Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project.

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.

Development and Validation of a META-Algorithm to Identify the Indications of Use of Biological Drugs Approved for the Treatment of Immune-Mediated Inflammatory Diseases from Claims Databases: Insights from the VALORE Project.

Purpose: This research aimed to develop and validate a META-algorithm combining individual immune-mediated inflammatory disease (IMID)-specific algorithms to identify the exact IMID indications for incident biological drug users from claims data within the context of the Italian VALORE project. Methods and Patients: All subjects with at least one dispensing of TNF-alpha inhibitors, anti-interleukin agents, and selective immunosuppressants approved for IMIDs were identified from claims databases of Latium region in Italy (observation period: 2010-2020). Validated coding algorithms for identifying individual IMIDs from claims databases were found from published literature and combined into a META-algorithm. Positive predictive value (PPV), sensitivity (Se), negative predictive value (NPV), specificity (Sp), and accuracy (Acc) were estimated for each indication against the electronic therapeutic plans (ETPs) of the Latium region as the reference standard. Lastly, the frequency of the indication of use across individual biologic drugs was compared with that reported in three other Italian regions (Lombardy, Apulia, and the Veneto region). Results: In total, 9755 incident biological drug users with a single IMID indication were identified. Using the newly developed META-algorithm, an indication of use was detected in 95% (n=9255) of the total cohort. The estimated Acc, Se, Sp, PPV, and NPV, against the reference standard were as follows: 0.96, 0.86, 0.97, 0.82, and 0.98 for Crohn's disease, 0.96, 0.80, 0.98, 0.85, and 0.97 for ulcerative colitis, 0.93, 0.76, 0.99, 0.95, and 0.92 for rheumatoid arthritis, 0.97, 0.75, 0.99, 0.85, and 0.98 for spondylarthritis, and 0.91, 0.92, 0.91, 0.88, and 0.94 for psoriatic arthritis/psoriasis, respectively. Additionally, no substantial difference was observed in the frequency of indication of use by active ingredient among Latium and the other three Italian regions included in the study. Conclusion: The newly developed META-algorithm demonstrated high validity estimates in the Italian claims data and was capable of discriminating with good performance among the most frequent IMID indications.

In the claims database, the lack of information on the indication of use represents a well-known limitation for the conduct of observational studies. This study was conducted to develop and validate a META-algorithm that accurately identifies the exact indication for the use of biological drugs in treating various immune-mediated inflammatory diseases. Using claims databases from the Latium region, we developed and validated a META-algorithm. The META-algorithm combines disease-specific algorithms for different immune-mediated inflammatory diseases (ie, Crohn's disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriasis, and psoriatic arthritis) and was tested against a reference standard (electronic therapeutic plans of the Lazio region). The META-algorithm reported high validity estimates and was able to distinguish with a good performance among the most frequent IMIDs as indications for use. Applying this META-algorithm may facilitate post-marketing surveillance of biological drugs such as TNF-alpha inhibitors, anti-interleukin, and selective immunosuppressants in specific therapeutic areas in an Italian setting.

Switching patterns of biological drugs in patients with psoriasis and psoriatic arthritis: insight from the VALORE database network.

BACKGROUND: Switch patterns among different biologics and from originators to biosimilars (and vice versa) can be complex in patients with psoriasis (PsO) and psoriatic arthritis (PsA). OBJECTIVE: The aim of this study was to describe switching patterns of biological drugs in PsO/PsA patients and to explore predictors of multiple switches and switch-back. RESEARCH DESIGN AND METHODS: A large-scale retrospective cohort study was conducted using the Italian VALORE database. Bio-naïve users treated for PsO/PsA during 2010-2022 were included. Time to switch/swap and predictors of multiple switches and switch-back were analyzed. RESULTS: Thirty-thousand seven hundred bio-naïve users were included. At 3 and 5 years of follow-up, patients with at least one switch/swap were 37.1% and 47.8%, respectively. The median time to first switch/swap was significantly shorter (p< 0.001) for TNF-α inhibitors (2,068 days) than anti-IL (2,780 days). At 1 year of follow-up patients starting with IL-23 switched/swapped biological therapy less frequently than those with anti-IL-12/23 and anti-IL-17 (4.9% vs. 8.7% and 9.4%, respectively). Patients starting with anti-IL-12/23 reported a significantly lower risk of multiple switches and switch-back (0.74, 95% CI, 0.67-0.83; 0.58, 95% CI, 0.44-0.77, respectively) than those with TNF-α inhibitors. CONCLUSIONS: Patients with PsO/PsA starting with TNF-α inhibitors switch/swap more rapidly and frequently than those with anti-IL, which are also associated with a reduced risk of multiple switches during follow-up.

Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project.

BACKGROUND: Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. OBJECTIVE: The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. METHODS: A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010-2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. RESULTS: From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015-2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. CONCLUSION: The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010-2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings.

An analysis of experimental conditions influencing the anti-beta2-glycoprotein I ELISA assay results.

Five components of the anti-beta(2)-glycoprotein I (abeta(2)GPI) enzyme-linked immunosorbent assay (ELISA) (coating buffer, microplate brand, blocking buffer, dilution buffer, and conjugate) were analyzed to evaluate how they affect variability in test results. Thirty-two samples from patients with antiphospholipid syndrome (APS) positive for abeta(2)GPI IgG antibodies and three calibrators (a pool of abeta(2)GPI-positive patients, the monoclonal HCAL antibody, and a home-made calibrator) were tested. No differences with regard to the blocking step were noted. Differences were found between the neutral and basic coating buffer when HCAL was used. There were significant differences between Maxisorp and all the other brands of tested microplates. Differences were found between phosphate-buffered saline (PBS) and all the other dilution buffers examined, with exception of TRIS when HCAL or the home-made calibrator was used. There were differences between our routine conjugate and one of the other four conjugates tested when using two of the three calibrators. There were also significant differences between the routine and another conjugate analyzed when using the third calibrator. As variations in abeta(2)GPI ELISA conditions determine significant differences in the results, selecting the appropriate test variables is an important step toward abeta(2)GPI assay standardization.

Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity.

In women diagnosed as having category I primary obstetric antiphospholipid syndrome, clinical characteristics and the risk of subsequent thromboembolic events and further unsuccessful pregnancy has not been clearly documented. Women with unexplained obstetric complications and no definite autoimmune systemic diseases were tested for lupus anticoagulant (LA), IgG/IgM anticardiolipin (aCL) and IgG/IgM anti-human beta2-Glycoprotein I (abeta2GPI) antibodies and diagnosed as having primary antiphospholipid syndrome (APS) in classification category I on the basis of more than one laboratory criteria present in any combination. Characteristics at the time of diagnosis and risk factors for subsequent clinical events during a mean follow-up of 6.3 years were evaluated. Fifty-three of 600 women studied were found to fulfil obstetric criteria and had more than one positive laboratory test at the time of diagnosis. All the women were aCL and abeta2GPI positive, and 16 were also LA positive. This latter group (triple positivity) had distinct features and had more frequently experienced previous thromboembolism (OR = 122.5, 95% CI 16-957, p < 0.001). They also had an increased rate of late pregnancy loss (OR = 16.2, 95%CI 0.9-292, p = 0.01), and a higher IgG abeta2GPI titer at diagnosis (median, 25(th) and 75(th) percentile were 118, 37-962, vs. 23, 18-32, respectively, p < 0.0001). During follow-up, the rate of thromboembolic events was significantly higher in the group of women with triple positivity and/ or previous thromboembolism (OR = 57.5, 95% CI 2.7-1160, p = 0.0004) which were the only independent predictors of TE in the multivariate model. Recurrent pregnancy loss took place in seven out of 47 women who had a new pregnancy. Triple positivity and/or previous thromboembolism were again the only independent markers (OR = 34.4, 95% CI 3.5-335.1, p = 0.003) of an unsuccessful new pregnancy. In conclusion, in primary APS with pregnancy morbidity in classification category I, quite different groups of patients may be identified on the basis of laboratory tests. Triple positivity and/or a history of thromboembolism predict new TE events and new unsuccessful pregnancies.

Use of a new silica clotting time for diagnosing lupus anticoagulant in patients who meet the clinical criteria for antiphospholipid syndrome.

The silica clotting time (SCT) is a phospholipid-dependent coagulation assay used for the laboratory diagnosis of lupus anticoagulant (LA) antibodies. The sensitivity and specificity of a new commercial SCT for identifying LA in patients who meet the clinical criteria for antiphospholipid syndrome (APS), and its association with thrombotic events were evaluated here. Forty-five patients who met the clinical criteria for APS according to the Sapporo International Consensus Statement were examined. Sixty-nine patients who did not meet the clinical criteria for APS, and 20 blood donors were used as controls. Plasma samples from the patients and controls were tested for LA using a new commercial SCT with low and high synthetic phospholipid concentrations. The results were compared with those obtained by diluted Russell's viper venom time (dRVVT) and activated partial thromboplastin time (APTT). SCT's sensitivity for identifying LA in patients who met the clinical criteria of APS was higher compared to APTT and dRVVT (53.3% vs. 31.1% and 31.1%), and the specificities of these assays were 96.6%, 100%, and 98.9%, respectively. When dRVVT was combined with SCT, and dRVVT was combined with APTT their sensitivities were 57.7% and 48.8%, and their specificities were 96.6% and 98.9%, respectively. A stepwise logistic regression analysis indicated that the combination of dRVVT with SCT was associated with total thrombotic events (odds ratio (OR)=11.5, 95% confidence interval (CI)=1.25-106.3, P=0.031) as well as with venous thrombosis (OR=4.09, 95% CI=1.16-14.43, P=0.028). According to our results, SCT is the most sensitive assay for identifying LA in patients who meet the clinical criteria for APS. Moreover, the highest sensitivity was reached with a combination of SCT and dRVVT. The method's association with total thrombotic events and venous thrombosis was in fact significant.