Abstract
Introduction:
Evidence has demonstrated that autoimmune diseases tend to coexist at a higher rate than expected, reflecting a common pathogenic pathway. In this study, we investigate the co-occurrence of systemic sclerosis, systemic lupus erythematosus, and Sjogren syndrome in patients with type 1 and type 2 diabetes mellitus.
Methods:
Our data were obtained using the 2019 Healthcare Cost and Utilization Project, and International Classification of Diseases, 10th Revision diagnosis codes were used to identify patients with systemic sclerosis, systemic lupus erythematosus, lupus nephritis, and Sjogren syndrome, as well as patients with type 1 and type 2 diabetes. We utilized Statistical Analysis System 9.4 for all analyses and included designated weight values to produce nationally representative estimates.
Results:
The prevalence of systemic sclerosis among patients with type 1 diabetes mellitus and type 2 diabetes mellitus was significantly lower than that for the non-diabetes mellitus control group (0.0007% vs 0.09%, p-value = 0.0064 and 0.01% vs 0.07%, p-value < 0.0001), respectively. Similarly, there was a significant decrease in the prevalence of systemic sclerosis with lung involvement in patients with type 1 and type 2 diabetes mellitus, with a statically significant difference in type 2 diabetes mellitus versus nondiabetic group (0.001% vs 0.006%, p-value < 0.0001). We noted a similar pattern regarding the prevalence of systemic lupus erythematosus and lupus nephritis in patients with type 1 and 2 diabetes. Similarly, there was a significant decrease in the prevalence of Sjogren syndrome in patients with type 1 diabetes and type 2 diabetes.
Conclusion:
The collected data demonstrates an inverse relation between some autoimmune connective tissue diseases and diabetes. This suggests that these diseases and diabetes mellitus may have different immune pathogenesis. There was also a significantly lower incidence of organ complications such as lupus nephritis and systemic sclerosis lung disease among patients with diabetes, suggesting that diabetes and treatment of diabetes may alter the clinical expression of these disorders.
Keywords: Systemic sclerosis, systemic lupus erythematosus, Sjogren syndrome, diabetes
Introduction
Systemic sclerosis (SSc) is a rare autoimmune disease characterized by excessive fibrosis and endothelial dysfunction that leads to a wide variety of clinical and systemic manifestations. 1 There have been multiple studies demonstrating an interesting association between SSc and other autoimmune conditions such as primary biliary cholangitis (PBC), for instance, the prevalence of clinical PBC was reported to be around 2.5% in SSc, 2 suggesting a possible common pathogenic pathway.
It has been widely accepted that autoimmune diseases tend to co-occur at a higher rate than seen in the general population. Thus, a recent study reported that autoimmune disorders were commonly associated with each other, particularly Sjögren’s syndrome, systemic lupus erythematosus, and SSc. Individuals with childhood-onset type 1 diabetes also had significantly higher rates of Addison’s disease, celiac disease, and thyroid disease (Hashimoto’s thyroiditis and Graves’ disease), while multiple sclerosis had a particularly low rate of co-occurrence with other autoimmune diseases. 3
Conversely, having one disease may protect from the development of another autoimmune disease as is the case with multiple sclerosis or even the treatment of one disease may alter the clinical expression and the development of organ involvement of concurrent autoimmune diseases. 3
Diabetes mellitus (DM) is a disease of abnormal carbohydrate metabolism, associated with a relative or absolute impairment in insulin secretion and by peripheral insulin resistance. Type 1 diabetes is considered an autoimmune disorder as over 90% of the patients with new-onset type 1 DM will have at least one autoantibody against components of the pancreatic islet. 4
While type 2 diabetes pathogenesis is primarily related to both insulin resistance and defective insulin secretion, 5 still, there is new evidence suggesting an autoimmune pathogenesis of type 2 diabetes. Accordingly, recent reports describe the presence of IgG antibodies that are involved in the development of insulin resistance. Furthermore, autoantibodies against pancreatic islets have also been described in type 2 diabetes. Moreover, in mouse models, inhibition of either B cells or T lymphocytes can attenuate the progression of obesity-related insulin resistance. 6
Although the association between type 1 diabetes and other autoimmune diseases such as celiac disease, thyroiditis, and Addison disease has been established, 7 there have not been many studies exploring the association between diabetes and autoimmune connective tissue diseases. However, the routine clinical practice hinted at the lack of representation of DM in patients with SSc.
In this study, our primary goal was to investigate the association between type 1 and type 2 diabetes and SSc. We also set out to investigate the association between diabetes and other autoimmune connective tissue diseases such as systemic lupus erythematosus (SLE) and Sjogren syndrome (SS).
Materials and methods
This study employed a cross-sectional design to address the research objective, using the 2019 Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample.
The HCUP database includes the largest collection of longitudinal hospital care data in the United States. This database collects nationwide inpatient data from community-based hospitals across the United States. We specifically used the 2019 HCUP sample, which includes data collected from 1 January 2019 to 31 December 2019.
Inclusion criteria
Patients must be assigned one of the following International Classification of Diseases, 10th Revision (ICD-10) codes for inclusion in the study group: E10: Type 1 diabetes mellitus, E11: Type 2 diabetes mellitus. Subjects who did not have any of the above codes were selected to represent the control group. Subjects with ICD-10 code E10 ranged in age from 15 to 84. Subjects with ICD-10 code E11 ranged in age from 22 to 90.
The International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis codes were used to identify patients with SSc, SSc with lung involvement, SLE, lupus nephritis (LN), and SS in the study and control groups.
Data were summarized using counts and percentages for categorical data and means and standard deviations (SD) for continuous data. Chi-square tests were used to assess differences in categorical data.
We utilized Statistical Analysis System (SAS) 9.4 (SAS Institute, Cary, NC, USA) for all analyses and included designated weight values to produce nationally representative estimates. We considered a two-tailed p-value < 0.05 as statistically significant.
Ethical approval statement
This study was conducted in compliance with the Good Clinical Practices and principles of the Declaration of Helsinki, per our institution guidelines review by an institutional review board (IRB) is not required for use of de-identified limited data sets.
Results
Prevalence of SSc in patients with type 1 and type 2 diabetes
The data included 7,083,805 admissions. This part of the study included 80,247 patients with type 1 DM, 1,593,823 patients with type 2 DM, 6462 SSc patients, and 523 SSc patients with lung involvement.
SSc and diabetes
The prevalence of SSc among patients with type 1 DM (0.0007%) was significantly lower than that for the non-DM control group (0.09%), with a p-value of 0.0064. Similarly, a lower prevalence was noted among patients with type 2 DM (0.014%). This was significantly lower than that for the control group (0.1%), with a p-value < 0.0001 (Table 1 and Table 2).
Table 1.
Prevalence of SSc and SSc-associated lung disease in type 1 diabetes.
| Type 1 DM | Controls | p value | |
|---|---|---|---|
| SSc | 50 (0.0007%) | 6412 (0.09%) | 0.0064 |
| SSc with lung involvement | 2 (0.00001%) | 521 (0.007%) | 0.1049 |
Table 2.
Prevalence of SSc and SSc-associated lung disease in type 2 diabetes.
| Type 2 DM | Controls | p value | |
|---|---|---|---|
| SSc | 1047 (0.0148%) | 5415 (0.076%) | <0.0001 |
| SSc with lung involvement | 80 (0.001%) | 443 (0.006%) | <0.0001 |
The prevalence of SSc with lung involvement among patients with type 1 DM was lower than that in the control. However, the difference was not statistically significant (p = 0.1049). While the prevalence of SSc with lung involvement among patients with type 2 DM (0.001%) was significantly lower than the control group (0.006%), with a p-value < 0.0001 (Table 1 and Table 2).
Impact of insulin use on the prevalence of SSc
The prevalence of SSc among insulin users (0.004%) was significantly lower than that for non-users (0.087%), with a p-value < 0.0001. The prevalence of SSc lung disease among insulin users was lower than that for non-users. The difference was statistically significant (p = 0.0008) (Table 3).
Table 3.
Impact of insulin use on the prevalence of SSc.
| Insulin | No insulin | p value | |
|---|---|---|---|
| SSc | 294 (0.0042%) | 6168 (0.087%) | <0.0001 |
| SSc-associated lung disease | 20 (0.0003%) | 503 (0.007%) | 0.0008 |
Prevalence of SLE and SS in patients with type 1 and type 2 diabetes
We identified patients with SLE and SS to evaluate whether these patient populations would have similar results to SSc patients: 12,056 patients with SS, 32,604 patients with SLE, and 5600 patients with LN. The prevalence of SLE among patients with type 1 diabetes (0.0047%) was significantly lower than the non-diabetes control group (0.46%), with a p-value of 0.0566. Interestingly, the prevalence of LN was lower among patients with type 1 diabetes (0.0005% in DM vs 0.08% in the control group), with a p-value of 0.0008.
The prevalence of SLE in type 2 diabetes was lower compared to the non-DM control group; however, this was not statistically significant (p-value 0.0651). There was a significant decrease in the prevalence of LN with type 2 DM (0.01 vs 0.069), with a p-value < 0.001.
Similarly, there was a significant decrease in the prevalence of SS in patients with type 1 diabetes (0.001%) compared to the control group (0.17%), with a p-value < 0.0001. The prevalence of SS was significantly lower in patients with type 2 DM (0.033%) compared to the control group (0.137%), with a p-value < 0.001(Tables 4 and 5).
Table 4.
Prevalence of SLE, lupus nephritis, and SS in patients with type 1 diabetes.
| Type 1 DM | Controls | p value | |
|---|---|---|---|
| SLE | 333 (0.0047%) | 32,271 (0.4556%) | 0.0566 |
| LN | 37 (0.0005%) | 5563 (0.078%) | 0.0008 |
| SS | 89 (0.0013%) | 11,967 (0.169%) | <0.0001 |
Table 5.
Prevalence of SLE, lupus nephritis, and SS in patients with type 2 diabetes.
| Type 2 DM | Controls | p value | |
|---|---|---|---|
| SLE | 7197 (0.102%) | 25,407 (0.359%) | 0.0651 |
| LN | 713 (0.01%) | 4887 (0.069%) | <0.0001 |
| SS | 2345 (0.033%) | 9711 (0.137%) | <0.0001 |
Discussion
This study is a cross-sectional observational study that demonstrated a decreased prevalence of SSc, SLE, and SS in patients with type 1 and type 2 diabetes. To our knowledge, there have been limited studies exploring the association between SSc and diabetes; in a large nationwide cohort done in Taiwan by Tseng et al., 8 it was shown that there is a decreased incidence of type 1 and type 2 diabetes in SSc patients.
The study proposed that SSc and diabetes patients have different cytokine profiles that might explain this inverse relation. For instance, SSc patients had increased serum interleukin (IL)-13 levels, which was found to have a protective effect against type 1 and type 2 diabetes by inhibiting the prefoliation of islet-reactive T cells in animal modules.8,9 SSc patients also had increased IL-10 levels; IL-10 was shown to have a protective effect against type 1 and type 2 diabetes by inhibiting diabetogenic T-cell proliferation and enhancing insulin sensitivity, respectively9 –11
Our study presented similar results by demonstrating a decreased prevalence of SSc in patients with type 1 and type 2 diabetes. An intriguing finding was that there was an inverse relation between SSc-related lung disease and diabetes, which was statistically significant in patients with type 2 DM (0.001% vs 0.006% with p-value < 0.0001), suggesting that possibly the course of diabetes and/or treatment of diabetes may influence the severity and clinical manifestation of SSc. This might explain why there was less prevalence of SSc in type 1 DM patients who were treated with insulin (0.41% vs 0.46% in non-insulin users, p-value of 0.0566).
One possible way that the treatment of diabetes can alter the pathogenesis of SSc is through the peroxisome proliferator–activated receptor gamma (PPARγ) pathway. In animal studies, it was shown that PPARγ normally suppresses fibrogenesis in vivo and the reduced PPARγ expression in SSc leads to persistent activation of fibroblasts, while the addition of PPARγ agonists induced reversal of these changes. 12
Thiazolidinediones (TZDs) are a class of oral antidiabetic drugs, which exert their antidiabetic effects through a mechanism that involves activation of the PPARγ. One study that investigated the effect of rosiglitazone in bleomycin-induced SSc showed that rosiglitazone ameliorated the development of fibrosis in this mouse model of SSc. The anti-fibrotic effect was achieved mainly through the blockade of tumor growth factor (TGF)-β-induced fibroblast activation, which is key in the pathogenesis of SSc. 13 The role of TZD in patients with SSc has not been studied in randomized trials yet.
There are not many studies that investigated the association between SLE and diabetes. It is known that there is an increased risk of glucocorticoid-induced type 2 diabetes in patients with SLE treated with high-dose steroids. Our study showed that patients with diabetes have a lower risk of SLE and LN, which again raises the question of whether diabetes or its treatment might affect the severity and manifestation of SLE.
The role of antidiabetic medications in SLE is now under investigation as recent studies have shown the possible benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in LN, SGLT2i have shown to be effective in slowing the progression of chronic kidney disease (CKD) in both diabetic and nondiabetic patients with CKD. 12 This is currently being studied in LN as some trials are showing promising cardiac and renal protective effects of SGLT2i in LN patients. 14
The association between diabetes and SS has been investigated in some studies before, and one study suggested that sicca symptoms are very common in patients with diabetes and that 32% of type 1 DM patients have positive anti-Ro antibodies by ELISA. 15 However, the study did not explore if these patients met the diagnostic criteria for SS, especially since most patients experienced sicca symptoms mainly during the hyperglycemic state. In this study, we found a statistically significant inverse relation between SS and diabetes (0.11% vs 0.17% in type 1 DM, 0.15 vs 0.18% in type 2 DM).
Some data implicate possible effects of DM treatment on SS and vice versa, and one study suggested that metformin use in patients with type 2 diabetes may decrease the risk of developing SS. 16 The use of metformin as a therapeutic option in SS has been explored in murine modules, and it was shown that metformin could decrease the inflammation in salivary glands by downregulating IL-6, tumor necrosis factor-α, and IL-17 in situ.15,17 On the other hand, hydroxychloroquine use in patients with SS might have a protective effect against developing new-onset DM as it was shown to reduce the incidence of DM in a time and dose-dependent manner. 18
Our study has certain limitations, first being that our data were collected from an insurance claim database using ICD-10 codes. Patient data is susceptible to being misclassified due to coding and diagnosis errors from caregivers. The database also lacks important clinical parameters such as severity of disease and extent of systemic manifestations. This gap may lead to selection and confounding biases. Furthermore, the presence of other diseases that could affect our results, such as overlap syndrome, was not excluded. Our study was a cross-sectional examination of association, which cannot sufficiently establish temporal relationship between the diseases discussed.
Further longitudinal studies will be needed to assess the significance of this association and whether the treatment of diabetes would affect the incidence or the extent and severity of autoimmune connective tissue diseases such as SSc, SLE, and SS.
In conclusion, our study demonstrates an inverse relationship between certain autoimmune connective tissue diseases such as SSc, lupus, and SS and type 1 and type 2 DM. This suggests that these diseases and diabetes may have different immune pathogenesis. There was also a significantly lower incidence of organ complications such as LN and SSc lung disease among patients with diabetes, suggesting that diabetes and/or its treatment can alter the course of these disorders.
Footnotes
Contributors: All authors participated in the preparation of this manuscript. All authors have reviewed and approved the final draft of this manuscript.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Aya Abugharbyeh 
https://orcid.org/0009-0009-5791-1378
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