Gliflozin (SGLT2 inhibitor) induced vulvitis.

INTRODUCTION: Sodium-glucose co-transporter 2 (SGLT2) inhibitors, or gliflozins, are used as mono or combined therapy in the management of diabetes. Genital infections are the most common reported adverse effect, as a result of induced glycosuria. Cutaneous features of patients experiencing vulval symptoms while on SGLT2 inhibitor therapy have not been clearly described in published literature. We have observed a specific inflammatory vulvitis with psoriasiform features in patients taking SGLT2 inhibitors, related to candidiasis in most cases. METHODS AND RESULTS: Demographic and treatment outcomes of 11 patients with characteristic inflammatory changes after starting SGLT2 inhibitors were extracted from electronic records. Ninety-one percent (n = 10) had candidiasis, treated with fluconazole. Six (54.5%) were able to continue SGLT-2 inhibitors through the addition of topical treatments, but five patients had to discontinue the drug. CONCLUSIONS: SGLT2 inhibitors can result in characteristic inflammatory vulvitis. Treatment with topical agents and single-dose antifungals may allow patients to continue their therapy to achieve improved glycemic control. In resistant cases, discontinuation of the drug is necessary. We highlight this effect so that early treatment can be initiated to alleviate symptoms and recognition of underlying cause.

Risk of Candida Infection and Serious Infections in Patients with Moderate-to-Severe Psoriasis Receiving Biologics: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Biological agents used to treat moderate-to-severe plaque psoriasis have been associated with Candida infection and other serious infections. It is, however, necessary to verify whether biologic agents increase the risk of Candida infection and serious infections and whether these risks vary among biologics. Methods: PubMed, EMBASE, and Cochrane Library were searched for eligible randomized controlled trials (RCTs) from their inception to December 2021. Results from individual RCT were pooled using Peto's method with a fixed-effects model, and I 2 was calculated to assess the heterogeneity. A Cochrane collaboration tool was used to examine bias risk, and Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) were used to assess the quality of evidence. Results: This study included 48 published articles with data from 52 RCTs involving 27297 participants. The anti-interleukin (IL)-17 agents (95% confidence interval (CI) = 1.54-3.45, P < 0.0001) and anti-IL-12/23 agents (95% CI = 1.69-3.83, P < 0.0001) were associated with an increased risk of Candida infection compared with placebos, but there was no difference in Candida infection risk between anti-IL-17 agents and tumor necrosis factor inhibitors (TNFi) (95% CI = 0.92-3.07, P=0.09). There was no evidence that the biological agents increased the risk of serious infections in adult psoriasis (95% CI = 0.93-2.06, P=0.11) or that the biologics differed in the risk of serious infections. Conclusions: Our results indicated that anti-IL-17 agents, especially secukinumab, were associated with the increased risk of Candida infection. The clinically used biological agents did not increase the risk of serious infections.

Safety of secukinumab for the treatment of active ankylosing spondylitis.

Introduction: Secukinumab is a fully human monoclonal antibody which targets and neutralizes interleukin (IL)-17A, a cytokine that plays an important role in the pathophysiology of ankylosing spondylitis (AS). Secukinumab is the first IL-17A inhibitor approved for the treatment of AS.Areas covered: This paper aimed to evaluate the role of IL-17 in human beings, and the blocking of this cytokine with secukinumab while reviewing its efficacy and safety in the treatment of AS from data of MEASURE clinical trials.Expert opinion: MEASURE clinical trials showed efficacy and safety of secukinumab in patients with AS. Mild infections were the most frequent adverse event observed. Mucocutaneous candidiasis was a relatively common side effect due to the role of IL-17A in mucocutaneous defense against extracellular organisms. Secukinumab remained generally well tolerated over the longer-term. The combination of efficacy and safety makes secukinumab a good option of treatment for patients with AS refractory to non-steroidal anti-inflammatory drugs.

Assessment of nanopolystyrene toxicity under fungal infection condition in Caenorhabditis elegans.

Due to the potential of release and accumulation in the environment, nanoplastics have attracted an increasing attention. In this study, we investigated the effect of exposure to nanopolystyrene (30 nm) in nematode Caenorhabditis elegans after the fungal infection. After Candida albicans infection, exposure to nanopolystyrene (10 and 100 µg/L) for 24-h could cause the more severe toxicity on lifespan and locomotion behavior compared with fungal infection alone. The more severe activation of oxidative stress and suppression of SOD-3:GFP expression and mitochondrial unfolded protein response (mt UPR) were associated with this observed toxicity enhancement induced by nanopolystyrene exposure. Moreover, the more severe C. albicans colony formation and suppression of innate immune response as indicated by the alteration in expression of anti-microbial genes (abf-2, cnc-4, cnc-7, and fipr-22/23) further contributed to the formation of this toxicity enhancement induced by nanopolystyrene exposure. Our results demonstrated that short-term exposure to nanopolystyrene in the range of µg/L potentially enhances the adverse effects of fungal infection on organisms.

Esophageal candidiasis in patients from a specialty hospital / Candidiasis esofágica en pacientes de un hospital de especialidades

Background: Esophageal candidiasis (EC) is the most common cause of infectious esophagitis. So far, its main risk factor has been HIV infection; in recent years, EC has been favoured by the increasing of diabetes mellitus, wide-spread use of acid-lowering agents, broad-spectrum antibiotics, and inhaled steroids. In Mexico EC has been poorly studied. Objectives: To determine the clinical and epidemiological characteristics of EC, and to identify its etiological agents as well as its antifungal susceptibility. Methods: Patients who revealed the presence of scattered white spots through an upper gastrointestinal system endoscopy, in a period of one year, in a tertiary care hospital, were included. Samples from patches were collected for microscopic examination, culture, and susceptibility tests. Results: Out of 1763 patients studied, 23 had scattered white spots, and most of them presented Kodsi grade I; 13 were men; half of the patients were between the ages 20 to 40; main comorbidity was liver cirrhosis; use of omeprazole was significant. 22 isolates were obtained from 17 patients. The most frequent species were C. albicans (14) and C. parapsilosis (3). In five cases we found a two-species association v. g. Candida famata with Trichosporon mucoides. Half of the isolates showed resistance to one or several antifungal drugs. Conclusions: EC frequency in this study was similar to other studies' results. Obtained isolates showed high resistance to azolic compounds and to caspofungin, which is relevant information to take a therapeutic decision.

Introducción: la candidiasis esofágica (CE) es la causa más común de esofagitis infecciosa. Su principal factor de riesgo ha sido la infección por VIH. En México ha sido poco estudiada. Objetivos: determinar las características clínico-epidemiológicas de la CE e identificar sus agentes etiológicos y su sensibilidad a antifúngicos. Métodos: se incluyeron pacientes a quienes se les detectaron placas blanquecinas durante una endoscopía esofágica, en un periodo de un año, en un hospital de tercer nivel de atención. Se tomó muestra de las placas para examen microscópico, cultivo, y estudios de sensibilidad. Resultados: de 1763 pacientes estudiados, 23 presentaron placas blanquecinas; 13 fueron hombres; la mitad tenía de 20 a 40 años de edad; la principal comorbilidad fue cirrosis hepática; el uso de omeprazol fue significativo. Se obtuvieron 22 aislados de 17 pacientes; predominaron Candida albicans (14) y Candida parapsilosis (3). En cinco casos se encontró asociación de dos especies v. g. Candida famata con Trichosporon mucoides. La mitad de los aislados mostró resistencia a antimicóticos. Conclusiones: la frecuencia de CE fue similar a la de otras casuísticas. Los aislados obtenidos mostraron resistencia elevada a compuestos azólicos y a caspofungina, información relevante para tomar una decisión terapéutica.

Are new variants of psoriasis therapy (IL-17 inhibitors) safe?

Psoriasis is a chronic, recurrent, inflammatory, and proliferative skin disease. Its etiology has not yet been fully assessed, but undoubtedly it is a multifaceted disease. The key role in its pathomechanism is played by genetic, immunologic, and environmental factors and stress. If traditional methods of psoriasis treatment (phototherapy, methotrexate, retinoids, cyclosporine A) fail, we reach for the following biopharmaceuticals - infliximab, etanercept, adalimumab, or ustekinumab. However, genetic engineering progress discovers new possibilities - the pending clinical trials involve IL-17, IL-23 antagonists, PDE4 and -3 and -1. Psoriasis etiopathogenesis mainly involves the IL-17A, IL-17F, and IL-17A/F subtypes, which affect the keratinocytes. The biological therapy molecularly oriented with the antagonists of interleukin 17 is based mainly on the influence onto the cytokine in the manner that prevents it from binding with the receptor. Three biopharmaceuticals are currently under third phase studies: two fully humanized antibodies neutralizing IL-17 - ixekizumab and secukinumab, and one human monoclonal antibody, brodalumab. The below work will be devoted to the analysis of possible undesirable symptoms, which were observed during the studies. We will try to review the latest literature concerning the most important clinical trials conducted in many centers.

A safety update on sodium glucose co-transporter 2 inhibitors.

Sodium glucose co-transporter 2 inhibitors (SGLT2is) are the first class of glucose lowering agent to be shown to reduce cardiovascular events. They are generally well tolerated with infrequent serious adverse events. The most frequent side effect is genital mycotic infections with candida species that are usually mild to moderate in severity, easily treated and infrequently recur. Urinary tract infections, although common in patients with diabetes, have not been shown to be increased in controlled studies with SGLT2i. Hypoglycaemia can occur when an SGLT2i is added to agents that cause hypoglycaemia, such as insulin or sulphonylureas. Volume depletion and hypotension is infrequent and can be minimized by adjusting diuretic and antihypertensive treatment in patients at risk. Acute renal failure or kidney injury was observed in early observational studies. However, in randomized controlled trials (RCTs) and in more recent observational studies a decreased incidence of acute kidney injury was observed in SGLT2-treated patients compared to those receiving either placebo or another class of glucose lowering agents. An increased incidence of amputation (largely feet and toes) was observed in the RCT with canagliflozin but not with the other SGLT2i. Observational studies have shown either an increased risk of amputation with other agents whereas another study showed no increase. Although the increased risk of amputation is very low, avoidance of SGLT2i in patients at high risk seems prudent. Increased incidence of fractures was observed with canagliflozin but not with SGLT2i nor in a meta-analysis that included canagliflozin, empagliflozin and dapagliflozin. No increased incidence of cancer has been observed in either RCTs or observational studies.

Safety of Ixekizumab in Patients With Psoriatic Arthritis: Results From a Pooled Analysis of Three Clinical Trials.

OBJECTIVE: To evaluate ixekizumab safety in adults with psoriatic arthritis (PsA). METHODS: Safety data from 2 integrated data sets are presented: 1) 24-week, double-blind, placebo-controlled period of SPIRIT-P1 and SPIRIT-P2; and 2) all ixekizumab-treated patients of SPIRIT-P1 and SPIRIT-P2 plus SPIRIT-P3 open-label period. We report adverse event (AE) frequency and exposure-adjusted incidence rates per 100 patient-years at 12-week intervals to week 96. RESULTS: The placebo-controlled period had 678 patients (safety population): 224 placebo, 229 ixekizumab every 4 weeks, and 225 ixekizumab every 2 weeks. Overall, 1,118 patients received ixekizumab (total exposure 1,373.4 patient-years). In the placebo-controlled period, the frequencies of ixekizumab-treated patients experiencing ≥1 treatment-emergent AE (TEAE) and those experiencing serious AEs were 68.1% (56.7% placebo) and 4.4% (2.7% placebo), respectively. Injection site reactions (ISRs) were very common (21.4% ixekizumab [4.5% placebo]), with ISR discontinuation rates of 1.1% (ixekizumab) and 0.4% (placebo). Through week 96, the incidence rates of ISRs decreased with increasing ixekizumab exposure. The frequencies of AEs of special interest were 32.8% (ixekizumab) and 27.7% (placebo); for serious infections, the frequencies were 1.3% and 0%, respectively; Candida infections, 2.6% and 0.4%; confirmed major adverse cardiac events, 0% and 0%; malignancy, 0.4% and 0%; hypersensitivities, 5.3% and 1.8%; and depression-related, 1.8% and 1.3%. The frequency of Crohn's disease and ulcerative colitis (investigator-reported) was 0% in both groups, and the frequencies of sponsor-determined inflammatory bowel disease were 0.2% in the ixekizumab group and 0% in the placebo group. Overall, no active tuberculosis, invasive Candida infections, anaphylaxis, or suicide/self-injury behaviors were reported. CONCLUSION: The PsA ixekizumab safety integrated data set reached 1,373.4 patient-years total exposure. Ixekizumab-treated patients had higher rates of overall TEAEs, serious infections, mucocutaneous Candida, hypersensitivities (non-anaphylactic), and ISRs than placebo-treated patients. No unexpected safety outcomes were reported.

Comparative risk of genital infections associated with sodium-glucose co-transporter-2 inhibitors.

The extent to which sodium-glucose co-transporter-2 (SGLT2) inhibitors increase the risk of genital infections in routine clinical care, compared with other antidiabetic medications, is not clear, or whether the increased risk is consistent across gender or age subgroups, within individual SGLT2 agents, or if it is more pronounced at a particular time after treatment initiation. We conducted a retrospective cohort study using two US commercial claims databases (2013-2017). In the primary analysis, 1:1 propensity score-matched cohorts of female and male subjects with type 2 diabetes mellitus initiating SGLT2 versus dipeptidyl peptidase-4 inhibitors were created. The outcome was a composite of genital candidal infections, vaginitis or vulvovaginitis in women, and genital candidal infections, balanitis, balanoposthitis, phimosis or paraphimosis in men. Among propensity score-matched cohorts of 129 994 women and 156 074 men, the adjusted hazard ratio (HR) and excess risk per 1000 person-years for SGLT2 versus DPP-4 inhibitors was 2.81 (95% confidence interval [CI], 2.64, 2.99) and 87.4 (95% CI, 79.1, 96.2) respectively for women, and was 2.68 (95% CI, 2.31, 3.11) and 11.9 (95% CI, 9.3-15.0) for men. Findings were similar in the SGLT2 inhibitor versus GLP-1 agonist comparison, more pronounced in the subgroup of patients aged ≥60 (HR, 4.45 [95% CI, 3.83-5.17] in women and 3.30 [95% CI, 2.56-4.25] in men), and no meaningful difference across individual SGLT2 inhibitors was identified. This increase in risk was evident in the first month of treatment initiation and remained elevated throughout the course of therapy. SGLT2 inhibitors were associated with an approximately 3-fold increase in risk of genital infections.

Antibiotic-induced alterations in taurocholic acid levels promote gastrointestinal colonization of Candida albicans.

Candida albicans is a fungal pathogen that poses a significant public health risk due to high incidence and mortality rates among immunocompromised patients. Candida albicans infections begin with successful gastrointestinal (GI) colonization; however, the mechanisms behind this colonization remain to be elucidated. In this study, we investigated the role of taurocholic acid (TCA) on growth and GI colonization of C. albicans. Our results indicate that cefoperazone-treated mice susceptible to C. albicans infection had significantly increased levels of TCA in the gut contents. In addition, an increase in TCA levels directly correlates with higher C. albicans load in the fecal and gut contents of antibiotic-treated infected mice. Using in vitro assays, we also demonstrated that TCA enhances the growth of C. albicans and its ability to develop filamentous hyphae. Furthermore, TCA significantly increased the ability of C. albicans to attach to mammalian cells. These results demonstrate that antibiotic treatment alters TCA levels in the gut and potentially enhances GI colonization of C. albicans.

Immunosuppression/Infections across Indications.

There is increasing use of cytokine inhibitors (including biologics) in the treatment of psoriasis as their efficacy and safety have been demonstrated. Cytokines are important signaling molecules evolved to coordinate a response to infectious threat. In this study, we review available trial, registry and cohort study data pertaining to the immunosuppressive effects of these medications when used to treat psoriasis. The risk of infection associated with these medications is small. Special considerations include the use of these agents in the setting of granulomatous infections, viral hepatitis, human immunodeficiency virus infection, fungal infection and in the perioperative state.

Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism.

Uveitis (intraocular inflammation) is a leading cause of loss of vision. Although its aetiology is largely speculative, it is thought to arise from complex genetic-environmental interactions that break immune tolerance to generate eye-specific autoreactive T cells. Experimental autoimmune uveitis (EAU), induced by immunization with the ocular antigen, interphotoreceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing complete Freund's adjuvant (CFA), has many clinical and histopathological features of human posterior uveitis. Studies in EAU have focused on defining pathogenic CD4+ T cell effector responses, such as those of T helper type 17 (Th17) cells, but the innate receptor pathways precipitating development of autoreactive, eye-specific T cells remain poorly defined. In this study, we found that fungal-derived antigens possess autoimmune uveitis-promoting function akin to CFA in conventional EAU. The capacity of commensal fungi such as Candida albicans or Saccharomyces cerevisae to promote IRBP-triggered EAU was mediated by Card9. Because Card9 is an essential signalling molecule of a subgroup of C-type lectin receptors (CLRs) important in host defence, we evaluated further the proximal Card9-activating CLRs. Using single receptor-deficient mice we identified Dectin-2, but not Mincle or Dectin-1, as a predominant mediator of fungal-promoted uveitis. Conversely, Dectin-2 activation by α-mannan reproduced the uveitic phenotype of EAU sufficiently, in a process mediated by the Card9-coupled signalling axis and interleukin (IL)-17 production. Taken together, this report relates the potential of the Dectin-2/Card9-coupled pathway in ocular autoimmunity. Not only does it contribute to understanding of how innate immune receptors orchestrate T cell-mediated autoimmunity, it also reveals a previously unappreciated ability of fungal-derived signals to promote autoimmunity.

Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study.

OBJECTIVE: To evaluate the effect of secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic changes through 2 years in patients with ankylosing spondylitis (AS). METHODS: In the phase III MEASURE 1 study, patients were randomised to receive intravenous secukinumab 10 mg/kg (at baseline, week 2 and week 4) followed by subcutaneous secukinumab 150 mg (intravenous 150 mg; n=125) or 75 mg (intravenous 75 mg; n=124) every four weeks, or matched placebo (n=122). Placebo-treated patients were re-randomised to subcutaneous secukinumab 150 or 75 mg from week 16. Clinical efficacy assessments included Assessment of SpondyloArthritis international Society 20 (ASAS20) response rates through week 104. Radiographic changes at week 104 were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). RESULTS: 97 (77.6%) and 103 (83.1%) patients in the intravenous 150 mg and intravenous 75 mg groups, respectively, completed week 104. In the full analysis set (intent-to-treat), ASAS20 response rates at week 104 were 73.7% and 68.0% in the intravenous 150 mg and intravenous 75 mg groups, respectively. Among patients with evaluable X-rays who were originally randomised to secukinumab (n=168), mean change in mSASSS from baseline to week 104 was 0.30±2.53. Serious adverse events were reported in 12.2% and 13.4% of patients in the 150 mg and 75 mg groups, respectively. CONCLUSIONS: Secukinumab improved AS signs and symptoms through 2 years of therapy, with no unexpected safety findings. Data from this study suggest a low mean progression of spinal radiographic changes, which will need to be confirmed in longer-term controlled studies. TRIAL REGISTRATION NUMBER: NCT01358175.

Short- and long-term safety outcomes with ixekizumab from 7 clinical trials in psoriasis: Etanercept comparisons and integrated data.

BACKGROUND: Safety of biologics is important when treating patients with psoriasis. OBJECTIVE: We sought to determine the safety of ixekizumab in psoriasis. METHODS: Integrated safety data are presented from a 12-week induction period, a 12- to 60-week maintenance period, and from all ixekizumab-treated patients from 7 clinical trials. Exposure-adjusted incidence rates (IRs) per 100 patient-years are reported. RESULTS: Overall, 4209 patients received ixekizumab (total exposure: 6480 patient-years). During the induction period, the IRs of patients experiencing 1 or more treatment-emergent adverse event (AE) were 251 and 236 among ixekizumab- and etanercept-treated patients, respectively, and for serious AEs was 8.3 in both groups. During maintenance, for ixekizumab, the IRs of treatment-emergent AEs and serious AEs were 100.4 and 7.8, respectively. Among all ixekizumab-treated patients from 7 trials, the IR of Candida infections was 2.5. The IRs of treatment-emergent AEs of special interest (including serious infections, malignancies, major adverse cardiovascular events) were comparable for ixekizumab and etanercept during the induction period. LIMITATIONS: Additional long-term data are required. CONCLUSION: Ixekizumab had an acceptable safety profile with no unexpected safety findings during ixekizumab maintenance in psoriasis.

Candida Esophagitis Associated With Mycophenolate Mofetil Treatment of Atopic Dermatitis.

OBJECTIVE: To describe a case in which a patient developed Candida esophagitis (CE) after treatment of atopic dermatitis (AD) with mycophenolate mofetil (MMF) for 22 months. CASE SUMMARY: A 59-year-old Caucasian female with long-standing history of AD successfully treated with MMF presented to the dermatology clinic for follow-up appointment with 3 months' history of projectile vomiting, choking, and trouble swallowing. Patient underwent esophagogastroduodenoscopy (EGD) that demonstrated whitish plaques in esophagus consistent with CE, which was confirmed by biopsy and cytology. DISCUSSION AND CONCLUSION: MMF is a lymphocyte selective immunosuppressive agent that has demonstrated very good therapeutic effects against cutaneous inflammatory skin disease and proved to have good efficacy and bioavailability. Generally, MMF is a safe medication with relatively low side effects. There are no case reports to date that describe CE in patients treated with MMF. Clinicians should be aware of this rare complication to enable timely intervention and treatment.

J Drugs Dermatol. 2016;15(10):1267-1269.

Epigastric Distress Caused by Esophageal Candidiasis in 2 Patients Who Received Sorafenib Plus Radiotherapy for Hepatocellular Carcinoma: Case Report.

Sorafenib followed by fractionated radiotherapy (RT) has been shown to decrease the phagocytic and candidacidal activities of antifungal agents due to radiosensitization. Moreover, sorafenib has been shown to suppress the immune system, thereby increasing the risk for candida colonization and infection. In this study, we present the 2 hepatocellular carcinoma (HCC) patients suffered from epigastric distress caused by esophageal candidiasis who received sorafenib plus RT. Two patients who had received sorafenib and RT for HCC with bone metastasis presented with hiccups, gastric ulcer, epigastric distress, anorexia, heart burn, and fatigue. Empiric antiemetic agents, antacids, and pain killers were ineffective at relieving symptoms. Panendoscopy revealed diffuse white lesions in the esophagus. Candida esophagitis was suspected. Results of periodic acid-Schiff staining were diagnostic of candidiasis. Oral fluconazole (150 mg) twice daily and proton-pump inhibitors were prescribed. At 2-weak follow-up, esophagitis had resolved and both patients were free of gastrointestinal symptoms. Physicians should be aware that sorafenib combined with RT may induce an immunosuppressive state in patients with HCC, thereby increasing their risk of developing esophagitis due to candida species.

Acid suppressing therapy as a risk factor for Candida esophagitis.

Studies were reviewed from PubMed for risk factors for the development, recurrence, prevention and therapy of Candida esophagitis, and for mechanisms induced by acid-suppressing therapy potentially influencing these factors. Documented observations included greatly increased Candida populations in the mouth, esophagus, stomach, and upper small intestine induced by acid-suppressing therapy. Among patients without HIV disease, PPI consumers more frequently had developed Candida esophagitis than did non-consumers and had also developed its recurrences more frequently. Similar phenomena associated with H2 -blocker use were less intense, and the possibility of similar phenomena in patients with HIV disease apparently had not yet been examined in spite of their high frequency of this disorder. PPI-induced elimination of the gastric acid barrier is a major mechanism leading to oro-pharyngeal and esophageal candida colonization, while PPI-induced impairment of absorption of most orally administered antifungal agents may limit the prophylactic and therapeutic success of these agents. These observations suggest potential value in limiting PPI use in populations of patients with Candida infections including esophagitis, as well as in patients at risk for their development, and also suggest that post-PPI rebound acid hypersecretion may provide additional anti-Candida benefit. Studies designed to develop the risk-benefit ratios of PPI use in these patients deserve investigation with high priority appropriate for studies in patients with HIV disease.