COVID-19 IN INFLAMMATORY BOWEL DISEASE: SHOULD WE BE MORE CAREFUL WITH THE USE OF SALICYLATES?

BACKGROUNDS: Fortunately, much has been studied about COVID-19 in patients with inflammatory bowel diseases (IBD). Evidence suggests that these patients do not appear to be at increased risk of severe COVID-19. However, there are still some uncertainties regarding the clinical manifestations of COVID-19 in patients with immune-mediated diseases. OBJECTIVE: This study aimed to describe the main symptoms of COVID-19 and their frequency in IBD patients and evaluate the impact of the IBD therapeutic drugs on clinical presentation of COVID-19 and to determine factors associated with COVID-19 in this population. METHODS: Adult patients with IBD from three tertiary-care public, teaching hospitals in Ceará, Northeastern Brazil, were evaluated during one scheduled appointment from March to December 2020. Patients with possible or confirmed COVID-19 were compared with patients without COVID-19. Furthermore, incidences of each symptom were evaluated based on the use of IBD therapeutic drugs. RESULTS: A total of 515 patients with IBD were included in the study: 234 with CD, and 281 with UC. Of these, 174 patients (34%) had possible/confirmed COVID-19 of whom 156 (90%) were symptomatic. Main symptoms were fever (65%) and headache (65%); gastrointestinal symptoms occurred in one third of patients and were higher than COVID-19 in general population. The factors associated with having COVID-19 were female gender (OR 1.71, 95%CI: 1.17-2.50); contact at home (OR 5.07, 95%CI: 3.31-7.78) and outside the home (OR 3.14, 95%CI: 2.10-4.71) with a case of COVID-19; work outside of the home (OR 1.87, 95%CI: 1.26-2.78); family history of COVID-19 (OR 2.29, 95%CI 1.58-3.33) use of salicylate (OR 1.71, 95%CI: 1.17-4.28); and asthma (OR 7.10, 95%CI: 1.46-34.57). CONCLUSION: IBD patients at high risk of COVID-19 infection may need to avoid salicylate therapy but further studies are necessary to confirm this association.

Allergic contact dermatitis to salicylic acid: A case series of relevant sensitization.

INTRODUCTION: Allergic contact dermatitis (ACD) to salicylic acid (SA) is widely unreported. Furthermore, cross-reactivity between SA and other salicylates has not been reported despite well-documented in-group salicylate cross-reactivity. OBJECTIVE: To describe our clinic's experience patch testing to SA, highlighting seven cases of relevant reactions and concomitant reactivity with other salicylates. METHODS: Results of patch testing to 5% SA in petrolatum between 1 January 2020, and 9 February 2024, are reported. Seven cases of relevant reactions to SA are detailed. RESULTS: A total of 489 patients (27.5%) were tested to SA, 21 of which were positive: 7 doubtful (+/-), 14 weak positive (+), and no strong/extreme positive reactions. Four irritant reactions were documented. Of the 14 weak positive (+) reactions, 7 had definite or probable clinical relevance, 5 of which also reacted to other salicylates. CONCLUSIONS: ACD to SA is likely underreported due to a lack of testing. In our experience, testing SA 5% petrolatum is tolerable without significant irritation. Cross-reactivity between SA and other salicylates is probable. Though SA appears to be the primary sensitizer in some cases, more studies are needed to understand its possible role as a marker for salicylate allergy.

Sensitisation to ethylhexyl salicylate: Another piece of the frontal fibrosing alopecia puzzle.

BACKGROUND: There is speculation that some environmental factors may be impacting the increasing incidence of frontal fibrosing alopecia (FFA). In a recent publication, sensitisation to benzyl salicylate was shown to be prevalent among 36 patients with FFA. Ethylhexyl salicylate (EHS), a light stabiliser, ultraviolet (UV) B absorber and UV filter, frequently found in photoprotectors/cosmetics and, rarely reported as a sensitiser, was not patch tested in said research. METHODS: From January 2021 to February 2022, 33 patients with FFA were patch-tested with the European Photopatch Series, including EHS 10% pet. in two hospitals. In addition, we conducted a literature review and a market survey. RESULTS: Patch test reactions to EHS were identified in 9 of 33 (27.3%). Four of nine also reacted to their personal sunscreens (containing EHS). All involved women with a mean age of 54 (30-65). Five patients had been diagnosed with FFA before the patch tests; and, four were diagnosed with FFA during the patch test investigations. CONCLUSION: Sensitisation to EHS was frequently found in a selected population of patients with FFA. We propose to expand the spectrum of contact allergens described in patients with FFA to include EHS and discuss the possible need for optimization of the patch test preparation.

Effectiveness of Personalized Low Salicylate Diet in the Management of Salicylates Hypersensitive Patients: Interventional Study.

Salicylic acid and its derivatives (including acetylsalicylic acid/aspirin) are popular in medicine. They also occur naturally in many food products. The aim of the study was to investigate the effect of the personalized low salicylate diet (PLSD) on the reduction of asthma, rhinosinusitis and urticaria symptoms in patients with hypersensitivity to aspirin (ASA) or nonsteroidal anti-inflammatory drugs (NSAIDs). To achieve the research goal, a prospective, nonrandomized, baseline-controlled intervention study was conducted. Thirty patients diagnosed with NSAIDs hypersensitivity, who despite pharmacotherapy had symptoms of hypersensitivity, were included in the study. The PLSD was recommended for all participants for a period of two to four weeks. The intensity of subjectively declared symptoms of asthma, rhinosinusitis and urticaria were measured before and after dietary intervention, using, respectively, the asthma control test (ACT), the sino-nasal outcome test (SNOT-22) and the four-item itch questionnaire (FIIQ). Diet adherence and salicylate intake were measured by a 3-day food record. The severity of symptoms improved significantly after the intervention. The median of the ACT score was 24 scores before and 25 after the dietary intervention (p < 0.002), the median of the SNOT-22 score was 25 before and 13 after a dietary intervention (p < 0.0002) and the median of the FIIQ score was 5 before and 0 after a dietary intervention (p < 0.0002). The intake of salicylates decreased from 0.79 mg/day (before intervention) to 0.15 mg/day (p < 0.001) (during intervention). Although the usefulness of a low salicylate diet in the treatment of salicylate hypersensitivity is controversial, the results of our study indicate that the PLSD may have a positive effect in reducing symptoms of salicylate hypersensitivity and could be an additional tool supporting the therapy of these patients.

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair.

Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Sensitization to benzyl salicylate and other allergens in patients with frontal fibrosing alopecia.

BACKGROUND: Contact sensitization is frequent among patients with frontal fibrosing alopecia (FFA) (52%-76%). OBJECTIVE: To evaluate the frequency of sensitization/photosensitization in an FFA population. METHODS: A population of FFA patients were patch tested (Spanish Contact Dermatitis Research Group [GEIDAC] baseline; cosmetic and fragrance series), and photopatch tested (sunscreen series). RESULTS: Thirty-six patients (mean age: 64.6 years; 35/36: women) were studied. A history of dermatitis was recorded in 69.4% (frequently involving the face). Overall, 80.5% patients showed positive patch-test reactions. The most frequently positive allergens were nickel sulfate (25%), benzyl salicylate (22%), gallates (16.6%), propolis (16.6%), and limonene hydroperoxides (13.8%). Benzyl salicylate was likely relevant to the dermatitis (labeled on personal care products and most patients reporting clinical improvement with allergen avoidance). Patch tests with sunscreens showed positive reactions to 11 materials (five patients). Photopatch tests were positive in one case. CONCLUSION: We speculate a possible relationship between sensitization to benzyl salicylate and FFA. Hypothetically, the most likely explanation is that sensitization to benzyl salicylate involving FFA patients is a consequence of increased exposure to it. It is unclear whether allergen avoidance may impact the prognosis of alopecia. However, it seems to significantly improve the patients´ quality of life by lessening dermatitis and pruritus.

Salicylate toxicity from chronic bismuth subsalicylate use.

A 79-year-old man presented to the emergency department with a 1-week history of worsening confusion, falls and hearing impairment. An initial workup for infectious, metabolic and structural causes was unrevealing. However, further history discovered that he had been ingesting one to two bottles of Pepto-Bismol (bismuth subsalicylate) daily for gastro-oesophageal reflux symptoms. On his second day of admission, the plasma salicylate concentration was 2.08 mmol/L (reference range 1.10-2.20 mmol/L), despite no sources of salicylate in hospital. He was diagnosed with chronic salicylate toxicity and Pepto-Bismol use was discontinued. The patient was treated supportively with isotonic intravenous fluids only and plasma salicylate concentration fell to less than 0.36 mmol/L. Concurrently, all his symptoms resolved. This case highlights the potential adverse effects of over-the-counter medications. The diagnosis of chronic salicylate toxicity is challenging, specifically in the elderly and in undifferentiated presentations, as it can be missed if not suspected.

Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome.

Oxidative stress (OS) and inflammation are often present in polycystic ovary syndrome (PCOS). We examined the effects of salsalate treatment on nutrient-induced OS and inflammation, ovarian androgen secretion, ovulation, and insulin sensitivity in PCOS. Eight lean insulin-sensitive women with PCOS and eight age- and body composition-matched ovulatory controls for baseline comparison participated in the study. The women with PCOS underwent a 12-wk treatment of salsalate, a nonsteroidal anti-inflammatory drug, at a dose of 3 g daily. Markers of OS and inflammation were quantified in mononuclear cells (MNC) and plasma from blood drawn fasting and 2 h after saturated fat ingestion before and after treatment. Ovarian androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration before and after treatment. Ovulation was documented based on biphasic basal body temperatures and luteal range progesterone elevations. A two-step pancreatic clamp was performed pre- and posttreatment to measure basal endogenous glucose production (EGP) and the steady-state glucose disposal rate (GDR) during the euglycemic phase and markers of OS and inflammation in MNC and plasma during the hyperglycemic phase. Salsalate administration suppressed lipid- and glucose-stimulated reactive oxygen species generation, activated nuclear factor-κB and circulating tumor necrosis factor-α, normalized basal androgen levels, and lowered HCG-stimulated androgen secretion without altering EGP or GDR. Four salsalate-treated subjects responded with two consecutive ovulations. We conclude that in PCOS, salsalate-induced suppression of OS and inflammation ameliorates ovarian androgen hypersecretion and may induce ovulation while maintaining insulin action.

Prevalence and characterization of severe asthma in Hungary.

BACKGROUND: Severe asthma (SA) database was established in Hungary to estimate the prevalence of SA and to define and analyze clinical phenotypes of the patients. METHODS: SA questionnaires were sent out to 143 public pulmonary dispensaries specialized for diagnosing and caring pulmonary patients. Data of 520 SA patients were evaluated. RESULTS: The prevalence of SA within the asthmatic population in Hungary was 0.89%. The mean age of patients were 56.4 ± 13.4 years, SA were more frequent in females (64%), the prevalence of allergy was 56.6%, 72.1% of patients had persistent airflow limitation (FEV1 < 80%), 37.9% severe airway obstruction (FEV1 ≤ 60%), 33.6% required systemic corticosteroid maintenance therapy, 21.5% had salicylate intolerance and 43.2% rhinosinusitis. A Bayesian dependency network was calculated which revealed several interdependencies between the characteristics. E.g. there was a strong association between salicylate intolerance and rhinosinusitis, more patients received regular systemic corticosteroid treatment who had salicylate intolerance and the proportion of salicylate intolerance was significantly higher in females. CONCLUSION: The prevalence of SA was determined in Hungary which was lower than in other studies. Using a Bayesian-based network analysis several interdependencies were revealed between patient characteristics.

Efficacy and safety of Jessner's solution peel in comparison with salicylic acid 30% peel in the management of patients with acne vulgaris and postacne hyperpigmentation with skin of color: a randomized, double-blinded, split-face, controlled trial.

OBJECTIVE: Antibiotics and retinoids have been used for acne vulgaris for decades. Though effective, each has its own drawbacks. Chemical peels have been used for treatment of acne vulgaris with inadequate clinical evidence. We sought to determine the efficacy and safety of Jessner's solution (JS) in comparison with salicylic acid (SA) 30% in the management of acne vulgaris and postacne hyperpigmentation in patients with colored skin. METHODS: A total of 36 subjects (94.5% Fitzpatick Type IV-V) were recruited in this randomized double-blinded, split-face, controlled trial. Each side of the face was randomly assigned for treatment with either JS or SA. Subjects were treated once fortnightly for a total of three sessions. Lesion counting, Michaelsson acne score (MAS), photographs, and postacne hyperpigmentation index (PAHPI) were used to objectively assess the improvement. Complications were assessed during each visit. Statistical analysis was conducted using SPSS v22.0. Significance was set at P = 0.05. RESULTS: At the end of therapy, significant reduction in inflammatory, noninflammatory lesions, MAS, and PAHPI scores (P < 0.001, respectively) were noted in comparison to baseline. Mixed model analysis revealed no significant outcome difference between the two groups. Patients who reported good and very good outcome were 76.4% (JS) and 85.3% (SA). Burning, stinging sensation, and exfoliation were the common complications reported. Postinflammatory hyperpigmentation was reported only once in the JS arm. CONCLUSION: Both JS and SA were equally effective in the treatment of acne vulgaris and reducing postacne hyperpigmentation in patients with colored skin.

Pink Prescribing: Bismuth Subsalicylate; History, Actions, Risks, and Future Use.

Recently, there seems to be more creative advertising regarding bismuth subsalicylate (BSS) for lots of gastrointestinal issues. I have found during medication reconciliation that some patients overuse and believe use of BSS products is without risks. From an advertising perspective, there seem to be many happy persons consuming BSS with no mention of restrictions or safety recommendations. What are the risks associated with its use? How effective is BSS? What about drug interactions?

Bismuth encephalopathy- a rare complication of long-standing use of bismuth subsalicylate.

BACKGROUND: Drugs containing bismuth, although usually safe, may rarely cause neurotoxicity. CASE PRESENTATION: We describe the case of a 44-year-old woman treated with bismuth subsalicylate for about 20 years, who developed abnormal behaviour and postural instability in two weeks. On examination, she had greyish discoloration of teeth, was confused and presented generalized myoclonic jerks. In the next days, her clinical condition deteriorated, with a reduction in alertness and more exuberant myoclonus. Brain MRI was unremarkable. CSF revealed mild elevation of protein content (47 mg/dL; reference range: 15-45 mg/dL) and elevation of white blood cell count (10/µL). Bismuth levels in urine (375 µg/L), serum (260 µg/L) and CSF (21.4 µg/L) samples were highly above the threshold for toxicity. Following supportive treatment and bismuth discontinuation, she made a full recovery within weeks. CONCLUSIONS: Although rare, bismuth encephalopathy should be considered in patients presenting with subacute encephalopathy and myoclonus. This encephalopathy can be subacute even after a chronic exposure. Cessation of bismuth can lead to a complete resolution in weeks.

Exploring the association between ingestion of foods with higher potential salicylate content and symptom exacerbation in chronic rhinosinusitis. Data from the National Chronic Rhinosinusitis Epidemiology Study.

INTRODUCTION: Pharmacological salicylates are known to trigger respiratory exacerbations in patients with Non-Steroidal Exacerbated Respiratory Disease (N-ERD), a specific phenotype of Chronic Rhinosinusitis (CRS) and asthma. The impact of dietary sources of salicylates across subgroups of CRS is not well understood. The hypothesis is that in patients with nasal polyps present, there is likely to be a higher incidence of symptom exacerbation due to dietary salicylates regardless of any known response to pharmacological salicylate. METHODS: The Chronic Rhinosinusitis Epidemiology Study (CRES) was a questionnaire-based case-control study which sought to characterise the UK CRS population in terms of sociological, economic and medical factors. Using specific questions to examine participant responses relating to symptom exacerbation from food groups thought to be high in salicylate content, this analysis of the CRES database sought to compare an estimate of the prevalence of dietary sensitivity due to food with higher potential salicylate content across patients with CRS with (CRSwNPs) and without nasal polyposis (CRSsNPs) and with allergic fungal rhinosinusitis (AFRS). RESULTS: The CRSwNPs group were significantly more likely than controls to report symptom exacerbation due to ingestion of food groups with higher potential dietary salicylate content. The same trend was observed amongst CRSsNPs participants to a lesser degree. Reported response to the individual specific food groups wine, nuts, spicy foods, fruit and vegetables demonstrated that a statistically significant proportion of CRSwNPs and AFRS participants reported sensitivity to wine. CONCLUSIONS: This analysis suggests that there is an association between symptom exacerbation in response to food products with higher potential salicylate content, specifically wine, in CRS patients both with and without nasal polyposis when compared to controls, but especially in the CRSwNPs and AFRS phenotypes. Further studies are needed to detail if this relationship represents a causal relationship to dietary salicylate. The data present the possibility that a wider group of CRS patients may elicit salicylate sensitivity than those with known N-ERD.

Increased metabolic activity and hysteretic enhanced GABAA receptor binding in a rat model of salicylate-induced tinnitus.

Tinnitus is relevant to neural hyperactivity in the central nervous system (CNS). Normal quantity and functioning of the γ-aminobutyric acid (GABA) receptor are crucial for maintaining the balance between excitation and inhibition in the brain. In this study, we applied a rat model of tinnitus via long-term salicylate administration. The combination of the gap pre-pulse inhibition of acoustic startle (GPIAS) and pre-pulse inhibition (PPI) tests were used to detect tinnitus-like behavior, and rats receiving 7 or 14 consecutive days of salicylate administration showed evidence of tinnitus. After positron emission tomography (PET) scan, we found that the metabolic activity was increased after salicylate treatment followed by enhanced GABAA receptor binding with cessation of salicylate administration in the auditory cortex (AC), medial prefrontal cortex (mPFC), hippocampus (HP), cingulate cortex (CiC) and insular (InC). The inferior colliculus (IC) showed an elevated metabolic activity with no change in the GABAA receptor binding. All the alterations returned to baseline several days after cessation of salicylate treatment despite a mismatch between the time-course of them. By contrast, we found alterations in neither the metabolic activity nor the GABAA receptor binding in the amygdala (AMY) and cerebellum (CRB). These findings indicate that enhanced neural activity in the auditory and limbic system may contribute to the development of tinnitus, while the hysteretic increase of GABAA receptor binding in specific areas of the CNS may be a compensation for hyperactivity, which may be involved in tinnitus relieving.

Comparison of Triflusal with Aspirin in the Secondary Prevention of Atherothrombotic Events; Α Randomised Clinical Trial.

BACKGROUND: Triflusal has demonstrated an efficacy similar to aspirin in the prevention of vascular events in patients with acute myocardial infarction (ΜΙ) and ischaemic stroke but with less bleeding events. OBJECTIVE: We performed a randomised, multicentre, phase 4 clinical trial to compare the clinical efficacy and safety of triflusal versus aspirin, administered for 12 months in patients eligible to receive a cyclooxygenase-1 (COX-1) inhibitor. METHODS: Patients with stable coronary artery disease or with a history of non-cardioembolic ischaemic stroke were randomly assigned to receive either triflusal 300 mg twice or 600 mg once daily or aspirin 100 mg once daily for 12 months. The primary efficacy endpoint was the composite of: (a) ΜΙ, (b) stroke (ischaemic or haemorrhagic), or, (c) death from vascular causes for the entire follow-up period. The primary safety endpoints were the rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria. RESULTS: At 12-month follow-up, an equivalent result was revealed between the triflusal (n=559) and aspirin (n=560) in primary efficacy endpoint. Specifically, the combined efficacy outcome rate (i.e. MI, stroke or death from vascular causes) difference was equal to -1.3% (95% confidence interval -1.1 to 3.5) and lied within the a-priori defined equivalence interval (p<0.001). Regarding the primary safety endpoints, patients on triflusal treatment were 50% less likely to develop bleeding events according to the BARC criteria, and especially any clinically overt sign of haemorrhage that requires diagnostic studies, hospitalisation or special treatment (BARC type 2). CONCLUSION: The efficacy of triflusal in the secondary prevention of vascular events is similar to aspirin when administered for 12 months. Importantly, triflusal significantly reduced the incidence of ΜΙ and showed a better safety profile compared with aspirin. (ASpirin versus Triflusal for Event Reduction In Atherothrombosis Secondary prevention, ASTERIAS trial; Clinical Trials.gov Identifier: NCT02616497).