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Walid Fakhouri,1 Pedro Lopez-Romero,2 Silvia Antonelli,3 Serena Losi,4 Veronica Rogai,4 Stefano Buda,5 Diego Sangiorgi,5 Valentina Perrone,5 Luca Degli Esposti5 1Eli Lilly & Company, Erl Wood, UK; 2Eli Lilly & Company, Madrid, Spain; 3Eli Lilly Italy S.p.A., Roma, Italy; 4Eli Lilly Italy S.p.A., Sesto Fiorentino, Italy; 5CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, Italy Objectives: This study aimed to: 1) describe treatment patterns and drug utilization profile (in terms of therapeutic strategy used, switch, persistence and drug consumption variation) among adult patients affected by rheumatoid arthritis (RA), and 2) estimate the health care resource utilization and its associated direct cost for the management of RA patients. Methods: A retrospective cohort analysis, using administrative databases of six Local Health Units in Italy, was performed. All adult patients with a confirmed diagnosis of RA between January 1, 2010 and December 31, 2014 were enrolled. The date of the first RA diagnosis according to the study criteria during the study period represented the index date (ID) for each patient. Patients enrolled were observed from the ID for at least 12 months (follow-up period), and their clinical characteristics were investigated for 12 months prior to the ID.Results: A total of 10,401 patients with a confirmed RA diagnosis were included. Mean age was 63.0 years and 25% were male; 67% of patients were untreated at ID. During the follow-up period, 67.8% of patients treated with biologic agents were persistent with initial therapy, compared to 45.7% for patients on conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), while 11% of patients treated with biologic agents switched during the follow-up period, compared to 17.6% of csDMARDs-treated ones. At the end of the follow-up period, 14.7% of all patients in the analysis had an increase and 12.6% of them had a decrease in their initial drug consumption. The mean cost per RA patient was €3,743.Conclusion: Our study showed that there is still much that needs to be learned about the prescription of csDMARDs and biologics to RA patients in Italy and to identify areas for future research. The knowledge of RA management in a real-life clinical setting could offer an opportunity to improve the management of RA in Italy. Keywords: rheumatoid arthritis, treatment patterns, drug utilization, real-world data

Maurizio Benucci,1 Veronica Rogai,2 Fabiola Atzeni,3 Volker Hammen,4 Piercarlo Sarzti-Puttini,3 Alberto Migliore5 1Rheumatology Unit, S.Giovanni di Dio Hospital, Florence, Italy; 2Eli Lilly Italia SpA, Sesto Fiorentino, Italy; 3Rheumatology Unit, L Sacco Hospital, Milan, Italy; 4Lilly Deutschland GmbH, Bad Homburg, Germany; 5Villa San Pietro Fatebenefratelli Hospital, Rome, Italy Abstract: This literature review examines available evidence on the current and past costs associated with rheumatoid arthritis (RA) in Italy, together with the future health-economic prospects for the disease. Studies have been conducted to date on the prevalence, or the associated costs, of RA in Italy. Although future changes in the incidence of RA are a matter of debate, the impact of RA on health care costs is expected to grow in coming decades in line with projected increases in life expectancy and in the proportion of elderly people in Italy. It has been estimated that the indirect (productivity loss and informal care) and intangible (deterioration in health-related quality of life) costs of the disease will contribute to an increase in national health service expenditure, which will correspond to 1% of the total health care costs of the nation in the near future. The introduction of biological agents for the treatment of rheumatic diseases has resulted in an increase in the direct costs of RA; however, economic analyses that exclude indirect costs will underestimate the full economic impact of RA. The effectiveness of innovative therapies in preventing disease progression and functional impairment may, over time, attenuate the cost impact of RA in terms of hospitalizations and work absenteeism. Further research is needed to develop estimates of the economic impact of different therapeutic approaches in patients with RA in Italy, in order to provide tools that can drive the choice of the most cost-effective therapeutic option while maintaining high-quality care. Keywords: rheumatoid arthritis, prevalence, disease costs, Italy

Objectives: Interstitial lung disease (ILD) occurs in up to 30% of patients with rheumatoid arthritis (RA), resulting in increased morbidity and death in the absence of proven therapies. The aim of this study is to estimate the number of incident ILD cases reported through development studies with baricitinib in patients with RA., Methods: Estimates were based on 3770 patients with RA from eight randomized clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension study on baricitinib for which ILD was not an exclusion criterion with 12,358 patient-years of exposure (PYE)., Results: Twenty-one non-infectious cases of ILD were reported with an exposure-adjusted incidence rate (EAIR) of 0.17 per 100 PYE. Of the 21 cases, six were reported as serious and 15 as non-serious resulting in an incidence rate of 0.05 per 100 PYE and 0.12 per 100 PYE, respectively. There were also 11 cases caused by an infectious agent: seven serious (IR: 0.06 per 100 PYE) and four non-serious cases (IR: 0.03 per 100 PYE)., Conclusions: The findings of this analysis in patients with RA treated with baricitinib are consistent with a low risk to develop non-infectious ILD during baricitinib treatment, similar to that observed with other Janus kinase inhibitors., (© 2021. The Author(s).)

This study aimed to evaluate the treatment patterns and pharmacoutilization of patients with rheumatoid arthritis (RA) in real-world settings in Italy. This retrospective observational analysis was based on administrative databases of selected Italian entities. All adult patients with RA diagnosis confirmed by ≥1 discharge diagnosis of RA (ICD-9-CM code = 714.0) or an active exemption code (006.714.0) were enrolled in 2019. Two cohorts were created: one included patients prescribed baricitinib, the other those prescribed biological disease-modifying antirheumatic drugs (bDMARDs). Overall, 47,711 RA patients were identified, most of them without DMARD prescription. As a first-line prescription, 43.2% of patients were prescribed conventional synthetic DMARDs (csDMARDs), 5.2% bDMARDs and 0.3% baricitinib. In 2019, 82.6% of csDMARD users continued with the same DMARD category, 15.9% had a bDMARD, while 1.5% had baricitinib as second-line therapy. Overall, 445 patients used baricitinib during 2019. During follow-up, baricitinib was prescribed as monotherapy to 31% of patients, as cotreatment with csDMARDs and corticosteroids to 27% of patients, with corticosteroids to 28% of patients and with csDMARDs to 14% of patients. In line with previous findings, a trend of bDMARD undertreatment was observed. The treatment patterns of baricitinib patients could help to better characterize patients eligible for new therapeutic options that will be available in the future.

Introduction: In the last 20 years, biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) have become available for treating rheumatoid arthritis (RA), and a treat-to-target strategy has been introduced. We hypothesise that these advances should have resulted in changes to the characteristics of patients with RA participating in clinical trials of the newest therapies. This study determined whether the baseline characteristics of patients with RA enrolled in clinical trials have changed in the past decade versus patients participating in earlier RA studies., Methods: This secondary analysis was based on randomised controlled trials (RCTs) identified in a systematic literature review. Baseline characteristics of patients with RA with inadequate response to conventional synthetic DMARDs were compared between RCTs published in 1999-2009 and those published in 2010-2017 using random-effects meta-analyses., Results: Forty RCTs were analysed: 22 from 1999-2009 and 18 from 2010-2017. No significant difference between the two timeframes and no obvious trend over time were observed for age, gender, disease duration, rheumatoid factor status, tender and swollen joint counts, physician and patient global assessments of disease activity, and pain scores. Variability between RCTs was high. Similar results were observed for Disease Activity Scores and Health Assessment Questionnaire-Disability Index scores, but with low variability between RCTs., Conclusion: The baseline characteristics of patients with RA participating in RCTs do not appear to have changed in the last decade despite the availability of new treatments and a different treatment approach. Further research should determine the impact of baseline patient characteristics on patients' response to RA treatments.

Introduction: The objective of this study was to evaluate treatment patterns in patients with rheumatoid arthritis (RA), with a focus on the utilization of baricitinib, an oral highly selective Janus kinase 1 and 2 inhibitor, in an Italian real-world setting., Methods: This observational retrospective analysis was based on data collected in selected Italian administrative databases. Patients aged ≥ 18 years with a diagnosis of RA defined by hospitalization discharge diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 714.0) or by disease exemption code 006 for RA in 2018 were included. The index date (ID) was defined as the date of first prescription for a drug indicated for RA during the inclusion period. Patients without a prescription for biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) before the ID were considered to be b/tsDMARD naïve. A further analysis was performed on patients only receiving baricitinib., Results: A total of 41,290 RA patients were enrolled, of whom 55.6% were not treated with conventional synthetic DMARDs (csDMARDs) or b/tsDMARDs, 39.4% were receiving therapy with csDMARDs, and 5.0% were using b/tsDMARDs. In the latter group, 2.7% (n = 56) were receiving therapy with baricitinib. In 2018, 13.2% of csDMARD-treated patients switched to b/tsDMARDs, of whom 4.3% (n = 93) of these switched to baricitinib. In total, 149 patients (mean age ± standard deviation 57.6 ± 12.1; 12.8% male) had a baricitinib prescription, of whom 51% were b/tsDMARD naïve. At baseline, 61.7% of baricitinib users were receiving combination therapy with csDMARDs plus corticosteroids, 26.2% were receiving combination therapy with corticosteroids, and 8.1% were receiving combination therapy with csDMARDs; 4% were receiving baricitinib monotherapy. During follow-up, the proportion of patients receiving baricitinib monotherapy increased to 38.9%, while 26.9, 18.8, and 15.4% of baricitinib users received combination therapy with corticosteroids, csDMARDs plus corticosteroids, and csDMARDs, respectively., Conclusion: This study provides a current view of the treatment patterns in Italian patients with RA in a real-world setting of daily clinical practice, with a focus on baricitinib utilization.

Objective: Baricitinib is an orally administered inhibitor of JAK1 and JAK2 that has been shown to be effective in treating rheumatoid arthritis (RA). This study was undertaken to analyze changes in lymphocyte cell subsets during baricitinib treatment and to correlate these changes with clinical outcomes., Methods: An integrated analysis was conducted by pooling data from 3 completed phase III trials comparing placebo with baricitinib treatment (RA-BEAM, RA-BUILD, and RA-BEACON) and 1 ongoing long-term extension study (RA-BEYOND) in patients with active RA (n = 2,186)., Results: Baricitinib treatment was associated with an early transient increase in total lymphocyte count at week 4, which returned to baseline by week 12. Transient changes within normal reference ranges in T cells and subsets were observed with baricitinib treatment, up to week 104. B cells and relevant subpopulations increased after 4 weeks of baricitinib treatment, with no further increases noted through 104 weeks of treatment. Natural killer (NK) cells temporarily increased after 4 weeks of baricitinib treatment, before decreasing below baseline levels and then stabilizing over time. With baricitinib treatment, few correlations were observed between changes in lymphocyte subsets and clinical end points, and most correlations were also observed within the placebo group. A modest potential association between low NK cell numbers and treatment-emergent infections was observed in the baricitinib 4 mg/day treatment group, but not for serious infections or herpes zoster., Conclusion: Overall, these findings demonstrate that changes in lymphocyte subsets were largely within normal reference ranges across the baricitinib phase III RA clinical program and were not associated with increased risk of serious infections., (© 2018 Eli Lilly and Company. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Purpose of Review: Understanding prevalence of diseases within specific regions of a country is important for optimal allocation of healthcare resources/funds. We performed a systematic review to obtain a clearer picture of the epidemiology of psoriasis and psoriatic arthritis across and within specific regions of Italy., Recent Findings: Prevalence of psoriasis in specific regions showed more variability (0.8-4.5%) than that in the total population (1.8-3.1%). Prevalence of psoriatic arthritis in the general population was reported for only two regions, Chiavari (0.09%) and Marche (0.42%). All other studies reported prevalence of psoriatic arthritis in patients with psoriasis in single centres and Italy-wide (4.7-47.1%). Prevalence of psoriatic arthritis was highest in patients with nail and/or scalp psoriasis and/or intergluteal/perianal region involvement. Based on current available data, these conditions appear to affect a substantial number of people and will likely have an important impact on the Italian healthcare system.

Systemic sclerosis (SSc) is a complex systemic disease. It is characterised by fibrosis, of the skin and internal organs, as lungs, kidney, heart and gastrointestinal tract. As the aetiology of SSc is unknown, numerous animal models have been developed to better understand the pathogenesis of the disease and to test potentially useful therapeutic interventions. Although several animal models have been described, predominantly in mice, none reproduces precisely all manifestations of SSc. However, all animal models display tissue fibrotic changes similar to those present in SSc. This review is focused on the principal animal models and the molecular pathways involved. Animal models can be divided into two groups. In one group the pathologic phenotype is the result of a genetic mutation ( tight skin 1 and tight skin 2,UCD 200). In the second group, the pathologic alterations are induced in normal animals by manipulation of their immune system (sclerodermatous graft-vs-host disease (Scl GVHD) induced by transplantation, or by administration of exogenous substances). In the future, the development of additional animal models may become important in the further understanding of the alteration of the molecular pathways that regulate a physiologic processes to induce tissue fibrosis, the hallmark of this disease, and to identify and test targeted therapeutic agents.

Objective: Microvascular disorders are relevant in systemic sclerosis (SSc). Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of microcirculatory disorders. An impaired availability of nitric oxide, related to polymorphisms in NOS3, the gene for endothelial cell nitric oxide synthase, might influence erythrocyte deformability. We undertook this study to investigate the hemorheologic profile in SSc and the role of NOS3 polymorphisms in modulating the hemorheologic status of SSc patients., Methods: We studied 113 consecutive SSc patients (75 with limited cutaneous SSc [lcSSc] and 38 with diffuse cutaneous SSc [dcSSc]) and 113 healthy controls. The hemorheologic profile was obtained by assessing whole blood viscosity (WBV; at shear rates of 0.512 and 94.5 seconds(-1)), plasma viscosity (PLV; at a shear rate of 94.5 seconds(-1)), and erythrocyte deformability index (DI). We determined NOS3 polymorphisms by molecular analysis., Results: A marked alteration of hemorheologic parameters was found both in patients with lcSSc and in those with dcSSc compared with controls (P < 0.0001). In multivariate analysis, rheologic variables were significantly associated with the disease (for WBV at a shear rate of 94.5 seconds(-1), odds ratio [OR] 5.4, 95% confidence interval [95% CI] 1.4-19.9, P = 0.01; for PLV, OR 2.8, 95% CI 1.2-6.5, P = 0.01; for DI, OR 3.9, 95% CI 1.4-10.8, P = 0.007), and NOS3 -786C and 894T alleles significantly affected the DI (for -786C allele, OR 2.3, 95% CI 1.01-5.4, P = 0.04; for 894T allele, OR 2.2, 95% CI 1.01-4.8, P = 0.04). The simultaneous presence of the -786C and 894T alleles represented a susceptibility factor for SSc (OR 2.8, 95% CI 1.4-5.7, P = 0.004)., Conclusion: Our findings document an altered rheologic profile in SSc and demonstrate a relationship between this alteration and NOS3 polymorphisms, thus shedding light on a potential novel mechanism influencing the microcirculation in this disease.

Objective: SSc is characterized by immune dysfunction and microvascular involvement. A different genetic background may determine a different polymorphic allele frequency between different populations, and data from literature reported conflicting results about the role of genetic components in predisposing to the disease. We carried out this study in order to compare the ACE I/D polymorphism genotype distribution and alleles frequency in two different populations from the Mediterranean area., Methods: Forty-eight Italian and 41 Greek SSc patients compared with 112 Italian and 93 Greek controls, have been studied. The ACE I/D polymorphism has been analysed., Results: The genotype distribution and allele frequency were in Hardy-Weinberg equilibrium for Italian and Greek SSc patients and controls. Among the Italian patients a significantly higher ACE D allele frequency than in the controls was found, whereas among the Greeks a higher prevalence was observed in the healthy subjects. A significant difference in ACE D allele frequency between Italian and Greek controls was observed (p = 0.04). ACE D allele was associated to the predisposition to SSc in Italians, but not in Greeks., Conclusion: We confirm that Italian SSc patients have a higher ACE D allele frequency that is not present in the Greek patients. Thus, the two populations living in different Mediterranean areas and resulting from the Mediterranean civilization, do not show the same ACE-gene related allele frequencies. Other populations of the Mediterranean area must be investigated by using unlinked genetic markers to verify the homogeneity of the genetic background, and to test for a "true" difference in their ethnic origin.

The main pathologic hallmark of systemic sclerosis (SSc) is endothelial derangement; the pathologic alterations of the vessel wall in SSc are strikingly similar to the modification detected in the atherosclerotic lesions, and it is now evident that SSc is also characterized by accelerated macrovascular disease. Peptides related to angiotensin II, the final product of the renin-angiotensin system (RAS), play a role as regulators of endothelial cell function. Angiotensin-converting enzyme (ACE), the key enzyme in the RAS, is the predominant pathway of angiotensin II formation in blood and tissues. In intron 16 of the gene encoding for ACE an insertion/deletion (I/D) polymorphism, consisting of the presence or absence of a 287-base pair Alu sequence, has been identified. This polymorphism has been related to ACE enzyme levels, and data from experimental studies reported a functional role for this polymorphism in modulating the angiotensin II levels. We previously documented a high ACE D allele frequency in SSc patients and its role in increasing the risk of SSc, thus suggesting that the I/D polymorphism might be a useful genetic marker to identify SSc patients at risk to develop a severe vascular disease, frequently leading to gangrene. Moreover, our preliminary data, besides supporting the role of ACE I/D polymorphism as a predisposing factor to SSc, demonstrated its involvement in accelerated macrovascular disease by increasing the intima media thickness. Therefore, in SSc, not only endothelial dysfunction, but also vascular damage, linked to ACE I/D polymorphism, may significantly contribute to accelerated macrovascular disease, as the ACE D allele, by regulating both the production of angiotensin II and the degradation of bradykinin, contributes to mechanisms involved in the induction and maintenance of vessel wall modification.