Severe cutaneous adverse reactions associated with the immune checkpoint inhibitors: A case/non-case analysis using the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND/OBJECTIVES: The immune checkpoint inhibitors (ICIs) have been increasingly associated with severe cutaneous adverse reactions (SCARs). These reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are uncommon but potentially lethal. Despite the severity of these reactions and growing association with the ICIs, their specific risk and mortality rates have been largely unexplored. METHODS: A case/non-case analysis was performed using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to examine the reporting odds ratios (RORs) for ICI-associated SCARs cases under two conditions: (1) ICIs compared with all drugs in FAERS and (2) ICIs compared with a reference group of pooled anticancer drugs to control for underlying malignancy. RESULTS: A statistically significant ROR for SJS (ROR: 5.44), TEN (ROR: 5.81) and DRESS (ROR: 1.38) were identified under Condition 1. Under Condition 2, this significance was maintained for SJS (ROR: 7.31), TEN (ROR: 7.40) and DRESS (ROR: 3.90), and mild significance was identified for AGEP (ROR: 1.89). Mortality rates for the ICIs were increased compared with the anticancer medications (28.5% vs. 24.5% for SJS, 55.3% vs. 46% for TEN, 3.0% vs. 2.1% for AGEP and 7.1% vs. 6.1% for DRESS). CONCLUSIONS: Our results suggest an association between SCARs and the ICIs independent of cancer status.

Medication Associations With Severe Cutaneous Adverse Reactions: A Case/Non-Case Analysis Using the FDA Adverse Event Reporting System.

BACKGROUND: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) are potentially life-threatening severe cutaneous adverse reactions (SCARs). Although the classical causal agents of SCARs (antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs, and allopurinol) are well characterized, there has been little update to this list to account for newly marketed medications. OBJECTIVE: To provide an updated and stratified list of medications with significant reporting odds ratios (RORs) of SCARs. METHODS: A case/non-case analysis using the United States FDA Adverse Event Reporting System was performed. RESULTS: As expected, the prototypical medication classes made up the majority of reported cases of SJS, TEN, AGEP, and DRESS (77%, 64%, 75%, and 72%, respectively). In addition, several infrequently or previously undescribed classes/medications implicated in SCARs were identified to have significant ROR signals, including acetylcysteine, anticoagulants, diuretics, immunotherapies, proton pump inhibitors, antivirals, and antifungals. Among these reported for SJS were acetylcysteine (ROR: 64.38) and fluconazole (ROR: 17.13). For TEN, we identified furosemide (ROR: 26.32), spironolactone (ROR: 14.45), fluconazole (ROR: 30.21), amphotericin B (39.06), and acetylcysteine (ROR: 93.12). For AGEP, we identified acyclovir (ROR: 61.72), valacyclovir (ROR: 30.76), and enoxaparin (ROR: 27.37). For DRESS, we identified vemurafenib (ROR: 17.35), acyclovir (ROR: 30.63), abacavir (ROR: 26.62), raltegravir (ROR: 23.27), and valacyclovir (ROR: 21.77) to have strong reporting odds. CONCLUSION: Our analysis provides an updated tool for physicians to reference when identifying suspected SCARs and a basis for future studies to investigate atypical medication causality.

Association of Nonmelanoma Skin Cancers, Melanoma, and Merkel Cell Carcinoma with Dermatologic Medications: A Case-Control Pharmacovigilance Study of the FDA Adverse Events Reporting System.

BACKGROUND: Medications used in the treatment of dermatologic conditions have been associated with squamous cell carcinoma (SCC), basal cell carcinoma (BCC), melanoma, and Merkel cell carcinoma (MCC). OBJECTIVE: The objective of the study was to examine the relationship between systemic dermatologic medications and skin cancer in the FDA Adverse Event Reporting System (FAERS). METHODS: Case-control analyses were performed in FAERS from 1968 to 2021 to examine the reporting odds ratios (RORs) for SCC, BCC, melanoma, and MCC. RESULTS: The oral immunosuppressants were all associated with increased ROR of SCC, BCC, melanoma, and MCC. Azathioprine had the highest ROR for SCC (34.13, 95% CI 29.07-40.08), BCC (21.15, 95% CI 20.63-25.98), and MCC (44.76, 95% CI 31.52-63.55), while quinacrine and guselkumab had the highest ROR for melanoma (13.14, 95% CI 1.84-93.89 vs. 12.73, 95% CI 10.60-15.30, respectively). The TNF-α inhibitors were associated with an increased ROR for all skin cancers investigated. CONCLUSIONS: The oral immunosuppressants and many biologic medications were associated with an increased ROR of skin cancers including TNF-α inhibitors (etanercept, adalimumab, infliximab), IL-23 or IL-12/23 inhibitors (ustekinumab, risankizumab), and the CD-20 inhibitor rituximab but not dupilumab or IL-17 inhibitors.

Multiple myeloma, haematologic malignancy and immunosuppressant and immunomodulatory medications are associated with sebaceous carcinoma, a pharmacovigilance study of the FDA adverse event reporting system.

BACKGROUND: Sebaceous carcinoma (SC) is a rare skin cancer with significant associated morbidity and mortality. A known association exists between immunosuppression, in particular solid organ transplant patients (SOTR), and SC. However, the comparative reporting odds ratios (ROR) of different immunosuppressive medications and SC are incompletely defined. OBJECTIVES: To examine the relationship between SC and medication exposure in the FDA adverse event reporting system (FAERS). METHODS: Case-control analyses were performed in FAERS from 1968 to 2021 to examine the reporting odds ratios (ROR) for SC. RESULTS: A total of 58 medication-associated SC cases were identified. Immunosuppressant medication exposure was noted in 81% cases, with 20% total cases occurring in SOTR. Medications affecting the TNF- α -IL-1-IL-2-IL-6 inflammatory axis were associated with elevated ROR for SC, including thalidomide (ROR 22.63, 95% CI 5.52-92.72), lenalidomide (ROR 10.86, 95% CI 4.93-23.94), cyclosporine, tacrolimus, tocilizumab, tofacitinib and ruxolitinib. Thirty per cent of cases of SC occurred with an associated haematologic malignancy or dyscrasia, including chronic lymphocytic leukaemia, non-Hodgkin lymphoma and multiple myeloma. CONCLUSIONS: SC is associated with exposure to immunosuppressive medications, especially in SOTR patients. A significant portion of cases with SC had an associated haematology malignancy, in particular multiple myeloma with exposure to lenalidomide.

Ingenol Mebutate Is Associated With Increased Reporting Odds for Squamous Cell Carcinoma in Actinic Keratosis Patients, a Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Recently the production and marketing of ingenol mebutate in the European Union (EU) and Canada was halted due to a possible increased risk of squamous cell carcinoma (SCC) in patients with actinic keratosis (AK). OBJECTIVE: To investigate the relationship between SCC and topical AK medications including ingenol mebutate in the FDA Adverse Event Reporting System (FAERS). METHODS: Case/non-case analyses were performed in FAERS using data from 2012 to 2020 to examine the reporting odds ratio (ROR) signal for SCC for ingenol mebutate and all classes of topical AK medications under multiple conditions: i. comparison to all other drugs in FAERs, ii. comparison to other topical AK medications, iii. comparison to all other topical AK medications where only a single agent was implicated, iv. comparison of ingenol mebutate vs. imiquimod. RESULTS: A statistically significant ROR for SCC was found for ingenol mebutate under all conditions (i. 31.57 (25.45, 39.16), ii. 50.35 (32.21, 78.82), iii 61.09 (35.36, 105.56), iv. 2.53 (1.27, 5.05). A significant but substantially smaller signal was observed for imiquimod (i. 12.38 (6.42, 32.84), ii. 5.18 (2.61, 10.26), iii 5.42 (2.49, 11.78), but not for fluorouracil or diclofenac. When compared to imiquimod directly, ingenol mebutate had a statistically significant ROR for SCC (2.53 (1.27, 5.05). CONCLUSION: Our findings support an association between SCC and ingenol mebutate. This association is maintained under controls to limit bias and falsely elevated signal including controlling for disease state and cases with multiple drug exposures and when compared to imiquimod as in Phase IV studies of ingenol mebutate.

Use of fractionated laser therapy for the treatment of androgenetic alopecia: a systematic review and meta-analysis.

Procedural management, including fractionated laser therapy, has been increasingly investigated for the management of androgenetic alopecia (AGA). However, no comprehensive resources exist detailing the efficacy of fractionated laser therapies used for the treatment of AGA. A systematic review investigating fractionated laser use for AGA was performed, separated into each distinct fractionated laser modality. A meta-analysis was performed to examine improvement in hair counts and hair shaft diameter. Fourteen studies were included for systematic review, which identified the use of erbium-glass, thulium, erbium-ytrrium:aluminum garnet (YAG), and carbon dioxide (CO2) fractionated laser for the treatment of AGA. In the meta-analysis, fractionated laser combination therapy showed significant improvement in hair shaft diameter (2.51, 95% CI 2.37-2.65, I2 = 90.54). Fractionated laser monotherapy alone significantly improved hair shaft diameter (2.28 95% CI 2.03-2.52, I2 = 91.20%). This effect was durable on subgroup analysis for both erbium-glass (2.36 95% CI 2.01-2.71, I2 = 92.05%) and thulium (1.61 95% CI 1.08-2.15, I2 = < 0.00%). There was no improvement in hair shaft count for any laser modality. Erbium-glass laser is an effective modality as either monotherapy or combination with topical/injectable therapies to improve hair shaft diameter in AGA.

Topical ophthalmic beta-blockers are associated with ocular pseudopemphigoid: A pharmacovigilance study of antiglaucoma medications utilising the FDA adverse event reporting system.

BACKGROUND/OBJECTIVE: The association between antiglaucoma medications and the development of ocular pseudopemphigoid (OPP) has been described; however, the independent risk of each medication has not been quantified. METHODS: Case/non-case analyses were performed in the FDA Adverse Events Reporting System (FAERS) using data from 2010-2020 to examine the reporting odds ratio (ROR) signal for OPP for all classes of antiglaucoma medications under multiple conditions: (i) comparison to all other drugs in FAERs, (ii) comparison to other antiglaucoma medications, (iii) comparison to vehicle/hydrating eye drops with cases of OPP and (iv) comparison to vehicle/hydrating eyedrops with and without cases of OPP to control for topical irritant and preservative effects. RESULTS: A statistically significant ROR for OPP was found for aggregate antiglaucoma medications under the first condition but not the third or fourth (i.96.97 (95% CI 52.54-178.98). The largest signal for OPP when compared to other glaucoma drugs and eye drops was seen with unoprostone (ii.68.96 (95% CI 8.35-569.50, iii.39.85 (95% CI 4.14-383.33), iv.581.67 (95% CI 49.38-6851.57) followed by carteolol (ii.32.51(95% CI 9.02-117.67), iii.10.67 (95% CI 1.77-64.13), iv.77.84 (95% CI 12.95-467.78) and betaxolol (ii.23.38 (95% CI 7.28-74.46), iii.6.94 (95% CI 1.27-38.01), iv.50.67 (95% CI 9.26-277.25). A statistically significant ROR was noted only for the beta-blockers class aggregate under conditions ii and iv. CONCLUSIONS: Our findings support an association between OPP and antiglaucoma medications; under the most stringent control for topical irritant/preservative effect by of comparison to topical eye drops, unoprostone, carteolol, betaxolol and timolol all had a significant ROR for OPP.

Polydactylous Squamous Cell Carcinoma of the Nail Unit: A Structured Review of the Literature.

Squamous cell carcinoma of the nail unit (SCCNU) is a rare neoplastic condition that involves multiple digits (polydactylous SCCNU) in only 3.9% of cases. Here, we report a case of polydactylous SCCNU and perform a comprehensive review of MEDLINE and Embase to collate 44 cases of polydactylous SCCNU reported to date. Polydactylous patients were younger on average (48 to 61-63 years) and had a longer diagnostic delay (44 vs 35.1 months) compared with reported monodactylous cases. Human papillomavirus (HPV) positivity was observed in 49% of cases, and the most common serotypes noted were 16 (25.8%), 73 (16.1%), 58 (9.7%), 18 (6.5%), and 33 (6.5%). Twenty percent of the cases were in immunosuppressed individuals who had a statistically significant lower age at diagnosis (39.33 years vs 51.12 years; P = .01) and diagnostic delay (2.50 months vs 132.46 months, P = .04). Patients with HPV positivity had a lower age at diagnosis (43.74 years vs 53.29 years, P = .04). Environmental exposures noted to be associated with polydactylous disease included X-rays, paint/solvents, soluble oils, and stagnant water. This comprehensive literature review serves to characterize polydactylous SCCNU and distinguish the differences in its characteristics to improve diagnosis and clinical recognition.

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes.

In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF (72%), as well as TP53 (26%), CRBN (12%), and CRBN pathway genes (10%) was observed. Longitudinal analyses performed in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response.

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2.

To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and small molecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-α or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy.

Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma.

Cereblon (CRBN) mediates immunomodulatory drug (IMiD) action in multiple myeloma (MM). Using 2 different methodologies, we identified 244 CRBN binding proteins and established relevance to MM biology by changes in their abundance after exposure to lenalidomide. Proteins most reproducibly binding CRBN (>fourfold vs controls) included DDB1, CUL4A, IKZF1, KPNA2, LTF, PFKL, PRKAR2A, RANGAP1, and SHMT2. After lenalidomide treatment, the abundance of 46 CRBN binding proteins decreased. We focused attention on 2 of these-IKZF1 and IKZF3. IZKF expression is similar across all MM stages or subtypes; however, IKZF1 is substantially lower in 3 of 5 IMiD-resistant MM cell lines. The cell line (FR4) with the lowest IKZF1 levels also harbors a damaging mutation and a translocation that upregulates IRF4, an IKZF target. Clinical relevance of CRBN-binding proteins was demonstrated in 44 refractory MM patients treated with pomalidomide and dexamethasone therapy in whom low IKZF1 gene expression predicted lack of response (0/11 responses in the lowest expression quartile). CRBN, IKZF1, and KPNA2 levels also correlate with significant differences in overall survival. Our study identifies CRBN-binding proteins and demonstrates that in addition to CRBN, IKZF1, and KPNA2, expression can predict survival outcomes.

Targeted sequencing using a 47 gene multiple myeloma mutation panel (M(3) P) in -17p high risk disease.

We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM.

Coronavirus disease 2019-associated immunoglobulin A vasculitis/Henoch-Schönlein purpura: A case report and review.

Immunoglobulin A (IgA) vasculitis or Henoch-Schönlein purpura is a predominantly pediatric disease occurring after a triggering viral or bacterial infection. Conversely, drug exposure is the most common inciting event in adult cases of IgA vasculitis. Recently, data has suggested a temporal association between coronavirus disease 2019 (COVID-19) and the development of IgA vasculitis in children and adults. Here, we describe a case of IgA vasculitis with nephritis in a 70-year-old man with COVID-19 and perform a comprehensive review of eight reported cases of suspected COVID-19-associated IgA vasculitis. When compared to classical IgA vasculitis, COVID-19-associated IgA vasculitis exclusively affects males (p < 0.00002) and is more common in adults (p < 0.005). Among cases of COVID-19-associated IgA vasculitis, adult cases were associated with significantly more arthralgia than pediatric cases (p = 0.04). In cases where skin biopsy was obtained, direct immunofluorescence (DIF) was negative for IgA in 50% of cases; thereafter, kidney biopsy DIF was positive for IgA in all cases. With this study, we provide support for an association between IgA vasculitis and severe acute respiratory syndrome coronavirus 2 infection and provide clinical information differentiating its manifestations from classical IgA vasculitis.

DPP-4 Inhibitors and Increased Reporting Odds of Bullous Pemphigoid: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS) from 2006 to 2020.

BACKGROUND: In recent years, an association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid has been detected in pharmacovigilance studies in European and Asian countries; however, no pharmacovigilance data have been published yet in the USA. OBJECTIVE: The objective of this study was to examine the relationship between bullous pemphigoid and DPP-4 inhibitors and other oral diabetes mellitus medications in the FDA Adverse Event Reporting System (FAERS). METHODS: Case/non-case analyses were performed in the FAERS using data from 2006 to 2020 to examine the reporting odds ratio (ROR) signal for bullous pemphigoid for all classes of oral diabetes medications. These analyses were performed under multiple conditions to control for bias: (1) comparison to all other drugs in the FAERS; (2) comparison to other diabetes medications; and (3) comparison to all other diabetes medications where only a single agent was implicated. RESULTS: A statistically significant ROR for bullous pemphigoid was found for DPP-4 inhibitors under all conditions: (1) 109.79 (95% confidence interval [CI] 101.61-118.62); (2) 74.46 (95% CI 60.58-91.52); and (3) 35.94 (95% CI 27.91-46.28). A larger signal was seen for non-US Food and Drug Administration (FDA)-approved (anagliptin, vildagliptin, teneligliptin) vs FDA-approved DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin), likely because of an overestimation of the ROR for non-FDA-approved drugs. The largest signal was seen under conditions 1 and 2 with vildagliptin (1) 1022.83 (95% CI 909.45-1150.35) and (2) 158.84 (95% CI 127.01-198.66) followed by anagliptin (1) 628.63 (95% CI 221.36-1785.24) and (2) 60.64 (95% CI 20.98-175.26), alogliptin, teneligliptin, linagliptin, sitagliptin, and saxagliptin. Under condition 3, the largest signal was seen with linagliptin 122.25 (95% CI 93.96-159.07). Both metformin and the sulfonylureas had a significant ROR under condition 2 [3.42 (95% CI 3.01-3.89) and 2.07 (95% CI 1.66-2.57) respectively]; however, this association was not present under condition 3 as only confounded cases occurred, and a large majority of reported cases had concurrent exposure to a DPP-4 inhibitor. CONCLUSIONS: Our findings support an association between DPP-4 inhibitors and bullous pemphigoid. This association was maintained under controls to limit bias and falsely elevated signal, including controlling for disease state and cases with multiple drug exposures. Non-FDA-approved DPP-4 inhibitors had a larger ROR compared with FDA-approved DPP-4 inhibitors, likely owing to fewer reported adverse effects overall for non-FDA-approved drugs in FAERS.