Hyperglycemia Is a Potential Prognostic Factor for Exacerbation in Severe Psoriasis with Diabetes or Prediabetes

Introduction

Psoriasis is a chronic immune-mediated skin disease that affects approximately 100 million people of all ages and genders worldwide, with prevalence rates ranging from <1% to 5%.^1,2 Plaque psoriasis, the most prevalent variant, is classically defined by erythematous scaly plaques that are frequently observed on extensor surfaces, as well as other body sites, such as the nail.³ The pathogenesis of psoriasis mainly involves the overactivation of the adaptive immune system, particularly the T-helper cell type 17 pathway.³ It is being recognized as a systemic inflammatory disease with associated disorders such as psoriatic arthritis, cardiometabolic diseases, chronic kidney disease, and hepatic diseases, leading to an increase in mortality, particularly in severe cases.^1,4,5

Hyperglycemia has a detrimental effect on our health in a variety of ways, including acute complications such as infection and diabetic coma, as well as chronic complications like cataract and myocardial infarction.⁶ Although it is still debatable whether or not psoriasis itself is a prediabetic condition,⁷ multiple studies have demonstrated that psoriasis is an independent risk factor for insulin resistance.^8–10 Moreover, type 2 diabetes mellitus (T2DM) is significantly more prevalent in patients with psoriasis than in the general population,^11–14 and large cohort studies have identified psoriasis as an independent risk factor for developing incident T2DM.^15,16 Patients with psoriasis may therefore be predisposed to type 2 diabetes mellitus (T2DM).

Certain environmental factors, such as infections and medications, are capable of triggering psoriasis flare.¹⁷ According to the “psoriatic march” theory, psoriasis-induced systemic inflammation leads to insulin resistance, endothelial dysfunction, atherosclerosis, and cardiovascular disease.¹⁸ Interestingly, insulin resistance may also worsen psoriatic skin lesions.^19,20 This is supported by the correlation between psoriasis severity and hemoglobin A1c (HbA1c), as well as insulin resistance;^21–23 however, it is unknown whether hyperglycemia can also cause psoriasis exacerbation. Understanding the association between hyperglycemia and psoriasis exacerbation is crucial for optimizing treatment and patient education; therefore, we aimed to determine whether hyperglycemia predicts psoriasis flares.

Materials and Methods

Study Design and Ethical Consideration

A 15-year retrospective cohort study of patients with psoriasis and either T2DM or impaired fasting glucose (IFG) was conducted. The study was approved by the Institutional Review Boards of Mahidol University (COA. MURA2022/541) which are in full compliance with international guidelines for human research protection such as the Declaration of Helsinki.

Patient Selection Process

Data extraction was conducted between September 2022 and June 2024, reviewing medical records of all outpatients aged 18 years or over who were treated at Ramathibodi Hospital, Bangkok, Thailand, from January 1, 2008, to September 1, 2022, with an International Classification of Diseases, 10th Revision (ICD-10) code of L40.0 (psoriasis vulgaris) and either R73.0 (abnormal glucose tolerance test) or E11.9 (T2DM) were reviewed.

Eligible patients must have had a diagnosis of psoriasis vulgaris along with T2DM or IFG, with at least 2 hbA1c values that were matched with respective values of Psoriasis Area and Severity Index (PASI) or extent of psoriasis lesions in percentage of body surface area (BSA) recorded not later than 3 months after the HbA1c measurement. In addition, at least one of their HbA1c levels must have been at least 5.7%, as the cutoff value of 5.7% was used as the diagnostic threshold for prediabetes, and we intended to investigate the possible contribution of hyperglycemia to psoriasis exacerbation in psoriasis patients with prediabetes or diabetes.²⁴ Patients on immunosuppressants due to organ transplantation or with autoimmune comorbidities, such as systemic lupus erythematosus, were excluded from the study. Patients who were receiving chemotherapy or systemic corticosteroids were also excluded.

Definitions of Psoriasis Severity and Exacerbations

Patients with a maximum PASI of ≥ 10 or a maximum BSA of ≥ 10% were classified as having severe psoriasis in our study, and those with a maximum PASI of < 10 and a maximum BSA of < 10% as having mild psoriasis. This classification was used throughout the data analysis. To ensure that the same psoriasis exacerbation criteria are used for all flare evaluations, two board-certified dermatologists (KT and PR) agreed upon exacerbation criteria that take into account the nature of flaring in mild and severe psoriasis, as well as dose escalations or initiation of systemic therapy. We defined a psoriasis flare in severe psoriasis as any of the following: an increase in dosage of the current systemic medication(s), an initiation of a new systemic medication or phototherapy, or an increase in PASI of ≥ 3 or in psoriasis involvement of ≥ 3% BSA from the previous visit. However, the usual dose escalation in the initial stage of treatment with methotrexate was not considered to be a flare. Meanwhile, any of the following was considered a mild psoriasis flare-up: an initiation of systemic therapy or phototherapy for psoriasis, or any increase in PASI or percentage of BSA affected by psoriasis from the previous visit.

Data Collection

The patient’s demographics, medical comorbidities, clinical presentations, laboratory results, type and dosage of systemic therapy (methotrexate, cyclosporine, acitretin, phototherapy, and biologic agents), reasons for changing or increasing dosage of systemic therapy, PASI, and percentage of BSA affected by psoriasis were extracted from the medical records. HbA1c values from within 3 months prior to the physical examination were used, and the cutoff level of 7% for categorizing HbA1c was adopted from the treatment goals for diabetes management in the most recent guideline from the American Diabetes Association.²⁵

Statistical Analysis

Frequency and percentage were used to describe categorical data. For continuous data, the mean and standard deviation (SD) were used. All analyses were carried out separately in patients with mild and severe psoriasis, according to the above-mentioned classification. Univariate analysis was performed on all available variables using mixed-effects logistic regression models with psoriasis exacerbation as the outcome. The variables with p-values < 0.2 from the univariate analysis and those considered to be clinically relevant to psoriasis severity (ie, type and dosage of systemic therapy for psoriasis, body mass index (BMI), smoking status, and alcohol consumption status) were included in multivariate mixed-effects logistic regression models. P-values of < 0.05 were considered statistically significant. The Stata statistical software package version 16.0 (StataCorp, College Station, TX) was used in all analyses.

Results

There were 418 outpatients with ICD-10 codes of L40.0 with either R73.0 or E11.9. Two hundred and seven of them were excluded for the reasons shown in Figure 1. The remaining 211 cases were reviewed further to eliminate cases that met the exclusion criteria, and 10 cases were dismissed. Finally, 201 psoriasis patients were eligible (Figure 1), with a median follow-up time of 4.67 years (range: 1.38 months to 11.25 years). They had a median number of visits of 6 (range: 2–41) and a total of 1717 visits. Of these, 95 patients, whose median number of visits was 7.5 (range: 2–41), were classified to have severe psoriasis. The other 106 patients had mild psoriasis, with a median number of visits of 5.5 (range: 2–25).

Figure 1 Flow diagram of the patient selection process.

Overall, the mean (SD) age was 56.96 (12.71) years, and 118 (58.71%) of the patients were male, with a mean (SD) BMI of 28.14 (5.96) kg/m². One hundred thirty-one (65%) patients had T2DM, while the remaining (34.83%) had IFG. Other common comorbidities include dyslipidemia in 177 (88.06%) patients, essential hypertension in 143 (71.14%) patients, metabolic syndrome in 118 (58.71%) patients, nonalcoholic fatty liver disease in 48 (23.88%) patients, chronic kidney disease 23 (11.44%) patients, and cardiovascular disease in 34 (16.92%) patients. The patients’ characteristics are summarized in Table 1.

Table 1 Patients’ Characteristics in Relation to Psoriasis Severity

Exacerbation was found in a total of 523 (30.46%) visits from 149 (74.13%) psoriasis patients, comprising 295 (31.25%) visits from 74 (77.89%) patients with severe psoriasis and 228 (29.50%) visits from 75 (70.75%) patients with mild psoriasis.

The results of univariate and multivariate analysis of potential prognostic factors for exacerbation in patients with severe psoriasis are shown in Table 2. Univariate analysis revealed HbA1c ≥ 7% and alcohol consumption status to be associated with psoriasis flares in patients with severe psoriasis, with odds ratios (OR) of 1.753 (95% confidence interval: 1.218–2.524) and 2.848 (1.020–7.953), respectively. Multivariate analysis revealed that HbA1c ≥ 7% and alcohol consumption status were factors independently associated with psoriasis flares in patients with severe psoriasis, with adjusted ORs of 1.905 (1.328–2.731) and 3.328 (1.235–8.965), respectively.

Table 2 Univariate and Multivariate Analysis of Potential Prognostic Factors for Exacerbation in Patients With Severe Psoriasis

From the univariate analysis in patients with mild psoriasis, HbA1c ≥ 7% was associated with psoriasis flares with OR of 1.544 (1.068–2.232), while male gender, cardiovascular disease, and chronic kidney disease were found to be protective for psoriasis flares with ORs of 0.592 (0.385–0.910), 0.530 (0.315–0.892), and 0.478 (0.263–0.867), respectively. However, the multivariate analysis revealed that none of these factors were significantly associated with psoriasis flares. Table 3 shows the results of univariate and multivariate analysis of potential prognostic factors for exacerbation in patients with mild psoriasis.

Table 3 Univariate and Multivariate Analysis of Potential Prognostic Factors for Exacerbation in Patients With Mild Psoriasis

Discussion

Our study was a 15-year retrospective cohort study aimed at investigating the association between hyperglycemia and psoriasis exacerbation. Previous studies have established that HbA1c and insulin resistance correlate with psoriasis severity.^21–23 In our study, we found that HbA1c ≥ 7% could be an independent prognostic factor for flare in patients with severe psoriasis, with an adjusted OR of 1.905. Our choice of HbA1c ≥ 7% as a threshold was based on established diabetes treatment targets from the American Diabetes Association. This clinically relevant cutoff point allows our findings to be readily integrated into existing diabetes management protocols while providing new insights into psoriasis care.

Psoriasis patients with comorbidities such as diabetes appear to be more resistant to treatment.^26–28 Insulin resistance may induce psoriasis exacerbation.^19,20 We hypothesize that hyperglycemia in diabetic or prediabetic psoriasis patients may also increase their overall inflammatory burden²⁹ or interfere with the mechanisms of psoriatic medications, thereby reducing the likelihood of successful treatment. A number of studies have demonstrated that the presence of diabetes has an impact on the effectiveness of specific anti-psoriatic medications, particularly biologic agents. Diabetes was found to significantly reduce the odds of achieving PASI75 and PASI90 in psoriasis patients taking interleukin-17 inhibitors by 39% and 31%, respectively, after adjusting for other prognostic factors including obesity.³⁰ Psoriasis with coexisting diabetes have been found to have a reduced likelihood of experiencing a positive response to ustekinumab^29,31,32 and secukinumab.²⁹ Higher HbA1c level was also identified as one of the predictors of secondary infliximab treatment failure.³³ Likewise, diabetes was found to significantly reduce the probability of achieving PASI75 and PASI50 in psoriasis patients taking methotrexate or cyclosporine.³⁴ In addition, acitretin can interfere with hypoglycemic agents and impair glycemic control in diabetic patients,^35,36 and since hyperglycemia may exacerbate psoriasis, a suboptimal response to acitretin in psoriasis patients with T2DM or IFG may be anticipated. Therefore, diabetic and pre-diabetic psoriasis patients who are resistant to therapy may benefit from glucose monitoring. Patients who experience an acitretin-induced psoriatic flare in the initial weeks^35,37 or exacerbations with no known precipitants may also benefit from glucose surveillance. The effects of hyperglycemia on psoriasis treatment response and its associated mechanisms require additional research.

Diabetes is one of the significant predictors for lack of improvement in the Dermatology Life Quality Index (DLQI) score of psoriasis patients.³⁸ Given that hyperglycemia may exacerbate psoriasis in diabetic or prediabetic psoriasis patients and that the presence of T2DM or IFG may be associated with a poorer response to medications, hyperglycemia control may contribute to psoriasis improvement and, accordingly, an improvement in quality of life. A recent meta-analysis revealed that psoriasis patients randomized to receive hypoglycemic medications exhibited a significant reduction in PASI score and an increased likelihood of achieving PASI75.³⁹ Managing hyperglycemia in psoriasis patients with diabetes may therefore reduce the likelihood of flares, lessen psoriasis severity, and improve treatment response. Consequently, in addition to treating psoriatic plaques, dermatologists and other healthcare professionals should also monitor diabetes management and surveillance in psoriasis patients, particularly those whose symptoms flare up or are resistant to treatment.

In mild psoriasis patients, however, after adjusting for various factors, hyperglycemia was not found to be associated with psoriasis flares with statistical significance in the present study. The dose-response relationship between diabetes, insulin resistance, and psoriasis has been shown in previous studies,^15,16,21,40 and so the stronger association between hyperglycemia and psoriasis flares in severe psoriasis patients is not unexpected. Since insulin resistance may also result in endothelial dysfunction, atherosclerosis, and subsequent cardiovascular diseases¹⁸ in addition to its potential role in psoriasis flare-ups, we believe that diabetes screening and early lifestyle interventions are essential for all psoriasis patients, regardless of disease severity.

Psoriasis patients are more likely to become excessive drinkers than the general population.⁴¹ Alcohol drinking was found to correlate with psoriasis severity, a poorer response to psoriasis treatment, and increased alcohol-related mortality from causes such as alcoholic liver diseases, liver fibrosis, and mental disorders in psoriasis patients.^41–44 In addition to diabetes, alcoholism is a significant predictor for absence of improvement in the DLQI score of psoriasis patients.³⁸ Our findings revealed that alcohol consumption status is one of the independent prognostic factors for psoriasis exacerbation in patients with severe psoriasis, with an adjusted OR of 3.328. In addition to increasing morbidity and mortality among psoriasis patients, alcohol also impacts the condition and treatment of the disease. Therefore, dermatologists and other healthcare professionals should strongly advise patients to abstain from alcohol consumption, and referral to specialists for specialized care may be necessary. Additionally, since lifestyle habits are closely linked to both glycemic control and alcohol abstinence, it is crucial for the entire healthcare system to adopt a person-centered approach.

Our research has a few limitations. A small sample was collected from a single university hospital. In addition, many records lacked information such as the degree of alcohol consumption and other details. We excluded from our analysis the history of exposure to known exacerbating factors, such as infection and drugs, because of the inherent reporting bias of the trigger questioning, which was conducted only during visits in which patients had a psoriasis flare. To confirm our findings, larger, multi-center, well-designed prospective studies are needed.

Conclusion

In our study, we found that hyperglycemia (HbA1c ≥ 7%) and alcohol drinking status were independent prognostic factors for exacerbation in severe psoriasis patients with diabetes or prediabetes. We believe that diabetes surveillance may be necessary for all psoriasis patients, and strict glycemic control may aid in managing severe psoriasis. Further research is required to confirm the impact of hyperglycemia on the severity and treatment of psoriasis.