015-0559-8

105. Mercer E, Rekedal L, Garg R, Lu B, Massarotti EM, Solomon DH. Hydroxychloroquine improves insulin sensitivity in obese non-diabetic individuals. Arthritis Res Ther. 2012;14(3):R135. doi:10.1186/ar3868

106. Wasko MCM, McClure CK, Kelsey SF, Huber K, Orchard T, Toledo FGS. Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial. Diabetologia. 2015;58(10):2336–2343. doi:10.1007/s00125-015-3689-2

107. Ozen G, Pedro S, Holmqvist ME, Avery M, Wolfe F, Michaud K. Risk of diabetes mellitus associated with disease-modifying antirheumatic drugs and statins in rheumatoid arthritis. Ann Rheum Dis. 2017;76(5):848–854. doi:10.1136/annrheumdis-2016-209954

108. Wasko MCM, Hubert HB, Lingala VB, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007;298(2):187–193. doi:10.1001/jama.298.2.187

109. Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S. Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA. 2011;305(24):2525–2531. doi:10.1001/jama.2011.878

110. Bili A, Sartorius JA, Kirchner HL, et al. Hydroxychloroquine use and decreased risk of diabetes in rheumatoid arthritis patients. J Clin Rheumatol. 2011;17(3):115–120. doi:10.1097/RHU.0b013e318214b6b5

111. Rekedal LR, Massarotti E, Garg R, et al. Changes in glycosylated hemoglobin after initiation of hydroxychloroquine or methotrexate treatment in diabetes patients with rheumatic diseases. Arthritis Rheum. 2010;62(12):3569–3573. doi:10.1002/art.27703

112. Desai RJ, Eddings W, Liao KP, Solomon DH, Kim SC. Disease modifying anti-rheumatic drug use and the risk of incident hyperlipidemia in patients with early rheumatoid arthritis: a retrospective cohort study. Arthritis Care Res. 2015;67(4):457–466. doi:10.1002/acr.22483

113. Saag KG, Teng GG, Patkar NM, et al. American college of rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762–784. doi:10.1002/art.23721

114. Combe B, Landewé R, Lukas C, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2007;66(1):34–45. doi:10.1136/ard.2005.044354

115. Toms TE, Panoulas VF, John H, Douglas KM, Kitas GD. Methotrexate therapy associates with reduced prevalence of the metabolic syndrome in rheumatoid arthritis patients over the age of 60- more than just an anti-inflammatory effect? A cross sectional study. Arthritis Res Ther. 2009;11(4):R110. doi:10.1186/ar2765

116. Dessein PH, Joffe BI, Stanwix AE. Effects of disease modifying agents and dietary intervention on insulin resistance and dyslipidemia in inflammatory arthritis: a pilot study. Arthritis Res Ther. 2002;4(6):R12. doi:10.1186/ar597

117. Zonana-Nacach A, Santana-Sahagún E, Jiménez-Balderas FJ, Camargo-Coronel A. Prevalence and factors associated with metabolic syndrome in patients with rheumatoid arthritis and systemic lupus erythematosus. J Clin Rheumatol. 2008;14(2):74–77. doi:10.1097/RHU.0b013e31816b2faa

118. Singh JA, Saag KG, Bridges SL, et al. 2015 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis & Rheumatol. 2016;68(1):1–26. doi:10.1002/art.39480

119. Calabrò A, Caterino AL, Elefante E, et al. One year in review 2016: novelties in the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34:357–372.

120. Gonzalez A, Maradit kremers H, Crowson CS, et al. The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum. 2007;56(11):3583–3587. doi:10.1002/art.22979

121. Simmons RK, Rahman M, Jakes RW, et al. Effect of population screening for type 2 diabetes on mortality: long-term follow-up of the ely cohort. Diabetologia. 2011;54(2):312–319. doi:10.1007/s00125-010-1949-8

122. Yamaoka K. Janus kinase inhibitors for rheumatoid arthritis. Curr Opin Chem Biol. 2016;32:29–33. doi:10.1016/j.cbpa.2016.03.006

123. Angelini J, Talotta R, Roncato R, et al. JAK-inhibitors for the treatment of rheumatoid arthritis: a focus on the present and an outlook on the future. Biomolecules. 2020;10(7):1002. doi:10.3390/biom10071002

124. Emery P, Pope JE, Kruger K, et al. Efficacy of monotherapy with biologics and JAK inhibitors for the treatment of rheumatoid arthritis: a systematic review. Adv Ther. 2018;35(10):1535–1563. doi:10.1007/s12325-018-0757-2

125. Fujita Y, Nawata M, Nagayasu A, Someya K, Saito K, Tanaka Y. Fifty-two-week results of clinical and imaging assessments of a patient with rheumatoid arthritis complicated by systemic sclerosis with interstitial pneumonia and type 1 diabetes despite multiple disease-modifying antirheumatic drug therapy that was successfully treated with baricitinib: a novel case report. Case Rep Rheumatol. 2019. Available from: Accessed December 4, 2020.

126. Trivedi PM, Graham KL, Scott NA, et al. Repurposed JAK1/JAK2 inhibitor reverses established autoimmune insulitis in NOD mice. Diabetes. 2017;66(6):1650–1660. doi:10.2337/db16-1250

127. Nicolau J, Lequerré T, Bacquet H, Vittecoq O. Rheumatoid arthritis, insulin resistance, and diabetes. Joint Bone Spine. 2017;84(4):411–416. doi:10.1016/j.jbspin.2016.09.001

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