A case of breathlessness and unexpected antibodies: stating the obvious.

Background: Severe cutaneous adverse reactions are rare but potentially life-threatening. Identifying the causative drug is crucial for managing and preventing recurrence. Two commonly used causality assessment methods are the Bégaud and the Naranjo algorithm, each with distinct approaches and limitations. The objective of our study is to compare these methods in assessing drug causality in severe cutaneous adverse reactions and to evaluate their concordance and practical applicability. Material and methods: We conducted a retrospective analysis of 116 cases reported to the Casablanca pharmacovigilance center between 2019 and 2023. Drugs implicated were assessed using both the Bégaud and Naranjo methods, and their scores were harmonized into four categories: doubtful, possible, probable, and highly probable. Statistical analysis was performed using Jamovi software. Results: A total of 442 drug observations were analyzed. Antibiotics were the most frequently involved drug class (34.5%). The Bégaud and Naranjo methods yielded identical causality classifications in only 37% of cases, with no statistical concordance (Kappa = 0.062). The Naranjo algorithm tended to implicate more drugs per case (median = 2.00) compared to the Bégaud method (median = 1.00; p < 0.001). Conclusion: The Bégaud and Naranjo methods demonstrated poor agreement in assessing the causality of severe cutaneous adverse reactions. The Naranjo algorithm offers simplicity and rapid application, making it suitable for emergency settings with limited drug exposure. The Bégaud method provides a more detailed analysis, better suited for complex and polymedicated cases. Both methods have complementary roles, and an integrated approach may improve diagnostic accuracy in pharmacovigilance.

Objectives: 1. To assess and analyse adverse drug reactions (ADRs) according to reporting and presentation. 2. To describe causality and severity analysis. Materials and methods: After taking approval from the Institutional ethical committee study was undertaken over a period of one year. A prospective observational study was conducted to monitor the ADRs in all the clinical departments and emergency units of the hospital. The ADRs forms were distributed to all the departments and informed them to report any suspected adverse drug reactions. ADRs were monitored both actively and passively. Reported forms were collected by active surveillance and Causality assessment was done by pharmacologist using Naranjo’s & WHO scale and severity by Hartwig’s scale respectively. Results: Total 85 ADRs were reported over a period of year. Most of the ADRs were reported from the ART centers 70.6%. The most common system involved in ADR was haematological system about 29.4% of overall reaction followed by 24.7% dermatological. Zidovudine induced anaemia was the most common ADR. Causality assessed using Naranjo’s scale showed that most of reported ADRs were probable 49.4%, 27.1% were doubtful and 23.5% were possible. Conclusion: Study showed that there was under reporting of ADRs. Most of the cases were reported from ART center. There is a need to improve awareness among the clinicians to emphasize their role in voluntary reporting of ADRs, on generating quality reports, critically monitor the ADRs so as to prevent them further. Keywords: Adverse drug reaction, Causality assessment, Naranjo scale, WHO scale and Hartwig’s scale.

Epidermal necrolysis (EN)--either Stevens-Johnson syndrome (SJS) or toxic EN (TEN)--is a severe drug reaction. We constructed and evaluated a specific algorithm, algorithm of drug causality for EN (ALDEN), in order to improve the individual assessment of drug causality in EN. ALDEN causality scores were compared with those from the French pharmacovigilance method in 100 cases and the case-control results of the EuroSCAR study. Scores attributed by ALDEN segregated widely. ALDEN pointed to a "probable" or "very probable" causality in 69/100 cases as compared to 23/100 with the French method (P < 0.001). It scored "very unlikely" causality for 64% of medications vs. none with the French method. Results of ALDEN scores were strongly correlated with those of the EuroSCAR case-control analysis for drugs associated with EN (r = 0.90, P < 0.0001), with probable causality being reported in 218/329 exposures. ALDEN excluded causality in 321 drugs that the case-control analysis had described as "probably not associated" and in 22/233 drugs that had been described as inconclusive exposures. Being more sensitive than a general method, ALDEN, which correlates well with case-control analysis results, can be considered a reference tool in SJS/TEN.

Objective: To monitor and evaluate adverse drug reactions (ADRs) of newer oral anti-diabetic drugs in type II diabetics by spontaneous/solicited ADR monitoring. Material and methods: Two hundred and thirty two diabetic patients on newer oral antidiabetic drugs were evaluated prospectively in a cross-sectional study over a period of eighteen months. All patients were followed up for ADRs which were evaluated for incidence, frequency, severity and causality. ADR severity was graded according to University of Virginia Health System Adverse Drug Reaction Reporting program criteria and causality assessment was done using WHO-UMC scale. Results: 190 out of 232 patients (42 patients lost to follow up) were evaluated. ADRs were observed in 34 cases (17.9%). Most common ADRs were gastrointestinal (44.2%) followed by musculoskeletal (17.6%), metabolic (14.7%), infections (5.9%) and others (17.6%). The maximal frequency of ADRs was seen with sitagliptin (6.4%) followed by vildagliptin(3.8%), saxagliptin(2.7%), saroglitazar(2.1%), linagliptin(1.6%), canagliflozin(1.6%). 25(73.5%), 8(23.5%) and 1(3%) ADRs were mild, moderate and severe respectively. 24(70%) ADRs were classified as possible, 9(27%) probable and 1(3%) unlikely on causality assessment. Conclusion : Newer oral antidiabetic drugs like gliptins and SGLT-2 inhibitors have potential to cause ADRs. Gastro-intestinal, musculoskeletal, metabolic were most common ADRs. Active pharmacovigilance should be carried out for risk identification and management.

The noise in investigator causality assessment in clinical trials can be substantially reduced by eliminating missing data, improved data quality, appropriate use of data, use of all causality factors, converting subjective judgment, and minimizing errors in assessment. An algorithm is proposed to guide the routine drug causality assessment in clinical trials. Special features of this algorithm include dealing only with treatment-emergent events, considering first the most important factors, allowing early exit, emphasizing the results of de-challenge and re-challenge, and applying the Bayesian concept. Recognizing that knowledge of drug safety profile is learned through a series of trials, known drug-event association is used in this algorithm to modify the causality rating based on results of de-challenge and re-challenge. The investigator is also asked to identify all possible etiologies at the outset, and to compare the relative likelihood of drug-causation versus an alternative etiology to form the f...

Background and Aim: Adverse drug reactions (ADR) are an important cause of morbidity and mortality. The Berlin Pharmacovigilance Center PVZ-FAKOS uses an active surveillance approach to identify hospitalised patients with serious rare, however often drug-induced diseases. Aim of FAKOS is to assess potential drug risks for the following diseases: acute Agranulocytosis (AGR), Immune Thrombocytopenia (ITP), acute Hepatitis (HEP), acute Pancreatitis (PAN), and LongQT Syndrome/Torsade de pointes (LQT/TdP). Materials and Methods: FAKOS recruits patients (age ≥18) with AGR and ITP (2000–2009), HEP and PAN (2002–2009) and LQT/TdP (2008–2009) from all Berlin hospitals. Only patients with idiosyncratic or drug-induced disease of the different disease entities are included. Information on drugs and other exposures is ascertained in a standardized personal interview. For each patient, a drug causality assessment is conducted according to the WHO causality assessment criteria. Results: Whereas most patients with AGR and HEP (&gt;90%) were categorized as possibly drug associated, for 65% of PAN and LQT/TdP and for 40% of ITP. The number of different drugs classified as at least probably causing one of the diseases were N=48 for AGR, N=57 for HEP, N=14 for PAN, N=19 for LQT/TdP and N=26 for ITP. Of those, suspected drugs assessed in &gt;2 cases were for AGR: Metamizole N=10, Clozapine N=10, Methimazole N=6, Sulfasalazine N=5; for HEP: Phenprocoumon N=5, Flupirtine N=5, Simvastatine, Clarithromycine, Ciprofloxacine, Moxifloxacine, Diclofenac and Olanzapine each with N=3; for PAN: Azathioprine N=4, for ITP: Tirofibane N=8; for LQT/TdP: (Levo-)/Methadon N=5. Conclusion: A broad range of drugs has to be considered in patients with unknown etiology of AGR, ITP, HEP, PAN and LQT/TdP. The disease based, active surveillance approach of PVZ-FAKOS with standardized causality assessment potentially overcomes problems of underdetection and underreporting of ADR. Acknowledgement: PVZ-FAKOS is being funded by the Federal Institute for Drugs and Medical Devices, Germany.

Causality assessment methods in drug induced liver injury: Strengths and weaknesses

The use of herbal products globally is substantial, but varying definitions and regulatory frameworks have led to differences in their status as medicinal products and in approaches to monitoring their safety. This article explores the current landscape of herbal pharmacovigilance, drawing insights from interviews with global experts in the field, and offers recommendations for best practices to enhance the safety and benefit-to-harm balance of herbal products. This study comprised semi-structured interviews with members of the International Society of Pharmacovigilance-Herbal and Traditional Medicines Special Interest Group and the Nutrivigilance Information Exchange Network, recruited using purposive sampling. Data were stored and coded using NVIVO® and analysed thematically using a qualitative inductive approach. Sixteen participants from 11 countries were interviewed, revealing diverse regulatory approaches and challenges in herbal pharmacovigilance. Key themes included legal status, awareness, identification and coding of herbal products, pre-/post-marketing product control, reporting of adverse drug reactions, causality assessment and signals of herbal products. This study yielded five general recommendations to further improve herbal pharmacovigilance worldwide. This study offers an overview of the global landscape of herbal pharmacovigilance, highlighting challenges in monitoring herbal products and presenting universal recommendations. These recommendations encompass increasing awareness, enhancing education and improving legislative frameworks. Given the growing use of herbal products, the implementation of strong pharmacovigilance practices is crucial to ensure consumer safety.

The integration of artificial intelligence (AI) and machine learning (ML) into pharmacovigilance (PV) marks a transformative step towards enhancing drug safety and patient outcomes. With their unparalleled ability to analyze vast and complex datasets, AI/ML technologies offer unprecedented opportunities to revolutionize adverse drug event (ADE) monitoring, signal detection, and causality assessment. This editorial explores the state-of-the-art applications, key challenges, and actionable strategies to unlock the full potential of AI in PV.

Objectives: 1. To characterize the pattern of drug use in dermatology and assess its appropriateness as per WHO prescribing indicators. 2. To assess causality of adverse drug reactions (ADRs). Methods: This was a cross sectional study, conducted on 171 newly diagnosed dermatological disease patients who attended the Dermatology and Venereology outpatient department of a tertiary care hospital. The prescriptions were collected for 12 months and details were recorded in a case record form. The distribution of various classes of dermatological drugs and their prescribing pattern was assessed using WHO prescribing indicators. Causality of adverse drug reactions assessed using WHO-UMC causality assessment scale. Results: Majority of patients (47%) were in age group 21-40 years. Maximum use among females (61%). Antifungals were most commonly prescribed (27%). Average number of drugs per encounter was 2.78 and percentage of encounter with antibiotic (14.61%) were within WHO standard (2-3 and &lt;40% respectively). Drugs prescribed by generic name (40.67%) and those from EDL (48.84%) were lower than WHO standard. Causality of ADR was possible (50%). Conclusion: There was no practice of polypharmacy but noticed irrational use of dermatological drugs as drugs were not prescribed by generic names and from EDL. This causes policy makers to put more emphasis on continuous medical education on rational prescribing.

Rethinking drug safety signal detection and causality assessment in the age of AI: the risks of incomplete data and biased insights

Adverse drug reactions and causality assessment in neonates

Drug-induced IgA vasculitis in children and adults: Revisiting drug causality using a dual pharmacovigilance-based approach.

As drug-induced disorders now occupy an increasing place in the activities of the pharmaceutical industry and the regulators, as well as in the diagnostic process of prescribers, every practitioner should ask himself whether the occurrence of an abnormality is the consequence of the treated disease or of its treatment. This is particularly true in the domains which are the main targets of drug toxicity, such as skin, blood, and liver, but it applies to all other clinical or laboratory abnormalities as well. Therefore, a physician must be aware of the most frequent causes of abnormalities and the simplest tests to detect them. Three examples of the advantages of the medical approach for diagnosis of adverse drug reactions demonstrate that quality of information and drug causality assessment are inseparable.

Purpose The presence of serious toxicities is a major problem in the treatment of childhood acute lymphoblastic leukemia (ALL). The objective of this research is to evaluate drug-induced liver injury (DILI) during consolidation therapy in childhood ALL. Methods Clinical data of pediatric patients who received consolidation therapy between August 2012 and July 2018 were collected. Characteristics (incidences and patterns) of DILI at different stratifications were determined. Risks of DILI were evaluated using binary logistic regression analysis. Drug causality assessment was carried out by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Results Patients with high risk (HR) and standard risk (SR)/intermediate risk (IR) received 270 and 1539 courses of consolidation therapy, respectively; among these courses, 15 (5.6%) and 38 (2.5%) developed DILI. The occurrences of DILI in SR/IR patients were primarily associated with age (≤5.2 years), treatment course (≥5), and baseline serum parameters before treatment (cystatin C > 0.79 mg/L, albumin ≤45 g/L, and gamma-glutamyl transpeptidase (GGT) > 17 U/L). The ROC curve generated using the parameters assigned to specific values achieved an area under the curve (AUC) of 0.846 (95% CI 0.827–0.863) with a cutoff value of 3, and the sensitivity and specificity were 94.7% and 62.3%, respectively. For HR patients, a decrease in baseline albumin and elevation of baseline liver enzymes (GGT and aspartate aminotransferase) were observed in DILI cases compared with the non-DILI subjects. In the SR/IR group with DILI, the causality gradings for high-dose methotrexate (HD-MTX) were highly probable in 5 (13.2%) cases, probable in 31 (81.6%) cases, and possible in 2 (5.3%) cases. Among the DILI cases in HR-1, HR-2, and HR-3 groups, high causality gradings (probable + highly probable) were detected in “100% of HD-MTX + 57% of high-dose cytarabine (HD-Ara-C),” “100% of HD-MTX + 20% of pegylated asparaginase (PEG-ASP),” and “100% of HD-Ara-C + 33.3% of PEG-ASP,” respectively. Conclusion Incidence of DILI in HR patients was significantly higher than that in SR/IR patients. A number of potential risk factors were identified, among which the preexisting liver conditions were suggested as shared risk factors in all stratification groups. HD-MTX, HD-Ara-C, and PEG-ASP were the main causative agents of DILI. The knowledge generated from this study will be helpful for understanding characteristics of DILI during consolidation treatment in childhood ALL.