Hydroxychloroquine and Glycemia in Women with Rheumatoid Arthritis and Systemic Lupus Erythematosus

doi:10.3899/jrheum.090994

J Rheumatol. Author manuscript; available in PMC 2012 September 25.

Published in final edited form as:

J Rheumatol. 2010 June; 37(6): 1136–1142.

Published online 2010 May 1. doi: 10.3899/jrheum.090994

PMCID: PMC3457696

NIHMSID: NIHMS400984

Hydroxychloroquine and Glycemia in Women with Rheumatoid Arthritis and Systemic Lupus Erythematosus

SARA KAPROVE PENN, AMY H. KAO, LAURA L. SCHOTT, JENNIFER R. ELLIOTT, FREDERICO G.S. TOLEDO, LEWIS KULLER, SUSAN MANZI, and MARY CHESTER M. WASKO

Department of Medicine, Division of Rheumatology, and Division of Endocrinology; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

S.K. Penn, MD; A.H. Kao, MD, MPH; J.R. Elliott, MD, Rheumatology and Osteoporosis Services, Lincoln, NE; S. Manzi, MD, MPH; M.C.M. Wasko, MD, MSc, Division of Rheumatology; F.G.S. Toledo, MD, Division of Endocrinology, Department of Medicine; L.L. Schott, PhD; L. Kuller, MD, DrPH, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh

Address correspondence to Dr. M.C.M. Wasko, University of Pittsburgh, School of Nursing, 440 Victoria Street, Room 453B, Pittsburgh, PA 15261, USA. Email: wasko/at/pitt.edu

The publisher's final edited version of this article is available at J Rheumatol

See other articles in PMC that cite the published article.

Abstract

Objective

To determine the relationship between current hydroxychloroquine (HCQ) use and 2 indicators of glycemic control, fasting glucose and insulin sensitivity, in nondiabetic women with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).

Methods

Nondiabetic women with SLE (n = 149) or RA (n = 177) recruited between 2000 and 2005 for a cross-sectional evaluation of cardiovascular risk factors were characterized by HCQ usage status. Unadjusted and multivariately adjusted mean fasting glucose, median insulin, and insulin resistance [assessed by the homeostasis model assessment (HOMA-IR) calculation] were compared among HCQ users and nonusers for disease-specific groups.

Results

More women with SLE were taking HCQ than those with RA (48% vs 18%; p < 0.0001; mean dose ~ 400 mg vs ~ 200 mg). For women with SLE or RA, after adjustment for age, waist circumference, disease duration, prednisone dosage, C-reactive protein, menopausal status, nonsteroidal antiinflammatory drugs, and disease-specific indicators, serum glucose was lower in HCQ users than in nonusers (SLE: 85.9 vs 89.3 mg/dl, p = 0.04; RA: 82.5 vs 86.6 mg/dl, p = 0.05). In women with SLE, HCQ use also was associated with lower _logHOMA-IR (0.97 vs 1.12, p = 0.09); in those with RA, no differences in _logHOMA-IR were seen. HCQ usage was not associated with fasting insulin levels in either patient group.

Conclusion

HCQ use was associated with lower fasting glucose in women with SLE or RA and also lower _logHOMA-IR in the SLE group. The use of HCQ may be beneficial for reducing cardiovascu lar risk by improving glycemic control in these patients.

Keywords: HYDROXYCHLOROQUINE, RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, HYPERGLYCEMIA, DIABETES MELLITUS

Diabetes mellitus (DM) is an established risk factor for atherosclerosis in the general population and in patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA)^1,2. Women with SLE or RA have a significantly higher risk of cardiovascular events than the age-matched normal population^3–5. Recent evidence from the Framingham Heart Study demonstrates an association between impaired fasting glucose and increased risk of coronary heart disease in women who do not fulfill diagnostic criteria for diabetes⁶. Treatments for SLE and RA that maintain euglycemia may be expected to reduce the risk of incident diabetes and hence cardiovascular disease (CVD) burden.

Hydroxychloroquine (HCQ) is an antimalarial quinoline prescribed for the treatment of SLE and RA since 1955^7,8. The drug is generally well tolerated and has low risk of toxicity with longterm use. Hypoglycemia is a rare but established side effect of quinoline therapy^9–11. Further, in patients with RA using HCQ for more than 4 years, > 75% reduction in risk of incident diabetes has been reported¹². However, the mechanism(s) of action of HCQ in regulating glycemia are not well understood.

Our aim was to determine the relationship between HCQ use and laboratory indicators of glycemic regulation in women with SLE or RA. Specifically, we examined the association between HCQ use and each of the following: fasting glucose, insulin, ß cell function calculated by the homeostasis model assessment (HOMA-B), and insulin resistance calculated by HOMA (HOMA-IR), as these are more sensitive measures of abnormal glucose metabolism than a diagnosis of diabetes¹³. We hypothesized that HCQ use was independently associated with lower fasting glucose, insulin, and HOMA-IR, and greater HOMA-B in women with SLE or RA.

MATERIALS AND METHODS

Patients

Women with either SLE (n = 161) or RA (n = 185) were recruited for cross-sectional studies of subclinical CVD and associated risk factors. Participants were > 18 years of age, fulfilled the American College of Rheumatology (ACR) criteria for either SLE^14,15 or RA¹⁶, and had no history of cardiovascular events (myocardial infarction, angina, or stroke). Women with RA were recruited from the University of Pittsburgh Rheumatoid Arthritis Research Registry, a database composed of outpatients with a stated interest in participating in RA-related research¹⁷. Women with SLE were recruited from the Pittsburgh Lupus Registry, which includes women diagnosed with SLE who have been seen at inpatient or outpatient facilities¹⁸. All studies were observational; severity of disease and individual treatment courses were not connected to research participation.

During a single visit, each woman completed a standardized history (including demographic and lifestyle information) and a physical examination, and gave a fasting blood sample. Additional testing, including carotid ultrasonography or electron beam computed tomography of the coronary arteries, was completed for the parent studies^17,18. For this analysis, patients with a diagnosis of diabetes by self-report, fasting glucose > 126 mg/dl, or reporting insulin or hypoglycemic drug use also were excluded (n = 20). Our study was approved by the Institutional Review Board of the University of Pittsburgh and all patients gave informed consent.

Outcomes

We performed a cross-sectional analysis of 326 nondiabetic women with SLE (n = 149) or RA (n = 177), comparing those taking HCQ with those not taking HCQ. Demographic data, disease measures, physical and blood assessments, and medication use were assessed separately for women with SLE and RA using equivalent protocols.

Our primary outcome measures were fasting serum glucose (mg/dl), fasting serum insulin (μU/ml), HOMA-B [defined as 20 × fasting insulin in (μU/ml)/(fasting glucose in mmol/l – 3.5)], and HOMA-IR, a calculated estimate of insulin resistance, defined as fasting glucose (mmol/l) × fasting insulin (μU/ml)/22.5¹⁹. Impaired fasting glucose is indicated at 100 mg/dl²⁰, and HOMA-IR > 2.114 is considered indicative of insulin resistance^13,21. For the non-normally distributed variables (insulin, HOMA-B, and HOMA-IR), log transformation of data was used.

Data analysis

Descriptive statistics were used to characterize women with SLE and RA. Comparisons by HCQ usage were made using the t-test for normally distributed continuous variables and chi-squared statistics for categorical variables. Non-normally distributed variables [e.g., C-reactive protein (CRP)] were compared using nonparametric testing, and natural log transformation was used for multivariable analyses. Additionally, prednisone dose was divided into 4 categories (0, > 0 to ≤ 2.5, > 2.5 to ≤ 5, > 5 mg/day), based on clinical cutpoints of our sample and menopausal status into 3 categories (pre/perimenopause, postmenopause, postmenopause on estrogen).

In separate analyses for women with SLE and RA using general linear modeling techniques controlling for multiple variables, least-squares means of glucose, insulin, HOMA-B, and HOMA-IR were calculated for women taking HCQ and compared to women not taking HCQ. All variables significantly different between groups (p < 0.15 in Table 1) were initially included in the multivariable model. Guided by these results and a priori hypotheses based on the literature, the final models included age, disease duration, waist circumference, prednisone dose, CRP, menopausal status, and nonsteroidal antiinflammatory drug use; plus immunosuppressants and SLE Disease Activity Index (SLEDAI) for women with SLE, or nonbiologic disease-modifying antirheumatic drugs (DMARD, excluding HCQ) and tumor necrosis factor inhibitors for women with RA.

Table 1

Characteristics of women dy HCQ status, unadjusted (mean ± SD unless otherwise noted).

Exploratory analyses were conducted regarding associations among postmenopausal women, a dose-response relationship in women with SLE, and steroid use (by examining interactions and stratification by prednisone use). The reduced sample size and multiple covariates in these additional models limited their interpretation.

RESULTS

Characteristics of the study participants are presented in Table 2. Mean disease duration was 16 years in both groups. The women with SLE were younger than those with RA, more likely to be premenopausal, and more likely to be taking HCQ than those with RA. Of the women taking HCQ, the mean daily dose for those with SLE was 336 ± 98 mg, and for those with RA, it was 213 ± 50 mg (p < 0.0001).

Table 2

Patient characteristics (mean ± SD unless otherwise noted).

For women with SLE, those taking HCQ had lower fasting glucose, HOMA-IR, and low-density lipoprotein (LDL) levels, and were more likely to report current daily prednisone use than those not taking HCQ (Table 1). For women with RA, those taking HCQ had higher HOMA-B and lower atherogenic ratio, and were less likely to be taking nonbiologic DMARD than those not taking HCQ.

In the multivariable models for women with SLE (Table 3), HCQ users had a significantly lower fasting glucose than the nonusers (85.9 vs 89.3 mg/dl, p = 0.04). In post-menopausal women, current use of hormone replacement therapy did not alter the effect of HCQ on fasting glucose levels (85.8 vs 91.2 mg/dl, p = 0.01); but hormone replacement therapy was associated with lower glucose in bivariate analyses (84.2 ± 8.4 vs 91.4 ± 10.6 mg/dl, p = 0.02). Exploratory analyses of a dose-response relationship between glucose and HCQ usage [comparing none, low (100–250 mg), and high (400 mg) doses of HCQ] were not significant. Back-transforming results of the adjusted means, for ease of clinical interpretation, suggested that HOMA-IR was lower in the HCQ users than nonusers (2.64 vs 3.06, p = 0.09). Stratified analyses (Tables 4a and and4b)4b) suggest that the association between HCQ and lower fasting glucose and higher HOMA-B was present in prednisone nonusers, while the association between lower HOMA-IR was more evident among prednisone users.

Table 3

Comparison of glucose metabolism by HCQ and disease status, by mean value adjusted for age, disease duration, waist circumference, prednisone dose, CRP, menopausal status, and NSAID; plus (a) immuno-suppressants and SLEDAI for women with SLE, or (b) nonbiologic (more ...)

Table 4A

Comparison of glucose metabolism by HCQ and disease status among women not using prednisone, by mean value adjusted for age, disease duration, waist circumference, predrisone dose, CRP, menopausal status, and NSAID; plus (a) immunosuppressants and SLEDAI (more ...)

Table 4B

Comparison of glucose metabolism by HCQ and disease status among prednisone users, by mean value adjusted for age, disease duration, waist circumference, prednisone dose, CRP, menopausal status, and NSAID; plus (a) immunosuppressants and SLEDAI for women (more ...)

In the multivariable models for women with RA (Table 3), HCQ users also had a significantly lower fasting glucose than the nonusers (82.5 vs 86.6 mg/dl, p = 0.051). The lower fasting glucose levels for women taking HCQ were more evident in postmenopausal women with RA (85.8 vs 91.2 mg/dl, p = 0.01), with no association between hormone replacement therapy and glucose in bivariate analyses (88.8 ± 10.3 vs 88.4 ± 10.3 mg/dl, p = 0.86). No differences in _logHOMA-IR or _loginsulin by HCQ usage were seen in women with RA. Back-transforming results of the adjusted means suggested that HOMA-B was higher in the HCQ users than nonusers (235 vs 181, p = 0.09). Exploratory analyses showed a trend for an interaction between HCQ use and prednisone use (any/none) in multivariable models for glucose (p = 0.02), _loginsulin (p = 0.04), _logHOMA-IR (p = 0.15), and _logHOMA-B (p = 0.002). Stratified analyses suggested that lower glucose may be most evident among prednisone users, while lower insulin and higher HOMA-B levels may be most evident in women not taking prednisone (Tables 4a and and4b4b).

DISCUSSION

In this cross-sectional study of women with SLE or RA, we found that HCQ use was significantly associated with lower fasting glucose levels. In the women with RA, calculated ß cell function (HOMA-B) was greater in HCQ users than nonusers. Calculated insulin resistance (HOMA-IR) was lower in HCQ users among women with SLE but not in those with RA. These relationships persisted after adjustment for the known covariates associated with blood glucose level. The mechanisms underlying these associations remain to be determined in mechanistic studies, but our data suggest that HCQ was not linked to improved insulin sensitivity, as HOMA-IR was not different between HCQ users and nonusers in the women with RA.

Differences in HOMA-B and HOMA-IR findings by disease may be due to a number of factors. In this observational study, HCQ usage was much more common in the women with SLE (48%), while less than 20% of the women with RA were taking HCQ; thus subtle differences in outcome measures perhaps would be detected in an RA group with a larger number of HCQ users. In addition, HCQ dosage among women with RA was much lower than in women with SLE. Disease-related distinctions such as peak age at onset, patterns of internal organ involvement, and treatment were not available for inclusion in the models but may also be influencing disease-specific results.

Postmenopausal estrogen use has been shown to lower blood glucose in older women²². While our findings indicate that this is true among postmenopausal women with SLE, the effect of HCQ on blood glucose levels in our cohort was independent of hormone replacement therapy.

HCQ and blood sugar

Numerous reports have suggested that antimalarials may cause a reduction in blood sugar. Scattered case reports highlight symptomatic hypoglycemia as a serious but uncommon adverse effect of HCQ in both diabetics and nondiabetics^9–11. HCQ has been used successfully as an adjunct treatment for patients with type 2 diabetes with poor control using traditional hypoglycemic agents^23,24.

In 1994, Petri, et al showed that in patients with SLE, HCQ is associated with lower random glucose levels²⁵, and in 1999, Shojania, et al described a case in which the use of HCQ reduced the insulin requirements of a patient with RA and type 2 diabetes⁹. In 2007, Wasko, et al reported a reduced incidence of diabetes in patients with RA taking HCQ¹².

In the early 1990s, 2 studies investigating the effect of antimalarials on diabetes control in patients with non-insulin-dependent DM (NIDDM) were performed. Among 38 patients with treatment-refractory NIDDM, glycemic control improved in those taking HCQ. This was not attributed to increased insulin secretion because serum C-peptide levels were unchanged²³. An insulin clamp study in 20 human subjects with NIDDM indicated that chloroquine affects insulin metabolism both by reducing insulin clearance from the circulation and by increasing insulin secretion, the latter shown by increased C-peptide levels²⁶. Our study does not address the mechanism(s) of action of antimalarials to improve glycemic control; this warrants future investigation.

Additional benefits of antimalarial therapy

Antimalarials possibly have other beneficial effects on the reduction of cardiovascular risk factors. Others have shown that HCQ use is associated with lower serum cholesterol markers²⁷. In our study, women with SLE using HCQ had notably lower LDL and total cholesterol compared to nonusers. Based on their beneficial effects on risk factors for CVD (i.e., lower blood sugar, cholesterol, and other lipids, as well as decreased thromboembolism^28,29), it would seem likely that antimalarials reduce the risk of CVD and may protect against the onset of DM. These hypotheses, however, have yet to be tested directly.

Risk factors for CVD in patients with rheumatic disease

The well known traditional cardiovascular risk factors include hypertension, smoking, male sex, advanced age, hypercholesterolemia, and diabetes. Higher fasting glucose has also been shown to be a cardiac risk factor³. Compared to age-matched and sex-matched control subjects, patients with SLE and RA have been shown to have a higher prevalence of hypertension and hyperlipidemia^2,30. In patients with SLE compared to controls, an increased prevalence of diabetes has been noted; this relationship in RA is less consistently reported^31,32. Those patients with SLE and DM may be at increased risk of developing renal impairment, neuropathy, retinopathy, and CVD — all complications that can be seen with either disease alone³³. Therefore, decreasing the risk of hyperglycemia and/or DM in patients with SLE is very important.

Patients with SLE or RA also have disease-associated cardiovascular risk. Potential explanations for this include the effects of a chronic inflammatory milieu on the vasculature, insulin resistance associated with systemic inflammation, sedentary lifestyle, decreased lean body mass with increased relative adiposity, and increased risk of premature menopause, the latter being especially relevant in women with SLE^29,34,35.

Use of other antirheumatic drugs may alter the risk of CVD as well. For example, in patients with SLE, Doria, et al found that cumulative prednisone dose was associated with subclinical atherosclerosis measured by carotid ultrasound, even after adjusting for traditional Framingham cardiovascular risk factors³⁶. It is not clear, however, if this relationship is due to longer disease duration, which is a known independent risk factor for subclinical atherosclerosis in these patients.

There are several potential study limitations. The cross-sectional design restricts the analysis to an association and provides no information about causal relationships. Because this is an observational study and women were not randomized to receive HCQ, our data may be biased based on confounding by indication, with fewer “sick” patients receiving HCQ, although we did adjust for use of other disease-modifying therapy (for RA) and concurrent immunosuppressive drugs (for SLE). Analyses were also completed on each disease group based on concurrent steroid usage status. Lean body mass and physical activity level, which may influence glucose metabolism, were not measured in all patients. Finally, the small number of participants may have precluded reaching statistical significance in some of the analyses, particularly given the small proportion of RA women using HCQ and their low mean daily dose.

HCQ is a safe and inexpensive medication used frequently in treatment of SLE and RA. In addition to direct benefits in managing rheumatic diseases, HCQ is associated with lower fasting glucose levels in women with SLE or RA. HCQ is also associated with lower insulin resistance in women with SLE. These results are consistent with our report of a protective association between HCQ use and incident DM in patients with RA¹². It is possible that HCQ could also reduce the risk of coronary heart disease among subjects with diabetes by improving glycemic control and dyslipidemia and reducing risk of thrombosis, although this has not yet been directly studied. Future work is warranted to identify specific patient subsets that may be particularly responsive to HCQ's beneficial effects on glycemia.

Acknowledgments

Supported by a grant from the National Institutes of Health (RO1 AR046588, K24 AR002213), the Arthritis Foundation of Western Pennsylvania, American Heart Association, and the National Institutes of Health (K23 AR47571); GCRC NIH Grant M01-000056.

REFERENCES

1. Gonzalez A, Maradit-Kremers H, Crowson CS, Ballman KV, Roger VL, Jacobsen SJ, et al. Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients? Ann Rheum Dis. 2008;67:64–9. [PubMed]

2. Bruce IN, Urowitz MB, Gladman DD, Ibanez D, Steiner G. Risk factors for coronary heart disease in women with systemic lupus erythematosus. Arthritis Rheum. 2003;48:3159–67. [PubMed]

3. Del Rincon 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;44:2737–45. [PubMed]

4. Maradit-Kremers H, Crowson CS, Nicola PJ, Ballman KV, Roger VL, Jacobsen SJ, et al. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis. Arthritis Rheum. 2005;52:402–11. [PubMed]

5. Bruce IN. `Not only′but also': factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus. Rheumatology. 2005;44:1492–502. [PubMed]

6. Levitzky YS, Pencina MJ, D'Agostino RB, Meigs JB, Murabito JM, Vasan RS, et al. Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study. J Am Coll Cardiol. 2008;51:264–70. [PubMed]

7. Scherbel AL, Schuchter SL, Harrison JW. Comparison of effects of two antimalarial agents, hydroxychloroquine sulfate and chloroquine phosphate, in patients with rheumatoid arthritis. Cleve Clin Q. 1957;24:98–104. [PubMed]

8. Tye MJ, White H, Appel B, Ansell HB. Lupus erythematosus treated with a combination of quinacrine, hydroxychloroquine and chloroquine. N Engl J Med. 1959;260:63–6. [PubMed]

9. Shojania K, Koehler BE, Elliott T. Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis. J Rheumatol. 1999;26:195–6. [PubMed]

10. Abu-Shakra M, Lee P. Hypoglycaemia: an unusual adverse reaction to chloroquine. Clin Exp Rheumatol. 1994;12:95. [PubMed]

11. Cansu DU, Korkmaz C. Hypoglycemia induced by hydroxychloroquine in a non-diabetic patient treated for RA. Rheumatology. 2008;47:378–9. [PubMed]

12. Wasko MCM, Hubert HB, Lingala VB, Elliott JR, Luggen ME, Fries JF, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007;298:187–93. [PubMed]

13. Matthews DR, Hosker JP, Rudenski AS, Baylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9. [PubMed]

14. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus (SLE) Arthritis Rheum. 1982;25:1271–7. [PubMed]

15. Hochberg M. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter] Arthritis Rheum. 1997;40:1725. [PubMed]

16. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24. [PubMed]

17. Kao AH, Krishnaswami S, Cunningham A, Edmundowicz D, Morel PA, Kuller LH, et al. Subclinical coronary artery calcification and relationship to disease duration in women with rheumatoid arthritis. J Rheumatol. 2008;35:61–9. [PubMed]

18. Thompson T, Sutton-Tyrrell K, Wildman RP, Kao A, Fitzgerald SG, Shook B, et al. Progression of carotid intima-media thickness and plaque in women with systemic lupus erythematosus. Arthritis Rheum. 2008;58:835–42. [PubMed]

19. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487–95. [PubMed]

20. National Diabetes Information Clearinghouse [Accessed March 1];Insulin resistance and pre-diabetes. [Internet. 2010.] Available from: http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/

21. Chung CP, Oeser A, Solus JF, Avalos I, Gebretsadik T, Shintani A, et al. Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis. 2008;196:756–63. [PubMed]

22. Kanaya AM, Herrington D, Vittinghoff E, Lin F, Grady D, Bitner W, et al. Glycemic effects of postmenopausal hormone therapy: the heart and estrogen/progestin replacement study. Ann Intern Med. 2003;138:1–9. [PubMed]

23. Quatraro A, Consoli G, Magno M, Caretta F, Nardozza A, Ceriello A, et al. Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus. Ann Intern Med. 1990;112:678–81. [PubMed]

24. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: A randomised controlled trial. Lancet. 2006;368:1096–105. [PubMed]

25. Petri M, Ferman D, Goldman D. Hypoglycemic effect of hydroxychloroquine in systemic lupus erythematosus [abstract] Arthritis Rheum. 1994;37(Suppl):R24.

26. Powrie JK, Smith GD, Shojaee-Moradie F, Sonksen PH, Jones RH. Mode of action of chloroquine in patients with non-insulin-dependent diabetes mellitus. Am J Physiol. 1991;260:E897–904. [PubMed]

27. Hodis HN, Quismorio FP, Wickham E, Blankenhorn DH. The lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus. J Rheumatol. 1993;20:661–5. [PubMed]

28. Valesini G, Pittoni V. Treatment of thrombosis associated with immunological risk factors. Ann Med. 2000;32(S1):41–5. [PubMed]

29. Loudon JR. Hydroxychloroquine and postoperative thromboembolism after total hip replacement. Am J Med. 1988;85:57–61. [PubMed]

30. Han C, Robinson DW, Hacket MV, Paramore LC, Freman K, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol. 2006;33:2167–72. [PubMed]

31. Doran M. Rheumatoid arthritis and diabetes mellitus: evidence for an association? J Rheumatol. 2007;34:460–2. [PubMed]

32. Gabriel SE, Crowson CS, O'Fallon WM. Comorbidity in arthritis. J Rheumatol. 1999;26:2475–9. [PubMed]

33. Cortes S, Chambers S, Jeronimo A, Isenberg D. Diabetes mellitus complicating systemic lupus erythematosus — analysis of the UCL lupus cohort and review of the literature. Lupus. 2008;17:977–80. [PubMed]

34. Magadmi ME, Ahmad Y, Turkie W, Yates AP, Sheikh N, Bernstein RM, et al. Hyperinsulinemia, insulin resistance, and circulating oxidized low density lipoprotein in women with systemic lupus erythematosus. J Rheumatol. 2006;33:50–6. [PubMed]

35. Pamuk ON, Unlu E, Cakir N. Role of insulin resistance in increased frequency of atherosclerosis detected by carotid ultrasonography in rheumatoid arthritis. J Rheumatol. 2006;33:2447–52. [PubMed]

36. Doria A, Shoenfeld Y, Wu R, Gambari PF, Puato M, Ghirardello A, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis. 2003;62:1071–7. [PMC free article] [PubMed]