Toxic epidermal necrosis syndrome after taking nonsteroidal antiinflammatory drugs: a case report

Severe acute generalized exanthematous pustulosis with toxic epidermal necrolysis-like desquamation: A case series of 8 patients

Objective To study the diagnostic value of capsule endoscopy for asymptomatic non–steroid antiinflammatory drugs(NSAID)–induced enteropathy. Methods A total of 110 health exam cases(38 cases taking NSAID orally)were recruited to the study and underwent capsule endoscopy. The incidence of small intestine lesion of NSAID takers and non–NSAID takers, that of those whose medication time longer than 3 months and less than 3 months, and who took low dose asprin and who took non–asprin NSAID were compared. The location of mucosal lesions and recovery status were followed up. Results The incidence of small intestine lesions was significantly different between NSAID group(55.3%, 21/38) and non–NSAID group(5.6%, 4/72)(P<0.01). The incidence of small intestine lesion was significantly higher in the over–three–month–medication group than in the less–than–three–month group(7/24 VS 4/14, P=0.01). The incidence of small intestine lesions was also significantly higher in the non–asprin group than asprin group(11/14 VS 10/24, P<0.05). The ulcerative lesions were predominantly located in the ileum(10/11), while the erosive lesions were predominantly found in the jejunum(8/10). Eight ulceration cases recovered after stopping taking NSAID or the use of rebamipide. Four erosion cases recovered after the use of rebamipide. Conclusion Capsule endoscopy is of favourable diagnostic and therapeutic value for asymptomatic NSAID–induced enteropathy. Key words: Small intestine; Non–steroid antiinflammatory drugs; Aspirin; Capsule endoscopy; Endoscopy

Epidemiological studies have shown that the regular use of non-steroidal anti-inflammatory (NSAIDs) drugs is associated with a reduced risk of various cancers. In addition, in vitro and preclinical mouse model experiments have demonstrated that NSAIDs decrease tumor initiation and/or progression of several cancers. In an attempt to clarify the mechanisms of tumor prevention by NSAIDs, we have studied the effects of two NSAIDs, diclofenac and indomethacin, in several ovarian cancer cell lines. Diclofenac and indomethacin treatment decreased cell growth by inducing cell cycle arrest and/or apoptosis. To identify the possible molecular pathways mediating the effects of NSAID treatment in ovarian cancer, ovarian cancer cell lines were treated with diclofenac or indomethacin and microarray analysis was performed. Among the genes differentially expressed in the different cell lines were genes involved in signaling, metabolism, and cell cycle regulation. Some of the genes found downregulated following diclofenac or indomethacin treatment are transcriptional target genes of E2F1 and E2F4, suggesting involvement of these transcription factors in the response of ovarian cancer cells to NSAID treatment. In addition, E2F1 was found downregulated at the protein level upon treatment with diclofenac and indomethacin. The levels of phosphorylated Rb protein also decreased upon treatment with NSAIDs, suggesting activation of Rb and involvement of the Rb/E2F pathway in the effects of NSAID treatment in ovarian cancer cells. In conclusion, NSAIDs diclofenac and indomethacin exert an anti-proliferative effect in ovarian cancer cells and we have identified a number of target genes and pathways that may be important for the NSAID-induced cell cycle arrest and apoptosis. Current efforts are focused on determining the exact roles of these genes and pathways in NSAID-mediated cancer growth inhibition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4673. doi:1538-7445.AM2012-4673

Nonsteroidal Anti-Inflammatory Drug-Induced Enteropathy: Case Discussion and Review of the Literature

Poststreptococcal Reactive Arthritis in Adults: A Case Series

The aim of the study was to analyze anti-inflammatory and gastroprotective drug utilization in patients with osteoarthritis comparing conventional non-steroidal anti-inflammatory drugs (NSAIDs) versus cyclo-oxygenase 2 (COX 2) inhibitors. A retrospective observational cohort study was conducted and health-assisted subjects from the Local Health Units of Turin and Caserta were enrolled. Data linkage techniques were used to cross demographical, pharmaceutical and nosological databases. All subjects aged ≥18 years who were hospitalized for osteoarthritis from July 1st 2002 to June 30th 2004 were enrolled in the study. Concurrent prescriptions of non-steroidal anti-inflammatory and gastroprotective drugs were considered. Other demographic and clinical characteristics were recorded. A total of 1,002 subjects with a diagnosis of osteoarthritis treated with NSAIDs were enrolled. Of these subjects, 438 patients were treated with non selective NSAIDs (80.8%), 104 with COXIBs (19.2%) and 460 with multiple therapy. There were no significant differences between the demographic and clinical characteristics of the three groups. Gastroprotective drugs were prescribed in 37.0% and 35.6% of subjects treated with NSAIDs and COXIBs, respectively. Gastroprotective drug prescriptions increased from the index date to the follow-up period (from 20.4% to 41.1% of subjects treated with NSAIDs). In high-risk subjects with gastrointestinal events, gastroprotective drug utilization was undersized and increased from the index date to the follow up period (from 19.4% to 40.8% of high-risk subjects). Evidence from this study indicated that non selective NSAIDs and COXIBs are used indiscriminately with respect to patient characteristics and gastroprotection.

Lessons from Lumiracoxib: Are cyclooxygenase‐2 inhibitors less hepatotoxic than non‐selective non‐steroidal anti‐inflammatory drugs?

Intersection of Drug Allergy and Food Allergy.

Acetaminophen plus a nonsteroidal anti-inflammatory drug decreases acute postoperative pain more than either drug alone

Does Concomitant Use of NSAIDs Reduce the Effectiveness of Antidepressants?

Effects of Helicobacter pylori and Nonsteroidal Anti-Inflammatory Drugs on Peptic Ulcer Disease: A Systematic Review

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

The selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of multiple psychiatric conditions. In vitro and ex vivo data with these agents indicate they may have varying degrees of antiplatelet activity via multiple receptors. Reports of bleeding in patients receiving SSRIs appeared soon after their introduction. A review of the literature suggests SSRI therapy may increase the risk of bleeding especially with concomitant aspirin or nonsteroidal anti-inflammatory agents. Clinicians should exercise caution when prescribing these agents in high risk patients and maintain awareness of the potential contribution of SSRIs to unexplained bleeding episodes.

The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and nephrotic syndrome has long been recognized. Minimal change disease and membranous nephropathy have been the most common findings in those patients in whom a kidney biopsy was performed (1–6). Regarding NSAIDs-related minimal change disease, it is a peculiar type of nephrotic syndrome in which most of reported patients present with a severe AKI accompanying nephrotic syndrome manifestations (edema, proteinuria >3.5 g/d, and hypoalbuminemia). Kidney biopsies typically show the characteristic pattern of drug-induced acute interstitial nephritis (AIN): a diffuse interstitial infiltrate composed predominantly of T lymphocytes, although eosinophils, macrophages, and plasma cells can also be observed (7). The glomeruli are normal in light microscopy, but a diffuse effacement of podocyte foot processes is observed in electron microscopy (1–4). NSAIDs-related minimal change disease could be, therefore, categorized as a complication of NSAIDs-induced AIN. However, a "pure" nephrotic syndrome has been described in some patients taking NSAIDs, with diffuse fusion of foot processes but no accompanying interstitial infiltrates. In some patients, tubular necrosis without interstitial infiltrates has been the most salient histopathologic finding. Patients with AIN accompanied by minimal change disease have been reported with a variety of conventional NSAIDs and selective COX-2 inhibitors. As usual in NSAIDs-induced AIN, the extrarenal manifestations (low-grade fever, skin rash, and eosinophilia) that frequently accompany AIN induced by antibiotics and other drugs are characteristically absent (7). Although NSAIDs are one of the most frequent causes of drug-induced AIN, the incidence of nephrotic syndrome seems to be low. In two patient series of drug-induced AIN, only three patients of a total of 121 showed nephrotic-range proteinuria, although NSAIDs were the offending drug in 40% of the patients (7). However, patients with NSAIDs-related AIN tend to present higher proteinuria values than other types of drug-induced AIN, although they rarely reach the nephrotic range (7,8). Notably, nephrotic syndrome and nephrotic-range proteinuria seem to be a specific complication of NSAIDs, because they have been only exceptionally reported with other types of drug-induced AIN. To explain this susceptibility for proteinuria, it has been suggested that a decrease in the synthesis of prostaglandins induced by NSAIDs could result in an increased conversion of arachidonic acid to leukotrienes, which could activate T-helper cells and induce a diffuse podocyte damage. However, no studies have confirmed this hypothesis. In most patients, NSAIDs-related minimal change disease resolves after drug discontinuation, which is accompanied in some patients by a short course of corticosteroids (1–4). It has been reported that early treatment with corticosteroids can induce a more rapid and efficient recovery of kidney function in NSAIDs-induced AIN accompanied or not by nephrotic proteinuria (8). Paradoxically, NSAIDs induce a marked reduction of proteinuria in different types of nondiabetic glomerular nephropathies and can potentiate the antiproteinuric effect of renin-angiotensin blockers (9). Changes in glomerular hemodynamic through a preglomerular vasoconstriction and an improvement of the glomerular protein permselectivity have been invoked to explain this effect. However, the frequent side effects of NSAIDs have prevented their clinical use for the treatment of glomerular diseases. Nephrotic syndrome with a histopathologic pattern of membranous nephropathy, a paradigmatic type of immune complex glomerular disease, is another side effect of NSAIDs, and different types of conventional and selective NSAIDs have been reported as causatives of this complication (1,5,6). The presence of electron-dense subepithelial deposits along the glomerular capillary loops and a complete effacement of foot processes were the most characteristic findings in kidney biopsies (5,6). Unlike NSAIDs-related minimal change disease, inflammatory interstitial infiltrates were absent in most reported patients. This histologic difference explains why most of the patients with NSAIDs-induced minimal change disease present with nephrotic syndrome accompanied by severe AKI, whereas nephrotic syndrome with normal kidney function is the most frequent presentation in NSAIDs-induced membranous nephropathy. Immunostaining for the different subclasses of IgG can help to differentiate NSAIDs-induced membranous nephropathy from primary forms of the disease. As in other types of secondary membranous nephropathy, deposition of IgG1 has been reported in patients with cases associated with NSAIDs (5), whereas deposition of IgG4 is characteristic of primary forms. The pathogenesis of membranous nephropathy associated with NSAIDs is unknown. Glomerular deposition of antigens bound to NSAIDs could elicit an immune response, although these drugs could also exacerbate or trigger autoimmune reactions against podocyte antigens. Intriguingly, positive immunostaining for PLA2R has been reported in a patient with membranous nephropathy precipitated by piroxicam, although serum anti-PLA2R was not available (5). The incidence of NSAIDs-related membranous nephropathy could be greater than suspected according with the study of Radford et al. (6). They reported 125 patients with early membranous nephropathy (stages 1 and 2 membranous nephropathy with small subepithelial deposits). Twenty-nine of them were taking NSAIDs at the time of diagnosis, of which 13 (10%) fulfilled the criteria defined by the authors to establish the diagnosis of NSAIDs-related membranous nephropathy: onset of the nephrotic syndrome while taking NSAIDs, exclusion of other causes of secondary membranous nephropathy, and rapid disappearance of proteinuria after NSAIDs withdrawal (6). Interestingly and reinforcing the causal association between NSAIDs and nephrotic syndrome, relapses of proteinuria have been reported after re-exposure to NSAIDs, and in some patients, re-exposure was to a type of NSAIDs different from the one causing the first episode of nephrotic syndrome (5). In this issue of CJASN, Bakhriansyah et al. (10) describe the results of a systematic observational matched patient-control study about the association between NSAIDs and nephrotic syndrome. The study used data from the Clinical Practice Research Datalink, a general practitioner database of the United Kingdom National Health Service. Patients had a diagnosis of nephrotic syndrome established in the period 1989–2017, and controls were patients without nephrotic syndrome before and at the date of diagnosis of nephrotic syndrome in matching cases. Exposure to NSAIDs was divided into current use (NSAIDs prescription within the last month before the date of diagnosis), recent use (prescription within 1–2 months before), or past use (prescription >2 months before). According to the duration of NSAIDs exposure, current use was divided into use of 1–14, 15–28, or >28 days. Patients with past use were divided into those in whom NSAIDs had been discontinued between 2 months and 2 years before the date of diagnosis and those with an NSAIDs discontinuation >2 years. NSAIDs were classified as acetic acid derivatives (such as indomethacin, ketorolac, and diclofenac), propionic acid derivatives (such as naproxen, ibuprofen, and ketoprofen), selective COX-2 inhibitors (coxibs), fenamates, and oxicams, and other NSAIDs. A total of 2620 patients and 10,454 matched controls were included in the analysis. The results show that current use for >2 weeks, recent use, and past use (discontinuation >2 months to 2 years) of conventional NSAIDs (acetic acid and propionic acid derivatives) were associated with a significantly higher risk of nephrotic syndrome (adjusted odds ratio, 1.34; 95% confidence interval, 1.06 to 1.70; adjusted odds ratio, 1.55; 95% confidence interval, 1.11 to 2.15; and adjusted odds ratio, 1.24; 95% confidence interval, 1.07 to 1.43, respectively) compared with nonuse and that the risk disappeared after 2 years of discontinuation. The use of selective COX-2 inhibitors was not associated with a higher risk of nephrotic syndrome, although there was not a statistically significant trend among patients with a past use (>2 months to 2 years). This study is the first systematic analysis of the association between NSAIDs consumption and the risk of developing a nephrotic syndrome. Its conclusions are clinically relevant, although several important caveats should be taken into account. One of them is the inevitable chronological imprecision when analyzing drugs, like conventional NSAIDs, that are frequently available over the counter and consumed in a discontinuous manner by a large number of normal subjects. Additionally, the accuracy of the diagnosis of nephrotic syndrome using pre-established codes should be taken with caution in studies like this that involve a large number of patients over a long period of time. The criteria used to establish the diagnosis of nephrotic syndrome are not reported, and therefore, we do not know if all included patients presented a proteinuria >3.5 g/d accompanied by hypoalbuminemia. A major constraint of the study is the low percentage of patients with histologic confirmation of kidney disease. Although patients 18 years old or younger were excluded (another limitation of the study), a kidney biopsy was performed in only 11% of the patients, despite the fact that kidney biopsy is considered a central tool in the diagnostic workup of most adult patients presenting with nephrotic syndrome. The list of histologic diagnoses is somewhat surprising, because only a minority of patients (15 of 167) taking NSAIDs and presenting a nephrotic syndrome received the diagnosis of minimal change disease or AIN, and other diagnoses (for instance, crescentic or mesangiocapillary GN) have no apparent pathogenic relationship with these drugs. The study of Bakhriansyah et al. (10) raises questions of great clinical importance for the clinician. Are we overlooking patients with NSAIDs-induced nephrotic syndrome? If so, are we prescribing long courses of immunosuppressive treatments to patients with minimal change disease or membranous nephropathy caused by NSAIDs that would have resolved with the discontinuation of the drug accompanied perhaps by a short course of corticosteroids? Considering that the existing literature on this topic is in general old and scarce, with only patient reports or short series of patients published, data from this study should encourage nephrologists to, on one hand, carefully review the current or recent intake of NSAIDs in any patient with nephrotic syndrome, particularly when minimal change disease or membranous nephropathy is found in kidney biopsies, and on the other hand, perform collaborative studies to collect large series of patients with unequivocal diagnosis of NSAIDs-induced nephrotic syndrome to identify their differential clinical and histopathologic characteristics and delineate their more efficient treatment. Basic research about the pathogenic mechanisms through which NSAIDs cause glomerular damage is also needed. Disclosures Dr. Praga has received personal fees for lectures from Alexion, Fresenius, Otsuka, and Retrophin and grant support and personal fees from Alexion, outside of the submitted work. Dr. Mérida has nothing to disclose.

Introduction